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The nucleus raphe magnus (RMg) is a key structure of the endogenous antinociceptive system, the activity of which is regulated by serotonin 5-HT1A receptors. A recipient of the RMg descending projections is the caudal ventrolateral medulla (cVLM)—the first supraspinal center for processing visceral and somatic pain signals. Intestinal pathology is known to cause persistent functional alterations in the RMg, which are associated with the development of visceral and somatic hyperalgesia. Presumably, a consequence of the alterations may be changes in the RMg modulating effects on cVLM nociceptive activity. However, the specific neuronal and molecular mechanisms underlying such influence in normal conditions, as well as their changes in pathology remain unexplored. The aim of our neurophysiological experiments performed in anesthetized adult male Wistar rats was to compare the effects of RMg electrical stimulation on the activity of cVLM neurons evoked by visceral (colorectal distension, CRD) and somatic (tail squeezing) pain stimulations that occur in normal conditions and after intestinal inflammation (colitis), with an assessment of the contribution to these processes of the supraspinal 5-HT1A receptor activation with intracerebroventricular buspirone. It has been shown that RMg can exert an inhibitory effect on both non-selective and differential responses of the cVLM neurons to diverse pain stimuli, causing a weakening of excitatory neuronal reactions and an increase in inhibitory responses to CRD while inhibiting both types of reactions to tail squeezing. The RMg-evoked suppression of nociceptive excitation in the caudal medullary neurons is enhanced under activation of supraspinal 5-HT1A receptors by buspirone. It has been established that in postcolitis period the RMg inhibitory action on different populations of cVLM neurons are significantly diminished, indicating an impairment of the nucleus' antinociceptive function. In these conditions, the RMg descending influence loses its 5-HT1A receptor-dependent component. The changes described may contribute to the supraspinal mechanisms underlying pathogenesis of post-inflammatory abdominal pain and comorbid somatic hyperalgesia. [ABSTRACT FROM AUTHOR]

Objectives: NLX-101 and NLX-204 are highly selective serotonin 5-HT1A 'biased' agonists, displaying potent and efficacious antidepressant-like activity upon acute administration in models such as the forced swim test. Methods: we compared the effects of repeated administration of NLX-101, NLX-204 and ketamine in the chronic mild stress (CMS) model of depression, considered to have high translational potential, on sucrose consumption (anhedonia measure), novel object recognition (NOR; working memory measure) and elevated plus maze (EPM; anxiety measure) in male Wistar and Wistar-Kyoto rats (the latter being resistant to classical antidepressants). Results: in Wistar rats, NLX-204 and NLX-101 (0.08–0.16 mg/kg i.p.), like ketamine (10 mg/kg i.p.) dose-dependently reversed CMS-induced sucrose intake deficit from treatment Day 1, with nearly full reversal observed at the higher dose at Days 8 and 15. These effects persisted for 3 weeks following treatment cessation. In the NOR test, both doses of NLX-101/NLX-204, and ketamine, rescued the deficit in discrimination index caused by CMS on Days 3 and 17; all three compounds increased time spent in open arms (EPM) but only NLX-204 achieved statistical significance on Days 2 and 16. In Wistar-Kyoto rats, all 3 compounds were also active in the sucrose test and, to a lesser extent, in the NOR and EPM. In non-stressed rats (both strains), the three compounds produced no significant effects in all tests. Conclusions: these observations further strengthen the hypothesis that biased agonism at 5-HT1A receptors constitutes a promising strategy to achieve rapid-acting/sustained antidepressant effects combined with activity against TRD, in addition to providing beneficial effects against memory deficit and anxiety in depressed patients. [ABSTRACT FROM AUTHOR]

Purpose: F13640 (a.k.a. befiradol, NLX-112) is a highly selective 5-HT1A receptor ligand that was selected as a PET radiopharmaceutical-candidate based on animal studies. Due to its high efficacy agonist properties, [18F]F13640 binds preferentially to functional 5-HT1A receptors, which are coupled to intracellular G-proteins. Here, we characterize brain labeling of 5-HT1A receptors by [18F]F13640 in humans and describe a simplified model for its quantification. Methods: PET/CT and PET-MRI scans were conducted in a total of 13 healthy male volunteers (29 ± 9 years old), with arterial input functions (AIF) (n = 9) and test–retest protocol (n = 8). Several kinetic models were compared (one tissue compartment model, two-tissue compartment model, and Logan); two models with reference region were also evaluated: simplified reference tissue model (SRTM) and the logan reference model (LREF). Results: [18F]F13640 showed high uptake values in raphe nuclei and cortical regions. SRTM and LREF models showed a very high correlation with kinetic models using AIF. As concerns test–retest parameters and the prolonged binding kinetics of [18F]F13640, better reproducibility, and reliability were found with the LREF method. Cerebellum white matter and frontal lobe white matter stand out as suitable reference regions. Conclusion: The favorable brain labeling and kinetic profile of [18F]F13640, its high receptor specificity and its high efficacy agonist properties open new perspectives for studying functionally active 5-HT1A receptors, unlike previous radiopharmaceuticals that act as antagonists. [18F]F13640's kinetic properties allow injection outside of the PET scanner with delayed acquisitions, facilitating the design of innovative longitudinal protocols in neurology and psychiatry. Trial Registration.: Trial Registration EudraCT 2017–002,722-21. [ABSTRACT FROM AUTHOR]

The effect of 5-HT1A receptor agonist 8-OH-DPAT (intraperitoneal injection in doses of 1, 2, and 4 mg/kg) on spontaneous alternation behavior of mice in Y-maze was studied without and with habituation procedure and food reward. In the first case, 8-OH-DPAT administration led to a decrease in spontaneous alternation and locomotor activity in mice. At the same time, 8-OH-DPAT treatment after habituation and food deprivation increased repeated choices of goal arms without affecting locomotor activity, which was consistent with perseverative behavior. 8-OH-DPAT-induced decrease in spontaneous alternation behavior in Y-maze in mice with habituation and food reward is the most suitable procedure for experimental modeling of the perseverative behavior and studying the anticompulsive activity of new substances. [ABSTRACT FROM AUTHOR]

Recombinant mouse strain B6.CBA-D13Mit76C (B6-M76C) and B6.CBA-D13Mit76B (B6-M76B), with 5-HT1A receptors with different sensitivities to chronic activation by agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetraline), were created recently. The 5-HT1A receptor is the key regulator in the brain serotonin (5-HT) system and is involved in controlling responses to stress. The studies reported here show that acute emotional stress (restraint for 40 min) increased the expression of the c-fos gene, a marker for stress responses, in the brains of mice of both strains. The stress-induced increase in c-fos expression in the striatum, hypothalamus, and cortex of B6-M76C mice was more marked. Reactions to emotional stress led to increases in the ratio of the serotonin metabolite 5-HIAA (5-hydroxyindoleacetic acid) to 5-HT in the midbrain and hippocampus in both strains. Post-stress increases in the 5-HIAA/5-HT ratio were seen in the hypothalamus of B6-M76C mice and the cortex of B6-M76B mice. The reaction to stress led to decreases in the noradrenaline level in the hippocampus and hypothalamus of B6-M76C mice. The dopamine, noradrenaline, and adrenaline levels and the dopamine/noradrenaline ratio in the adrenals increased in response to stress only in B6-M76C mice. The present study showed that the sympathodrenal system in B6-M76C mice is more sensitive to acute stress. The stress reaction in B6-M76C mice led to increases in noradrenaline and adrenaline contents in adrenal tissue. The increased dopamine/noradrenaline ratio in the adrenals may be evidence of a faster conversion of the intermediate product of catecholamine biosynthesis (dopamine) into noradrenaline and then to adrenaline as a result of acceleration of the biosynthesis process in response to stress in B6-M76C mice. Furthermore, all measures of hypothalamic neuron sensitivity to stress in B6-M76C mice were elevated. Thus, B6-M76C mice are of significant interest for studies of the hypothalamo-hypophyseal-adrenal system with a hyperactive response to stress and may help identify novel biomarkers for stress-related diseases. [ABSTRACT FROM AUTHOR]

Abstract—Recently, it has become apparent that the interaction between the serotonin (5-HT) system and the brain-derived neurotrophic factor (BDNF) system plays an important role in the regulation of behavior, and in various physiological and neuroplasticity processes. Moreover, there is data indicating the involvement of the 5-HT1A receptor, a key regulator of the central serotonergic system, in the control of the BDNF system. Recently, we have created new recombinant mouse strains, B6.CBA-D13Mit76C (B6-M76C) and B6.CBA-D13Mit76B (B6-M76B) in which 5-HT1A receptors have different sensitivity to chronic activation. In this paper, using these mice, we studied acute stress-induced changes in the levels of BDNF protein and its precursor proBDNF. It was shown that B6-M76C mice with reduced sensitivity of presynaptic 5-HT1A receptors differ from B6-M76B mice; B6-M76C mice have a lower level of proBDNF in the midbrain and hippocampus and an increased BDNF/proBDNF ratio in the hippocampus. Acute stress caused a decrease in the level of proBDNF in the midbrain of mice of the control B6-M76B line leading to a significant increase in the BDNF/proBDNF ratio, which reflects the intensity of "maturation" of BDNF. Thus, it was discovered that changes in the sensitivity of the key regulator of the central serotonergic system, 5-HT1A receptor, lead to significant changes in the response of the BDNF system to acute stress. It was also revealed that the function of the 5-HT1A receptor is associated with the pattern of basal expression of elements of the BDNF system, namely, the expression of the proBDNF precursor protein. In addition, the data suggest that the changes in the functional activity of the BDNF system caused by acute stress are associated primarily with neuroplasticity mechanisms that determine the emotional and behavioral response to emotional stress. [ABSTRACT FROM AUTHOR]

The serotonergic 5-HT1A receptor is known to be involved in both impulsivity and anxiety-related behavior. Although anxiety and impulsivity are different constructs, it has been shown that anxiogenesis can result in impulsiveness. It is therefore important to determine if the 5-HT1A receptor is involved in the commission of impulsive actions independent of its effects on anxiety. The 5-HT1A agonist 8-OH-DPAT (0.0125–0.1 mg/kg subcutaneous) increased impulsive action at low doses, but decreased it at higher doses, on the novel paced variable consecutive number with discriminative stimulus task (VCN). Neither the 5-HT1A antagonist WAY 100,635 (0.2–1.2 mg/kg subcutaneous), nor the noradrenergic antagonist and pharmacological stressor yohimbine (1–2 mg/kg intraperitoneal) altered measures of impulsivity. Stress induced by yohimbine was sufficient to produce anxiety-like behavior in the elevated zero maze, confirming that the VCN task is a selective assay of impulsive action that is not affected by anxiety. We hypothesize that the biphasic effect of 8-OH-DPAT is due to actions on presynaptic raphe 5-HT1A autoreceptors, and also postsynaptic 5-HT1A receptors. These results suggest that this receptor mediates impulsive action and that this is not secondary to its role in anxiety. [ABSTRACT FROM AUTHOR]

5-MeO-DMT is a tryptamine being developed as a potential antidepressant that may display a distinct therapeutic mechanism due to its unique pharmacology and subjective effects compared to typical psychedelics. In this article, we parallel the relatively distinct phenomenology and behavioral effects of the acute and post-acute effects of 5-MeO-DMT to those induced by epileptiform activity, particularly in instances within epileptogenic zones of the temporal lobes. This is done by reviewing aberrant 5-HT1A receptor functioning in epilepsy, noting that 5-MeO-DMT has notable 5-HT1A receptor agonist properties—and then comparing the acute behavioral and subjective effects induced by 5-MeO-DMT to those that occur in seizures. It might be that 5-MeO-DMT's therapeutic mechanism is partly mediated by evoking temporary epileptiform activity, suggesting a similarity to electroconvulsive therapy. It is also noted that “reactivations,” the sudden re-experiencing of drug effects common after 5-MeO-DMT but not after typical psychedelics, may suggest that 5-MeO-DMT produces recurrent epileptiform activity. Overall, this review indicates that further evaluation of 5-MeO-DMT's unique mechanisms in research settings and among naturalistic users are warranted. [ABSTRACT FROM AUTHOR]

Peak-dose dyskinesia is associated with the dramatic increase in striatal dopamine levels that follows l-DOPA administration. The ‘false neurotransmitter’ hypothesis postulates that the latter is likely due to an aberrant processing of l-DOPA by serotonergic neurons. In keeping with this hypothesis, two highly selective ‘biased agonists’ of 5-HT1A receptors—namely F13714 and F15599 (NLX-101)—were recently shown to exhibit exceptionally potent anti-dyskinetic activity without impairing l-DOPA therapeutic properties despite their differential targeting of 5-HT1A receptor sub-populations. In this study, we investigated whether these two compounds dampened peak l-DOPA-induced dopamine microdialysate levels in the striatum of hemi-parkinsonian rats. Acute administration of either F13714 (0.04 and 0.16 mg/kg i.p.) or F15599 (0.16 and 0.64 mg/kg, i.p.) blunted l-DOPA (2 mg/kg)-induced increases in dopamine microdialysate levels in the denervated striatum (following unilateral injection of 6-OHDA into the medial forebrain bundle). No significant changes were observed on the intact side of the brain. Concurrently, both drugs profoundly reduced striatal serotonin levels on both sides of the brain. In addition, F13714 and F15599, in the presence of l-DOPA, produced a dose-dependent increase in glutamate levels, but this effect was restricted to later time points. These finding support the interpretation that F13714 and F15599 mediate their anti-dyskinetic effects by blunting of the peak in dopamine levels via activation of somatodendritic serotonin 5-HT1A receptors and the consequent inhibition of serotonergic neurons. This study adds to the growing body of evidence supporting the development of a potent 5-HT1A receptor agonist for treatment of peak-dose dyskinesia. [ABSTRACT FROM AUTHOR]

The effects of chronic 5-HT1A receptor activation on the behavior, functional activity of 5-HT1A receptors, and expression of key genes of the brain 5-HT system were studied in mice of the catalepsy-prone CBA strain and the catalepsy-resistant C57BL/6 strain. Chronic treatment with 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (1.0 mg/kg i.p., 14 days) led to a significant decrease in the hypothermic response to acute administration of 8-OH-DPAT in CBA and C57BL/6 mice, which indicates the desensitization of 5-HT1A receptors in both strains. Pretreatment with the 5-HT7 receptor agonist SB 269970 did not affect the hypothermic response to the acute administration of 8-OH-DPAT, which suggests an independent functional response of 5-HT1A receptors. The treatment did not induce any changes in the behavior in the open field paradigm in CBA mice, but significantly increased the total path, the time spent in the center, and the number of rearings in C57BL/6 mice, which indicates the enhancement of locomotor and exploratory activity in C57BL/6 mice. The chronic activation of 5-HT1A receptor downregulated 5-HT1A gene expression, as well as the expression of the gene that encodes tryptophan hydroxylase 2, a key enzyme of 5-HT biosynthesis, in the midbrain and the expression of the gene that encodes the 5-HT2A receptor in the frontal cortex of CBA, but not C57BL/6 mice. The obtained data provide a new evidence on the receptor-gene cross talk in the brain 5-HT system that may underlie the loss of pharmacological efficacy of 5-HT1A receptor agonists. In turn, the loss of the behavioral response and compensatory alterations in key genes of the brain 5- HT system in CBA mice suggests that catalepsy-prone and -resistant genotypes demonstrate different sensibility to the effects of drugs. [ABSTRACT FROM AUTHOR]

The neurotransmitter mechanisms underlying the individual/group characteristics of behavior in animals were studied by comparing the effects of modulation of serotoninergic transmission in the amygdala in rats with different manifestations of conditioned reflex fear (high- and low-freezing rats). Administration of a 5-HT1A receptor agonist (8-OH-DPAT, 0.3 μg/0.5 μl) into the basolateral amygdala before testing of a previously acquired classical defensive reflex decreased freezing time in response to sound in low-freezing animals and weakened the signs of conditioned reflex fear in response to the signal. Administration of the receptor antagonist (WAY-100635, 0.2 μg/0.5 μl) decreased freezing time during exploration of context and in response to sound in all rats, which probably occurred as a result of increases in motor activity and the occurrence of a panic-like state. Administration of both the agonist and antagonist before extinction sessions accelerated extinction of the reflex in high-freezing rats, though the mechanisms of the effects of different ligands were different. Administration of receptor antagonist before retraining prevented acquisition of conditioned reflex freezing in all rats. 5-HT1A receptors in the amygdala play a major role not only in the manifestations and repeat acquisition, but also the extinction of conditioned reflex fear. High-freezing rats, as compared with low-freezing animals, were more sensitive to administration of 5-HT1 receptor ligands into the amygdala in relation to extinction and repeat acquisition. [ABSTRACT FROM AUTHOR]

Galanin N-terminal fragment (1-15) [GAL(1-15)] is associated with depression-related and anxiogenic-like effects in rats. In this study, we analyzed the ability of GAL(1-15) to modulate 5-HT1A receptors (5-HT1AR), a key receptor in depression. GAL(1-15) enhanced the antidepressant effects induced by the 5-HT1AR agonist 8-OH-DPAT in the forced swimming test. These effects were stronger than the ones induced by Galanin (GAL). This action involved interactions at receptor level since GAL(1-15) affected the binding characteristics and the mRNA levels of 5-HT1AR in the dorsal hippocampus and dorsal raphe. The involvement of the GALR2 was demonstrated with the GALR2 antagonist M871. Proximity ligation assay experiments indicated that 5-HT1AR are in close proximity with GALR1 and GALR2 in both regions and in raphe RN33B cells. The current results indicate that GAL(1-15) enhances the antidepressant effects induced by 8-OH-DPAT acting on 5-HT1AR operating as postjunctional or as autoreceptors. These results may give the basis for the development of drugs targeting potential GALR1-GALR2-5-HT1AR heteroreceptor complexes linked to the raphe-hippocampal 5-HT neurons for the treatment of depression. [ABSTRACT FROM AUTHOR]

Background: The 5-HT 1A receptor subtype has been postulated to modulate aggressive behavior particularly when it is excessive. F15599 is a high affinity and selective 5-HT 1A receptor agonist that exhibits biased agonism for postsynaptic receptors that are preferentially coupled to Gαi3 protein subunits, with more potent action in the cortex, and with potential for selectively reducing aggression. Objectives and methods: The aims of the current study were to investigate the anti-aggressive effects of the novel 5-HT 1A receptor agonist, F15599, microinjected into the ventral orbital prefrontal cortex (VO PFC) and into the infralimbic cortex (ILC) of CF-1 male mice that had been previously socially provoked and to confirm the specific action at this receptor by blocking its effects using the 5-HT 1A receptor antagonist, WAY100,635. Results: Microinjection of the lower doses of F15599 (0.03 and 0.1 μg) into the VO PFC, but not into the ILC, significantly reduced the frequency of attack bites and sideways threats, without affecting other elements of the behavioral repertoire related to aggression such as pursuing and sniffing the intruder and tail rattle. There were also no changes observed in the duration of walking and rearing. Pretreatment with WAY100,635 prevented the anti-aggressive effects of F15599 when microinjected into VO PFC. Conclusions: The present results demonstrated that F15599 is effective in reducing the most intense behavioral elements of aggressive behavior in male mice, when microinjected into the VO PFC, but not into the ILC, without affecting nonaggressive behavior, and confirmed the critical role of this cortical region and specifically the 5-HT 1A heteroreceptors in the modulation of escalated aggressive behavior. [ABSTRACT FROM AUTHOR]

Rationale: Cannabidiol (CBD) is a non-psychotomimetic constituent of Cannabis sativa plant that promotes antianxiety and anti-panic effects in animal models after acute systemic or intra-dorsal periaqueductal gray (DPAG) administration. However, the effects of CBD repeated administration, and the possible mechanisms involved, in animal models of anxiety- and panic-related responses remain poorly understood. Objective: The present study evaluates the role of the serotonergic neurotransmission within the DPAG in the modulation of escape responses of rats chronically treated with CBD. Methods: Male Wistar rats received acute or repeated (5 mg/Kg/daily/21 days) administration of CBD and were submitted to the elevated T-maze (ETM). We also investigated if CBD effects on the ETM depend on facilitation of 5-HT1A-mediated neurotransmission in the DPAG. To this latter aim, we verified if these effects would be prevented by intra-DPAG injection of the 5-HT1A receptor antagonist WAY100635 (0.37 nmol/0.2 μL). Also, we verified, by in vivo microdialysis, if CBD chronic treatment increases serotonin (5-HT) release and, by quantitative polymerase chain reaction, if there are changes in 5HT-1A or 5HT-2C mRNA expression in DPAG. Results: The results showed that repeated but not acute peripheral administration of CBD decreases escape responses in the ETM, suggesting a panicolytic effect. This treatment did not change 5HT-1A or 5-HT-2C receptor mRNA expression nor modify serotonin extracellular concentrations in the DPAG. CBD effects were prevented by DPAG injection of the 5-HT1A receptor antagonist. Conclusions: Together, these findings suggest that repeated treatment with CBD induces anti-panic effects by acting on 5-HT1A receptors in DPAG. [ABSTRACT FROM AUTHOR]

Background: Serotonin (5-HT) has a role in respiratory function and dysfunction. Although 5-HT affects respiratory drive to both phrenic and cranial motoneurons, relatively little is known about the role of 5-HT receptor subtypes in the control of upper airway muscle (UAM) respiratory activity. Materials and methods: Here, we performed central injections of 5-HT1A agonist (8-OHDPAT) or antagonist (WAY100635) in anesthetized rats and analyzed changes in the electromyographic activity of several UAM and other cardiorespiratory parameters. We also compared the pattern of Fos expression induced after central injection of a control solution or 8-OHDPAT. Results: Results showed that 8-OHDPAT induced a robust increase in UAM activity, associated with either tachypnea under volatile anesthesia or bradypnea under liquid anesthesia. Injection of WAY100635 switched off UAM respiratory activity and led to bradypnea, suggesting a tonic excitatory role of endogenous 5-HT1A receptor activation. Co-injection of the agonist and the antagonist blocked the effects produced by each drug alone. Besides drug-induced changes in respiratory frequency, only slight increases in surface of diaphragm bursts were observed. Significant increases in Fos expression after 5-HT1A receptor activation were seen in the nucleus tractus solitarius, nucleus raphe pallidus, parapyramidal region, retrotrapezoid nucleus, lateral parabrachial, and Kölliker-Fuse nuclei. This restricted pattern of Fos expression likely identified the neural substrate responsible for the enhancement of UAM respiratory activity observed after 8-OHDPAT injection. Conclusions: These findings suggest an important role for the 5-HT1A receptors in the neural control of upper airway patency and may be relevant to counteract pharyngeal atonia during obstructive sleep apneas. [ABSTRACT FROM AUTHOR]

ASC (Antidepressant-Sensitive Catalepsy) mice, bred for a high predisposition to catalepsy, are characterized by depression-like behavior and decreased immune responses. Chronic administration of fluoxetine, which is a selective serotonin reuptake inhibitor antidepressant widely used in clinical practice, to mice of this strain weakened catalepsy and normalized the number of rosette-forming cells in the spleen. In mice of the parental cataleptic strain CBA/Lac, fluoxetine had no effect on the level of catalepsy or the immune response. Analysis of the effects of fluoxetine on the functional activity of 5-HT1A and 5-HT2A receptors, and the expression of 5-HT1A receptor genes in the frontal cortex and midbrain and 5-HT2A receptors in the frontal cortex, as well as the tryptophan hydroxylase-2 and the serotonin transporter genes in the midbrain showed that the antidepressant had no effect on these parameters in ASC mice, but decreased the functional activity of 5-HT2A receptors in CBA/Lac mice. The possibility that the actions of fluoxetine on catalepsy and the immune response in mice with depression-like states are mediated via other serotoninergic mechanisms is discussed. [ABSTRACT FROM AUTHOR]

Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder caused by the hemizygous deletion of 28 genes on chromosome 7, including the general transcription factor GTF2IRD1. Mice either hemizygously ( Gtf2ird1 +/−) or homozygously ( Gtf2ird1 −/−) deleted for this transcription factor exhibit low innate anxiety, low aggression and increased social interaction, a phenotype that shares similarities to the high sociability and disinhibition seen in individuals with WBS. Here, we investigated the inhibitory effects of serotonin (5-HT) on the major output neurons of the prefrontal cortex in Gtf2ird1 −/− mice and their wildtype (WT) siblings. Prefrontal 5-HT receptors are known to modulate anxiety-like behaviors, and the Gtf2ird1 −/− mice have altered 5-HT metabolism in prefrontal cortex. Using whole cell recording from layer V neurons in acute brain slices of prefrontal cortex, we found that 5-HT elicited significantly larger inhibitory, outward currents in Gtf2ird1 −/− mice than in WT controls. In both genotypes, these currents were resistant to action potential blockade with TTX and were suppressed by the selective 5-HT1A receptor antagonist WAY-100635, suggesting that they are mediated directly by 5-HT1A receptors on the recorded neurons. Control experiments suggest a degree of layer and receptor specificity in this enhancement since 5-HT1A receptor-mediated responses in layer II/III pyramidal neurons were unchanged as were responses mediated by two other inhibitory receptors in layer V pyramidal neurons. Furthermore, we demonstrate GTF2IRD1 protein expression by neurons in layer V of the prefrontal cortex. Our finding that 5-HT1A-mediated responses are selectively enhanced in layer V pyramidal neurons of Gtf2ird1 −/− mice gives insight into the cellular mechanisms that underlie reduced innate anxiety and increased sociability in these mice, and may be relevant to the low social anxiety and disinhibition in patients with WBS and their sensitivity to serotonergic medicines. [ABSTRACT FROM AUTHOR]

Background and the purpose of the study: The available literatures show that 5-HT1A receptors are widely distributed throughout the basal ganglia, and their activation facilitate dopamine release. Neuroleptic drugs such as haloperidol induce Parkinson-like syndrome through blocking brain D2 receptors. This study aimed to investigate effect of buspirone, a partial agonist of 5HT1A receptor, on motor dysfunctions induced by haloperidol and involvement of 5HT1A receptors in this regard. Methods: Study was performed on the male mice weighing 25-30 g. Animals were divided randomly to groups of 10 animals. Motor dysfunction was induced by intraperitoneal (i.p.) injection of haloperidol (1 mg/kg). Catalepsy was assayed by bar-test method 5, 60, 120 and 180 minutes after drug administration and motor imbalance was studied by rotarod test. Results and major conclusion: Results showed that buspirone (20 mg/kg, i.p.) decreased significantly haloperidol-induced catalepsy and balance disorder in a dose dependent manner. Furthermore, 8-OH-DPAT (10 mg/kg, i.p.), as an agonist of 5-HT1A receptor, decreased haloperidol-induced catalepsy and balance disorder. The effect of buspirone (20 mg/kg, i.p.) on haloperidol-induced motor disorders was abolished by NAN-190 (10 mg/kg, i.p.), as a 5-HT1A receptor antagonist. From the results it may be concluded that buspirone improves haloperidol-induced catalepsy and balance disorder through activation of 5-HT1A receptors. [ABSTRACT FROM AUTHOR]

Activation of kappa opioid receptors (kappa-OR) with the selective agonist rimorphin (0.1 mg/kg) produced marked suppression of the immune response in CBA mice. This effect was not seen on administration of rimorphin on the background of a reduction in the activity of the serotoninergic (5-HTergic) system resulting from stimulation of presynaptic (8-OH-DPAT, 0.1 mg/kg) or blockade of postsynaptic (WAY-100635, 1.0 mg/kg) 5-HT1A receptors. These data led to the conclusion that 5-HTergic mechanisms involving preand postsynaptic 5-HT1A receptors have a role in kappa-opioid-mediated immunosuppression. [ABSTRACT FROM AUTHOR]

Non-competitive NMDA receptor antagonists markedly increase neuronal activity in medial prefrontal cortex (mPFC), an effect which partly underlies their schizomimetic actions. Projection pyramidal neurons and local GABAergic interneurons in mPFC express 5-HT1A receptors, whose activation modulates dopaminergic (DA) and serotonergic (5-HT) activity in midbrain and the cortical release of both monoamines. To examine whether the presence of 5-HT1A receptors can modulate the effect of NMDA receptor blockade with MK-801 (dizocilpine) on DA and 5-HT release in mouse mPFC. Brain microdialysis and locomotor activity measures in wild-type and 5-HT1A receptor knockout mice. Systemic MK-801 administration (0.125, 0.25, 0.50, and 1 mg/kg i.p.) induced a dose-dependent increase in mPFC 5-HT output, which was independent of the genotype. MK-801 increased DA output in a dose-dependent manner with a significant effect of genotype on low doses (0.125, 0.25 mg/kg). These differences were not paralleled by differences in gross locomotor activity. Overall, MK-801 increased more markedly DA than 5-HT output in both genotypes. Finally, the local perfusion of MK-801 in mPFC (30, 100, 300 μM) by reverse dialysis did not elevate dialysate DA or 5-HT concentrations in mPFC. 5-HT1A receptors partly modulate the increase in mPFC DA (but not 5-HT) release produced by NMDA receptor blockade. The lack of effect observed after the local MK-801 application suggests that the change in cortical monoamines is mainly driven by subcortical NMDA receptor blockade, without a significant involvement of PFC 5-HT1A receptors. [ABSTRACT FROM AUTHOR]

Lipid rafts regulate functions of various G protein-coupled receptors and signaling proteins. We show that human primary neuronal cultures contain high levels of 5-HT1A receptors. Stimulation with the 5-HT1A/7 receptor agonist, 8-OH-DPAT, reduced P-T185/Y187-ERK2. This reduction could be blocked by the 5-HT1A receptor antagonist, WAY100635. Pretreatment with the cholesterol sequestering agent, methyl-β-cyclodextrin, before adding 8-OH-DPAT, significantly counteracted the inhibitory influence of 8-OH-DPAT on P-T185/Y187-ERK2 and P-S133-CREB. These data indicate that reduction of cholesterol levels significantly influence signaling via 5-HT1A receptors in intact neurons. [ABSTRACT FROM AUTHOR]

Gz, a member of the Gi G protein family, is involved in the coupling of dopaminergic and serotonergic receptors. In the present study, we investigated behaviour of mice deficient in the α subunit of Gz and focused on pre-pulse inhibition (PPI) and anxiety-like responses and the role of serotonin-1A (5-HT1A) receptors. We compared male and female wild-type and knock-out mice on either a C57Bl/6 or Balb/c background. We used automated startle boxes to assess startle and PPI and elevated plus maze to assess anxiety-like behaviours. Balb/c mice showed higher baseline PPI than C57Bl/6 mice, and there was no difference between the genotypes. The 5-HT1A receptor agonist, 8-hydroxy-di-propylaminotetralin (8-OH-DPAT), had no effect on PPI in C57Bl/6 mice but markedly increased PPI in Balb/c mice, with the effect being attenuated in Gαz knock-outs. On the elevated plus maze, there was little effect of the knock-out or 8-OH-DPAT in C57Bl/6 mice, whereas in Balb/c mice, Gαz knock-outs showed a phenotype of high levels of anxiety-like behaviour. 8-OH-DPAT was anxiogenic in Balb/c mice, but this effect was attenuated in Gαz knock-outs. 5-HT1A receptors couple to Gz. In a strictly background strain-dependent manner, Gαz knock-out mice display high levels of anxiety-like behaviour and are less sensitive to the action of 8-OH-DPAT. Balb/c mice show much more clear effects of the Gαz knock-out than C57Bl/6 mice, which are often considered the standard background strain for genetic modifications. Therefore, our results suggest caution when studying the behavioural effects of genetic modifications only in C57Bl/6 mice. [ABSTRACT FROM AUTHOR]

The gastrin precursor peptide, progastrin (PG), is secreted from enteroendocrine cells in the intestine and increased in patients with hypergastrinemia and colorectal cancers. In recent years, we and others have demonstrated an important role of PG peptides in colorectal carcinogenesis, and were surprised to note significant changes in the behaviors of transgenic mice overexpressing PGs. In the present studies, we examined emotional behaviors of transgenic mice overexpressing PG in the intestinal and peripheral circulation. Aggression, locomotor activity and anxiety-like behaviors of the homozygous transgenic (Tg/Tg) mice and the wild-type (WT) littermates were examined by intruder/resident test, open field and elevated plus maze, respectively. A significant increase in the aggression, locomotor activity, and anxiety-like behaviors was detected in the Tg/Tg vs WT mice. As CCK, CCK2 receptors (CCK2R), and 5-HT1A receptors (5-HT1AR) in the CNS play an important role in these behaviors, possible changes in the expression of CCK and CCK2R and the density of CCK2R and 5-HT1AR were determined by either real-time RT-PCR or autoradiography of ligand binding assays. The results suggest that the expressions of CCK and CCK2R were increased in the hypothalamus, and the density of CCK2R were increased in the hypothalamus and amygdala of Tg/Tg vs WT mice. Similarly, the density of 5-HT1AR was increased in the hypothalamus. Our results suggest that an upregulation of the CCK response system and 5-HT1AR in the hypothalamus of Tg/Tg mice may mediate the alterations in the observed behaviors of these mice.Neuropsychopharmacology (2007) 32, 1813–1821; doi:10.1038/sj.npp.1301304; published online 17 January 2007 [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the interaction of sex steroid hormones, particularly oestrogen, in the regulation of prepulse inhibition (PPI) by serotonin-1A (5-HT1A) receptors. We studied aromatase knockout (ArKO) mice, which are unable to produce oestrogen but have high levels of testosterone, and the effects of castration. Treatment of male ArKO mice with the 5-HT1A receptor agonist, 8-hydroxy-dipropyl-aminotetralin (8-OH-DPAT), caused an increase in PPI that was significantly greater than in male wild-type controls. Castration of male mice caused a significant enhancement of the effect of 8-OH-DPAT in control mice; however, there was no change in the effect of this drug in ArKO mice. There was no significant effect of 8-OH-DPAT on PPI in either female ArKO or wild-type controls. In all experiments, the effects of 8-OH-DPAT on startle were not different between the groups. [3H]8-OH-DPAT autoradiography showed no differences in 5-HT1A receptor binding densities in areas of the forebrain, hippocampus or raphe region that could explain the PPI results. These data show that the absence of oestrogen in male ArKO mice leads to a greater effect of 5-HT1A receptor stimulation on PPI. This effect can be mimicked in male control mice by castration. The differential involvement of oestrogen and testosterone in these animal models is discussed. [ABSTRACT FROM AUTHOR]

The function of serotonin transporters (SERTs) is related to mood regulation. Mice with deficient or reduced SERT function (SERT knockout mice) show several behavioral changes, including increased anxiety-like behavior, increased sensitivity to stress, and decreases in aggressive behavior. Some of these behavioral alterations are similar to phenotypes found in humans with short alleles of polymorphism in the 5-hydroxytryptamine (5-HT) transporter-linked promoter region (5-HTTLPR). Therefore, SERT knockout mice can be used as a tool to study 5-HTTLPR-related variations in personality and may be the etiology of affective disorders. This article focuses on the cellular and molecular alterations in SERT knockout mice, including changes in 5-HT concentrations and its metabolism, alterations in 5-HT receptors, impaired hypothalamic-pituitary-adrenal gland axis, developmental changes in the neurons and brain, and influence on other neurotransmitter transporters and receptors. It also discusses the possible relationships between these alterations and the behavioral changes in these mice. The knowledge provides the foundation for understanding the cellular and molecular mechanisms that mediate the SERT-related mood regulation, which may have significant impact on understanding the etiology of affective disorders and developing better therapeutic approaches for affective disorders. [ABSTRACT FROM AUTHOR]

Serotonin (5-HT) receptors are increasingly recognized as major targets for cognitive enhancement in schizophrenia. Several lines of evidence suggest a pathophysiological role for glutamate NMDA receptors in the prefrontal cortex in schizophrenia and associated disorders in attention and executive functioning. We investigated how the interactions between 5-HT1A and 5-HT2A and glutamate NMDA receptor mechanisms in the medial prefrontal cortex (mPFC) contribute to the control of different aspects of attentional performance. Rats were trained on a five-choice serial reaction time (5-CSRT) task, which provides indices of attentional functioning (percentage of correct responses), executive control (measured by anticipatory and perseverative responses), and speed. The competitive NMDA receptor antagonist CPP (50 ng/side) was infused directly into the mPFC 5 min after infusion of either 8-OH-DPAT (30 and 100 ng/side) or M100907 (100 and 300 ng/side) into the same brain area. Impairments in attentional functioning induced by CPP were completely abolished by both doses of 8-OH-DPAT or M100907. In addition, M100907 abolished the CPP-induced anticipatory responding but had no effects on perseverative over-responding, while 8-OH-DPAT reduced the perseverative over-responding but had no effects on anticipatory responding induced by CPP. The selective 5-HT1A receptor antagonist WAY100635 (30 ng/side) antagonized the effects of 8-OH-DPAT (100 ng/side). 8-OH-DPAT at 30 ng/side reduced the latency of correct responses in controls and CPP-injected rats and lowered the percentage of omissions in CPP-injected rats. The data show that 5-HT1A and 5-HT2A receptors in the mPFC exert opposing actions on attentional functioning and demonstrate a dissociable contribution of 5-HT1A and 5-HT2A receptors in the mPFC to different aspects of executive control such as impulsivity and compulsive perseveration.Neuropsychopharmacology (2006) 31, 757–767. doi:10.1038/sj.npp.1300893; published online 28 September 2005 [ABSTRACT FROM AUTHOR]

Rationale: Clozapine inhibits sympathetic outflow to the cutaneous vascular bed. Clozapine reverses hyperthermia and cutaneous vasoconstriction induced by 3,4- methylenedioxymethamphetamine (MDMA, Ecstasy) or by lipopolysaccharide (LPS). Clozapine also reverses cutaneous vasoconstriction elicited by exposure to cold. These actions distinguish clozapine from haloperidol. Clozapine could also inhibit sympathetic cutaneous vasomotor alerting responses (SCVARs), vasoconstrictor episodes that reflect emotional/psychological function, and this property might also distinguish clozapine from haloperidol. Objectives: Experiments in rats determined whether clozapine and haloperidol inhibit SCVARs, and whether SR46349B (a 5HT2A receptor antagonist), 8-OH-DPAT (a 5-HT1A agonist), L741,626 (a dopamine D2 antagonist) or SCH23390 (a dopamine D1 antagonist) have clozapinelike effects on SCVARs. Methods: Mean level and pulse amplitude of the tail artery Doppler flow signal were recorded in conscious freely moving rats before and after alerting stimuli (e.g. tapping the cage), and expressed as a SCVAR index (fall to zero flow implies SCVAR index of 100%, no fall implies 0%). Results: Clozapine (0.0625- 1.0 mg/kg, s.c.) dose-dependently increased resting tail blood flow. After 1 mg/kg, the SCVAR index was 18±1%, compared with 83±2% after vehicle. SR46349B (0.01- 1.0 mg/kg) and 8-OH-DPAT (0.25 mg/kg) had similar but less potent effects on cutaneous blood flow and o SCVARs. Haloperidol (0.005-0.5 mg/kg) and L741,626 (1 mg/kg) had no or little effect on these variables. SCH23390 mildly inhibited SCVARs. Conclusions: Clozapine, but not haloperidol, increases resting cutaneous blood flow and decreases SCVARs. Antagonism at 5-HT2A receptors and agonism at 5-HT1A receptors could contribute to these actions. [ABSTRACT FROM AUTHOR]

Rationale: Performance on progressive ratio schedules has been proposed as a means of assessing the effects of drugs on the efficacy of reinforcers. A mathematical model (Killeen PR (1994) Mathematical principles of reinforcement. Behav Brain Sci 17:105-172) affords a basis for quantifying the effects of drugs on progressive ratio schedule performance. The model postulates a bitonic function relating response rate and ratio size. One parameter of the function, a, expresses the motivational effect of the reinforcer, whereas another parameter, δ, expresses the minimum time needed to execute a response, and is regarded as an index of 'motor capacity'. Previously we found that the atypical antipsychotic clozapine increased a, indicating an increase in reinforcer efficacy; a similar effect was observed with the 5-hydroxytryptamine (5-HT)1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). It has been suggested that some of clozapine's behavioural effects are mediated by agonistic action at 5-HT1A receptors. Objective: This study was conducted to compare the effects of clozapine and 8-OH-DPAT on progressive ratio schedule performance. Methods: Rats were trained under a time-constrained progressive ratio schedule (50-min sessions). In experiment 1, they received acute doses of clozapine (4 mg kg-1) and 8-OH-DPAT (100 µg kg-1), alone and in combination with the 5-HT1A receptor antagonist N-[2-(4- [2-methoxyphenyl]-1-piperazinyl)ethyl]-N-2-yridinylcyclohexanecarboxamide (WAY-100635; 30 µg kg-1). In experiment 2, the effects of clozapine (2, 4 and 8 mg kg-1) and 8-OH-DPAT (25, 50 and 100 µg kg-1) were compared between intact rats and rats whose 5-HTergic pathways had been ablated by 5,7-dihydroxytryptamine (5,7-DHT). Results: In both experiments, clozapine and 8-OH-DPAT increased a and δ. In experiment 1, WAY-100635 abolished the effect of 8-OH-DPAT on a and δ, but did not alter clozapine's effects on these parameters. In experiment 2, the effects of clozapine and 8-OH-DPAT did not differ between sham-lesioned and 5,7-DHT-lesioned rats. Conclusions: The results confirm previous findings on the effects of clozapine and 8-OH-DPAT on progressive ratio schedule performance. 8-OH-DPAT's effects are probably mediated by post-synaptic 5-HT1A receptors; clozapine's effects are mediated by a different mechanism, which does not appear to involve 5-HT1A upon an intact 5-HTergic pathway. [ABSTRACT FROM AUTHOR]

The seroton in 5-HT1A receptor agonist, 8-OH-DPAT (8-hydroxy-2-di-n-propylamino-tetralin), impairs retention performance in a passive avoidance learning task in rats. In the hippocampus of rats trained on this procedure and killed 1 h after the acquisition trial, an increase in the membrane levels of both Ca2+/calmodulin-dependent protein kinase II (CaMKII) and phosphorylated CaMKII, as well as in total and Ca2+-independent enzyme activity in tissue lysates was found. These effects were learning-specific as no changes in CaMKII levels or activity were found in rats receiving a footshock identical to the trained rats. The effect of training on CaMKII was prevented by a low 8-OH-DPAT dose. The S-HT1A agonist also reduced protein kinase A (PKA) activity and increased the membrane levels of phosphatase 1 (PPI) and PPI enzyme activity in the hippocampus. All of the changes induced by 8-OH-DPAT were reversed by the selective 5-HT1A antagonist WAY- 100635, indicating receptor-specific effects. We suggest that S-HT1A receptor-mediated disruption of retention performance is a consequence of the reduced PKA activity and the ensuing enhancement in PPI activity, possibly through decreased phosphorylation/activation of endogenous PPI inhibitors, that cause a reduced activity of phosphorylated CaMKII, a key enzyme in early stages of memory formation. This study provides an in vivo molecular basis for the cognitive deficits induced by stimulation of hippocampal 5-HT1A receptors. [ABSTRACT FROM AUTHOR]

A distinct role for serotonin transmission from the dorsal and median raphé nuclei (DRN and MRN, respectively) was identified in regulating the behavioral and neurochemical effects of acute and repeated cocaine administration. Serotonin 1A (5-hydroxytryptophan (5-HT) 1A) receptors were stimulated by intraraphé microinjection of 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT; 5 or 10 μg) and behavior, as well as extracellular neurotransmitter content in the nucleus accumbens was measured. Pretreatment of the DRN with DPAT caused a sensitization-like potentiation off acute cocaine-induced motor activity and an elevation in extracellular dopamine and glutamate. In contrast, DPAT microinjection into the MRN did not alter acute cocaine induced motor activity or extracellular levels of dopamine or glutamate. Acutely, DPAT microinjection into either raphé nucleus reduced the basal and acute cocaine-stimulated levels of extracellular serotonin. Pretreatment with DPAT before systemic cocaine administration was continued for 5 days, and 3 weeks after the last injection, all rats were administered a cocaine challenge injection. The sensitized behavioral and neurochemical response produced by repeated cocaine in control subjects was unaffected by the intra-DRN administration of DPAT. However, in animals administered DPAT into the MRN, both the sensitized motor response and the increase in glutamate were augmented, while the sensitized serotonin response was blocked, without altering dopamine sensitization. These data show a differential role for 5-HTIA receptors in the DRN and MRN in the acute and sensitized effects of cocaine. While the DRN is involved in the acute effects of cocaine, neuroadaptations in the MRN may regulate the long-term consequences of repeated cocaine exposure. [ABSTRACT FROM AUTHOR]

Rationale. Reduced central serotonin (5-HT) activity has been associated with impulsive choice behaviour, but there is no consensus about the precise nature of these effects. Behavioural and neurochemical effects of 5-HT1A agonists such as buspirone depend critically on the dose and the duration of treatment. We thus undertook a parametric study of the effects of acute and chronic buspirone on the performance on a test of delayed gratification, as well as on the efflux of serotonin and dopamine (DA) in cortical and subcortical regions in rats. Objectives. Three experiments examined (i) the effects of acute buspirone on impulsive choice and how such effects were modified by prior chronic exposure to buspirone; (ii) the effects of chronic buspirone on impulsive choice; (iii) the effects on impulsive choice of a selective 5-HT1A antagonist, WAY-100635 tested alone and in combination with buspirone; (iv) the effects of chronic and acute buspirone on 5-HT and DA efflux in anaesthetised rats. Methods. In experiment 1, rats previously trained on the delayed gratification task were tested with acute buspirone (0.5, 1 and 2 mg/kg). The same rats were then treated with chronic buspirone (1 mg/kg/day) over the next 65 days, and the effects of acute buspirone (1 mg/kg) re-determined at 20, 45 and 65 days of chronic treatment. In experiment 2, two groups of rats trained on the delayed gratification task were treated either with saline or buspirone (1 mg/kg/day) continually for 65 days before being tested with acute buspirone (1 mg/kg), WAY-100635 (0.08 mg/kg), or a combination of the two drugs. In experiment 3, rats received the same regimen of buspirone dosing as in experiment 2, before receiving in-vivo microdialysis for 5-HT and DA in the ventral hippocampus, nucleus accumbens and medial prefrontal cortex. Results. Acute buspirone dose dependently increased the choice for the small, immediate reinforcer (impulsive choice) but the effects of 1 mg/kg were reversed on chronic administration of buspirone. This increased choice of the large, delayed reinforcer, which was not accompanied by any changes in baseline (non-drugged) performance, was blocked by the 5-HT1A receptor antagonist WAY-100635. The chronic buspirone regimen did not alter buspirone-evoked reductions in 5-HT efflux in hippocampus but did lead to a differential effect of acute buspirone in medial prefrontal cortex, with the chronic buspirone and saline groups exhibiting decreases and increases in efflux, respectively. There were no systematic changes in DA efflux under any condition. Conclusions. These findings show that the effects of acute buspirone on impulsive choice are reversed following chronic treatment and are mediated by 5-HT1A receptors, and suggest, in addition, that the behavioural effects may involve changes in 5-HT functioning in medial prefrontal cortex. [ABSTRACT FROM AUTHOR]

Rationale and objectives. Serotonin (5-hydroxytryptamine, 5-HT) is widely distributed in the central nervous system and it is well established that this neurotransmitter plays an inhibitory role in the control of ingestive behavior. Administration of various 5-HT agonists and selective serotonin reuptake inhibitors, including fluoxetine (FLU), suppress food intake under free-feeding and food-restricted conditions. In contrast, activation of somatodendritc 5-HT1A receptors in the raphe nuclei reduces forebrain 5-HT bioavailability and agonists of these receptors, including 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), reliably stimulate eating behavior. Methods. In the present study male (n=8 per group) and female (n=8 per group) rats were pretreated with 8-OH-DPAT in an attempt to reverse FLU’s inhibitory effect on feeding. 8-OH-DPAT was injected into either the dorsal or median raphe of male and female rats at doses of 0.1–0.4 nmol. FLU was then injected IP at a dose of 2 mg/kg. Both compounds were administered just prior to the onset of the dark cycle. Food intake was measured 2 h post-injection. Similar effects were also measured in female rats after ovariectomy. Results and conclusions. FLU suppressed food intake comparably in male and female rats. Dorsal and median raphe injections of 8-OH-DPAT dose dependently reversed the anorectic effect of FLU in male rats. Higher doses of 8-OH-DPAT completely antagonized this response. In female rats, however, 8-OH-DPAT pretreatment was largely ineffective except in ovariectomized females where results were similar to male rats. These findings suggest that male and female rats are differentially sensitive to the ability of 5-HT1A receptor agonists to antagonize the feeding suppressive action of FLU and imply a role for neuroendocrine mechanisms in enabling the somatodendritic autoreceptor to control serotonergic neurotransmission under these conditions. [ABSTRACT FROM AUTHOR]

This study employed [35S]guanosine 5′-O-(3-thiotriphosphate) ([35S]GTPγS) binding to compare the actions of antipsychotic agents known to stimulate cloned, human 5-HT1A receptors with those of reference agonists at postsynaptic 5-HT1A receptors. In rat hippocampal membranes, the following order of efficacy was observed (maximum efficacy, Emax, values relative to 5-HT=100): (+)8-OH-DPAT (85), flesinoxan (62), eltoprazine (60), S14506 (59), S16924 (48), buspirone (41), S15535 (22), clozapine (22), ziprasidone (21), pindolol (7), p-MPPI (0), WAY100,635 (0), spiperone (0). Despite differences in species and tissue source, the efficacy and potency (pEC50) of agonists (with the exception of clozapine) correlated well with those determined previously at human 5-HT1A receptors expressed in Chinese hamster ovary (CHO) cells. In contrast, clozapine was more potent at hippocampal membranes. The selective antagonists p-MPPI and WAY100,635 abolished stimulation of binding by (+)8-OH-DPAT, clozapine and S16924 (p-MPPI), indicating that these actions were mediated specifically by 5-HT1A receptors. Clozapine and S16924 also attenuated 5-HT- and (+)8-OH-DPAT-stimulated [35S]GTPγS binding, consistent with partial agonist properties. In [35S]GTPγS autoradiographic studies, 5-HT-induced stimulation, mediated through 5-HT1A receptors, was more potent in the septum (pEC50~6.5) than in the dentate gyrus of the hippocampus (pEC50~5) suggesting potential differences in coupling efficiency or G protein expression. Though clozapine (30 and 100 µM) did not enhance [35S]GTPγS labelling in any structure, S16924 (10 µM) modestly increased [35S]GTPγS labelling in the dentate gyrus. On the other hand, both these antipsychotic agents attenuated 5-HT (10 µM)-stimulated [35S]GTPγS binding in the dentate gyrus and septum. In conclusion, clozapine, S16924 and ziprasidone act as partial agonists for G protein activation at postsynaptic 5-HT1A receptors in the hippocampus. These data support a role of postsynaptic 5-HT1A receptors in the functional profiles of certain antipsychotic agents. [ABSTRACT FROM AUTHOR]

Selective serotonin reuptake inhibitors (SSRIs) are extensively used for the treatment of depression. Aside from their antidepressant properties, they provoke a deficit in paradoxical sleep (PS) that is most probably mediated by the transporter blockade-induced increase in serotonin concentration in the extracellular space. Such an effect can be accounted for by the action of serotonin at various types of serotonergic receptors involved in PS regulation, among which the 5-HT1A and 5-HT1B types are the best candidates. According to this hypothesis, we examined the effects of citalopram, the most selective SSRI available to date, on sleep in the mouse after inactivation of 5-HT1A or 5-HT1B receptors, either by homologous recombination of their encoding genes, or pharmacological blockade with selective antagonists. For this purpose, sleep parameters of knockout mice that do not express these receptors and their wild-type counterparts were monitored during 8 h after injection of citalopram alone or in association with 5-HT1A or 5-HT1B receptor antagonists. Citalopram induced mainly a dose-dependent inhibition of PS during 2-6 h after injection, which was observed in wild-type and 5-HT1B-/- mice, but not in 5-HT1A-/- mutants. This PS inhibition was fully antagonized by pretreatment with the 5-HT1A antagonist WAY 100635, but only partially with the 5-HT1B antagonist GR 127935. These data indicate that the action of the SSRI citalopram on sleep in the mouse is essentially mediated by 5-HT1A receptors. Such a mechanism of action provides further support to the clinical strategy of antidepressant augmentation by 5-HT1A antagonists, because the latter would also counteract the direct sleep-inhibitory side-effects of SSRIs. [ABSTRACT FROM AUTHOR]

Using extracellular ex vivo recording we studied changes in the reactivity of rat frontal cortical neurons to the 5-HT1A, 5-HT2 and 5-HT4 receptor agonists (±)-2-dipropyloamino-8-hydroxy-1,2,3,4-tetrahydronaphtalene hydrobromide (8-OH-DPAT), (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) and zacopride, respectively, induced by a repeated treatment with imipramine or citalopram. Rats were treated with imipramine or citalopram for 14 days (10 mg/kg p.o.) twice daily. Frontal cortical slices were prepared 2 days after the last drug administration. Spontaneous epileptiform discharges were induced in slices by perfusion with a medium devoid of Mg2+ ions and with added picrotoxin (30 μM). While the application of 2 μM 8-OH-DPAT resulted in a reversible decrease of the discharge frequency, in the presence of DOI (1 μM) or zacopride (5 μM), the discharge frequency was increased. Both repeated imipramine and citalopram enhanced the effect of the activation of 5-HT1A receptor and attenuated the effect related to 5-HT2 receptor activation, while the effect of the activation of 5-HT4 receptor remained unchanged. Moreover, imipramine, but not citalopram, induced a reduction of epileptiform discharge frequency and an increase of the time of occurrence of epileptiform activity. These data indicate that antidepressants enhance the 5-HT-mediated inhibition in neuronal circuitry of the frontal cortex. [ABSTRACT FROM AUTHOR]

VN2222 (1-(benzo[b]thiophen-3-yl)-3-[4-(2-methoxiphenyl piperazin-1-yl]propan-1-ol) is a potential antidepressant with high affinity for the serotonin transporter and 5-HT1A receptors. Locally applied, VN2222 enhanced the extracellular 5-hydroxytryptamine (5-HT) concentration (5-HText) in rat striatum to 780% of baseline whereas its systemic administration (1-10 mg/kg s.c.) reduced 5-HText. In the presence of citalopram, 8-OH-DPAT or VN2222 applied in medial prefrontal cortex reduced 5-HText. Fluoxetine, VN2222, and 8-OH-DPAT suppressed the firing rate of dorsal raphe 5-HT neurons (ED50: 790, 14.9, and 0.8 µg/kg i.v., respectively). These effects were antagonized by WAY 100635. Administration of VN2222 for 2 weeks desensitized 5-HT1A receptors as assessed by microdialysis and single-unit recordings (ED50 values for 8-OH-DPAT were 0.45 and 2.34 µg/kg i.v. for controls and rats treated with 6 mg/kg day VN2222). These results show that VN2222 is a mixed 5-HT reuptake inhibitor/5-HT1A agonist that markedly desensitizes 5-HT1A autoreceptors. These properties suggest that it may be a clinically effective dual action antidepressant drug. [ABSTRACT FROM AUTHOR]

Systemic administration of the muscarinic-receptor antagonists atropine and scopolamine produces cognitive deficits in humans, nonhuman primates and rodents. In humans, these deficits resemble symptoms of dementia seen in Alzheimer's disease. The passive avoidance (PA) task has been one of the most frequently used animal models for studying cholinergic mechanisms in learning and memory. The present study examined the ability of two selective 5-HT1A receptor antagonists WAY 100635 and NAD-299 (robalzotan) and two acetylcholinesterase (AChE) inhibitors tacrine and donepezil to attenuate the impairment of PA retention caused by the nonselective muscarinic receptor antagonist scopolamine in the rat. Although demonstrating differences in their temporal kinetics, both WAY 100635 and NAD-299 attenuated the impairment of PA caused by scopolamine (0.3 mg/kg s.c.). Donepezil did not block the PA deficit caused by the 0.3 mg/kg dose of scopolamine, but it prevented the inhibitory effects of the 0.2 mg/kg dose of scopolamine. In contrast, tacrine was effective vs both the 0.2 and 0.3 mg/kg doses of scopolamine. These results indicate that (1) a functional 5-HT1A receptor antagonism can attenuate the anterograde amnesia produced by muscarinic-receptor blockade, and (2) the AChE inhibitors tacrine and donepezil differ in their ability to modify muscarinic-receptor-mediated function in vivo. These results suggest that 5-HT1A receptor antagonists may have a potential in the treatment of cognitive symptoms in psychopathologies characterized by reduced ACh transmission such as Alzheimer's disease. [ABSTRACT FROM AUTHOR]

The effects of serotonin (5-HT) as well as 5-HT1A and 5-HT4 receptor agonists, (±)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (8-OH-DPAT) and zacopride, respectively, on population spikes evoked by electrical stimulation and on spontaneous epileptiform activity were investigated in CA1 area of hippocampal slices. Spontaneous epileptiform activity was recorded from slice in a nominally Mg2+-free medium. While 5-HT application resulted in a decrease of population spikes evoked in standard incubation conditions, in accordance with earlier studies, it exerted two opposite effects on epileptiform activity. The early inhibitory effect was mimicked by 8-OH-DPAT while the later, excitatory, by zacopride. The application of 8-OH-DPAT decreased, and that of zacopride increased, the amplitude of population spikes. A comparison of the dose-dependence of the excitatory and inhibitory effects of serotonergic agonists on the amplitude of the population spike and on the frequency of epileptiform discharges indicated that the latter is a more sensitive measure of the activation of 5-HT1A and 5-HT4 receptors than the former. Thus, spontaneous epileptiform activity recorded in a nominally Mg2+-free slice medium represents a convenient model for investigation of hippocampal neuronal reactivity to the activation of various 5-HT receptor subtypes. [ABSTRACT FROM AUTHOR]

The characteristics of endogenous serotonin (5-HT)-mediated synaptic transmission were investigated in the hippocampal CA1 and CA3 fields of anaesthetized rats. Electrophysiological approaches were used to elucidate the effects of a selective 5-HT reuptake inhibitor, fluvoxamine, on synaptic transmission by determining the population spike amplitude (PSA). Fluvoxamine (10 or 30 mg/kg i.p.) increased the PSA in the CA1 and CA3 fields concentration dependently, whereby this facilitatory response was greater in the CA3 than in the CA1 field. Fluvoxamine (30 mg/kg i.p.)-induced increases in the PSA were augmented by the 5-HT1A receptor antagonist NAN 190 (0.5 mg/kg i.p.) and prevented by the 5-HT4 receptor antagonist GR 113808 (20 µg/rat i.c.v.) or by the 5-HT7 receptor antagonist DR 4004 (10 µg/rat i.c.v.) in the CA1 field. Thus, fluvoxamine-induced facilitatory effects appear to be mediated via 5-HT1A and 5-HT4/5-HT7 receptors in an inhibitory and a stimulatory manner, respectively. In the CA3 field, excitability produced by fluvoxamine was abolished by either NAN 190 or DR 4004, but not by GR 113808, suggesting that 5-HT1A and 5-HT7 receptors contribute to this facilitation. These findings were supported in part by the results obtained by exogenously applied 5-HT receptor agonists: the 5-HT1A receptor agonist tandospirone (10 mg/kg i.p.) decreased PSA in the CA1 field, whereas the 5-HT4 receptor agonist SC 53116 (10 µg/rat i.c.v.) increased it. In contrast, in the CA3 field, tandospirone increased PSA, whereas SC 53116 had no effect. Taken together, the present study revealed that characteristics of synaptic transmission mediated via 5-HT receptors differ between the CA1 and CA3 fields: in the CA1 field, three 5-HT receptors, 5-HT1A, 5-HT4 and 5-HT7, are associated with the endogenous 5-HT-induced facilitation in an opposite and independent manner. In the CA3 field, at least two 5-HT receptors, i.e. 5-HT1A and 5-HT7, are involved in this mediation in a facilitatory manner. 5-HT neurons may modulate pyramidal neuron responses to incoming stimuli by complex mechanisms involving these 5-HT receptors. In other words, the net effects resulting from the differential characteristics in the CA1 and CA3 fields may play an important role in the physiological functions of the hippocampus. [ABSTRACT FROM AUTHOR]

Neurochemical, molecular, immunohistochemical and behavioral methods were used to examine the in vivo effects of the neuropeptide galanin on central 5-HT neurotransmission and on 5-HT1A receptor-mediated responses. Intraventricularly infused galanin caused a long-lasting and dose-dependent reduction of basal extracellular 5-HT levels in the ventral hippocampus of awake rats as measured by microdialysis. Infusion of galanin into the dorsal raphe nucleus (DRN), but not intra-hippocampally, reduced 5-HT release. The effect of i.c.v. galanin on 5-HT release was blocked by the galanin receptor antagonist M35, acting most likely via galanin receptors at the level of the DRN. Galanin also reduced the levels of tryptophanhydroxylase mRNA in the DRN. Therefore, the effects of galanin on 5-HT1A receptor-mediated responses were further investigated. Surprisingly, galanin significantly attenuated the reduction of hippocampal 5-HT release induced by systemic injection of the 5-HT1A receptor agonist 8-OH-DPAT. Galanin also attenuated 8-OH-DPAT-induced hypothermia and locomotor activity in rats. These results indicate that galanin has important inhibitory actions on central 5-HT neurotransmission and on 5-HT1A receptor-mediated events. [Copyright &y& Elsevier]

The hypothermia produced by 5-HT1A agonists had initially been claimed to be caused by the activation of cell body 5-HT1A autoreceptors resulting in decreased 5-HT transmission in laboratory animals. In order to address this issue in humans, 12 healthy volunteers underwent a dietary tryptophan depletion paradigm to decrease 5-HT availability, under double-blind conditions, during which body temperature was monitored following oral administration of the 5-HT1A agonist buspirone (30 mg). In addition, plasma prolactin and growth hormone evaluations, two responses that are mediated via the direct activation of postsynaptic 5-HT1A receptors, were determined. The hypothesis was that if responses are mediated by decreased transmission at postsynaptic 5-HT1A receptors, resulting from dampened 5-HT release as a consequence of 5-HT1A autoreceptors activation, then responses to the exogenous 5-HT1A agonist should be attenuated when 5-HT availability has been markedly decreased beforehand. Buspirone produced the same significant increase in prolactin and growth hormone in the tryptophan-depleted state as in the control condition. Similarly, the degree of hypothermia produced by buspirone was not significantly different in the two experimental conditions. In conclusion, these results strongly suggest that the hypothermia and the increases in prolactin and growth hormone produced by buspirone are attributable to the enhanced activation of postsynaptic 5-HT1A receptors, and not to a decrease in 5-HT transmission resulting from the activation of the 5-HT1A cell body autoreceptors on 5-HT neurons. [Copyright &y& Elsevier]

Factors influencing the disappearance of radioactivity from mouse brain after injections of tracer doses of the very selective receptor antagonists [3H]raclopride and [3H]robalzotan (NAD-299) which bind with high affinity to dopamine-D2 and 5-hydroxytryptamine1A receptors, respectively, were studied. For both ligands the amount of radioactivity in cerebellum was taken as non-specific binding and subtracted from the amount of radioactivity found in the brain regions studied. The disappearance of the radioactivity in naive mice followed apparent first-order reactions with T1/2=16.8±1.4 min for [3H]raclopride in striatum and T1/2=22±2 min and 17±2 min for [3H]robalzotan in hippocampus and frontal cortex, respectively. Pretreatment of mice with 1 mg/kg s.c. reserpine 20 h before the experiment strongly prolonged the dissociation phase for the two ligands. Injection of the dopamine-D2 receptor antagonist etioclopride 1 h after [3H]raclopride in the reserpinized mice rapidly reduced the radioactivity in striatum to the same level as in cerebellum. Similarly, the 5-HT1A receptor antagonist WAY-100,635 injected 1 h or 4 h after [3H]robalzotan rapidly reduced the radioactivity in hippocampus and frontal cortex to the cerebellum level showing that the intact drugs were still bound to the receptors. In reserpinized mice kept at 30°C 1 h before and during the experiment, which normalised the body temperature, the disappearance of radioactivity was more like that in untreated animals but was still significantly higher than in the control animals. Mice treated with anaesthetic agents, e.g. γ-butyrolactone (GBL), pentobarbital sodium and chloral hydrate, also strongly prolonged the rate of disappearance of [3H]raclopride and [3H]robalzotan from the receptor-rich brain regions. The pronounced effect of hypothermia on the dissociation of these 3H ligands from their receptors is probably caused by a general decrease in brain nervous activity. However, the decreased rate of dissociation evoked by reserpine, GBL, baclofen and prazosin after normalisation of the body temperature may be due to specific actions of these compounds causing decrease in dopaminergic and serotoninergic nerve activity which results in reduced synaptic concentration of the transmitter amines. In accordance with this view, increased synaptic 5-HT evoked by the 5-HT releasing agent p-chloroamphetamine enhanced the disappearance of [3H]robalzotan from hippocampus and frontal cortex. [ABSTRACT FROM AUTHOR]

The effects of hypothyroidism on 5-HT1A and 5-HT2A receptors and the serotonin transporter protein were studied in thyroidectomized male Wistar rats in two experimental groups: 1) animals kept on an iodine-free diet (hypothyroid rats) and 2) animals kept on thyroxine (15 μg/kg) for 21 days (giving normal thyroid hormone levels, euthyroid animals). Sham-operated rats served as controls. Binding of [3H]8-OH-DPAT with 5-HT1A receptors and [3H]citalopram with the transporter protein in the hippocampus and midbrain showed no changes in hypothyroid rats as compared with controls. Conversely, there were significant decreases in [3H]ketanserin binding to 5-HT2A receptors in the frontal cortex in hypothyroid rats as compared with controls; this decrease was reversed by thyroxine treatment. Thus, losses of cortical 5-HT2A receptors appears to be the main consequence of hypothyroidism at the level of the serotonin system of the brain. [ABSTRACT FROM AUTHOR]

Using extracellular and intracellular ex vivo recording techniques we studied changes in the reactivity of hippocampal pyramidal CA1 neurons to serotonin (5-HT) and to the 5-HT1A- and 5-HT4 receptor agonists (±)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (8-OH-DPAT) and zacopride, respectively, evoked by repeated electroconvulsive shock (ECS), imipramine and corticosterone treatments. Rats were subjected to ECS for 1 or 10 days, treated with imipramine for 1, 7, 14 or 21 days (10 mg/kg p.o., twice daily) and with corticosterone for 7 days (10 mg/kg s.c., twice daily). Hippocampal slices were prepared 2 days after the last treatment. Activation of 5-HT1A receptors decreased the amplitude of population spikes evoked by stimulation of the Schaffer/collateral-commissural pathway and hyperpolarized CA1 cells. Activation of 5-HT4 receptors increased the population spike amplitude and decreased the amplitude of slow afterhyperpolarization. Both repeated ECS and imipramine enhanced the effects related to 5-HT1A receptor activation and attenuated the effects of 5-HT4 receptor activation. The action of imipramine was significant after a 7-day treatment and reached a maximum after 14 daily applications, remaining at the same level in a group of animals treated for 21 days. Repeated corticosterone attenuated the inhibitory effect of 5-HT and 8-OH-DPAT on the population spike amplitude and enhanced the increase in population spike amplitude induced by zacopride. These findings indicate that antidepressant treatments and repeated corticosterone have opposite effects on hippocampal responsiveness to 5-HT1A and 5-HT4 receptor activation. In consequence, antidepressants enhance, whereas corticosterone reduces the 5-HT-mediated inhibition of hippocampal CA1 cells, which may be relevant to the antidepressant and pro-depressant effects of either treatment, respectively. [ABSTRACT FROM AUTHOR]

The arylalkylamine, pindolol, may potentiate the clinical actions of antidepressant agents. Although it is thought to act via blockade of 5-HT1A autoreceptors, its efficacy at these sites remains controversial. Herein, we evaluated the actions of pindolol at 5-HT1A autoreceptors and specific populations of postsynaptic 5-HT1A receptors employing [35S]GTPγS autoradiography, a measure of receptor-mediated G-protein activation. Both 8-OH-DPAT (1 µM) and 5-HT (10 µM) elicited a pronounced increase in [35S]GTPγS binding in the dorsal raphe nucleus, which contains serotonergic cell bodies bearing 5-HT1A autoreceptors. Pindolol abolished their actions. In the dentate gyrus, lateral septum and entorhinal cortex, structures enriched in postsynaptic 5-HT1A receptors, 8-OH-DPAT (1 µM) and 5-HT (10 µM) also elicited a marked increase in [35S]GTPγS binding which was likewise blocked by pindolol. The antagonism of 5-HT-induced [35S]GTPγS labelling in the dentate gyrus was shown to be concentration-dependent, yielding a pIC50 of 5.82. Pindolol did not, itself, affect [35S]GTPγS binding in any brain region examined. In conclusion, these data suggest that, as characterised by [35S]GTPγS autoradiography, and compared with 5-HT and 8-OH-DPAT, pindolol possesses low efficacy at both pre- and postsynaptic 5-HT1A receptors. [ABSTRACT FROM AUTHOR]

The presence of serotonin 5-HT1A receptors and their physiological role were further characterized in the goldfish retina. The effects of the 5-HT6/7 receptor antagonists pimozide, fluphenazine and amoxapine, the 5-HT1A receptor antagonist WAY-100,135, and the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, on the 5-HT1A receptor agonist [3H]8-hydroxy-2-(di-n-propylamino)tetralin binding to retinal membranes, were evaluated. In addition, the effects of serotonin, 8-hydroxy-2-(di-n-propylamino)tetralin, WAY-100,135, the adenylate cyclase inhibitors SQ22536 and MDL12330A, and the cyclic AMP analog 8-bromoadenosine-3′:5′ cyclic monophosphate were also studied on neuritic outgrowth from retinal explants. WAY-100,135 but not 5-HT6/7receptor antagonists inhibited [3H]8-hydroxy-2-(di-n-propylamino)tetralin binding to retinal membranes N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline decreased [3H]8-hydroxy-2-(di-n-propylamino)tetralin binding sites up to 70%, while receptor turnover was similar to that reported in other tissues. Serotonin and 8-hydroxy-2-(di-n-propylamino)tetralin stimulated cyclic AMP production, both ex vivo and in vitro, and these increases were related to inhibition of neuritic outgrowth. The inhibitory effect was reduced by SQ22536 and by WAY-100,135, and was mimicked by 8-bromoadenosine-3′:5′cyclic monophosphate. This study supports previous findings about the role of serotonin as a regulator of axonal outgrowth during in vitro regeneration of the goldfish retina and demonstrates that this effect is mediated, at least in part, by 5-HT1A receptors through a mechanism which involves an increase of cyclic AMP levels. [ABSTRACT FROM AUTHOR]

The effect of N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ) on 5-HT1A receptors was studied in Sprague Dawley rats. A single dose of EEDQ (4 mg/kg body wt., i.p.) significantly inactivated 5-HT1A receptors, as measured by [3H]8-hydroxy-2-[di-n-propylamino]-tetralin ([3H]8-OH-DPAT), in cortex (64%, p < 0.0001) and hippocampus (48%, p < 0.0001). A significant (p < 0.01) increase in the affinity of 5-HT1A receptors for radioligand was observed in both regions. A dose dependent protection of cortical 5-HT1A receptors from EEDQ inactivation with pre-treatment of different doses of 8-OH-DPAT (4–20 mg/kg) was observed, along with recovery of affinity of [3H]8-OH-DPAT for 5-HT1A receptors in both regions. Although, a dose of 4 mg/kg of 8-OH-DPAT failed to attenuate the effect of EEDQ on hippocampal 5-HT1A receptors, a significant protection of these receptors was observed with 10 and 20 mg/kg of 8-OH-DPAT. Displacement studies revealed that EEDQ has more affinity for cortical (Ki = 101.3 ± 11.8 nM) than hippocampal (Ki = 133.5 ± 25.8 nM) 5-HT1A receptors. A time dependent natural recovery of 5-HT1A receptors from inactivation by a single dose of EEDQ (4 mg/kg) was observed more in cortex compared to hippocampus over a period from 1 day to 14 days. The results of this study suggest that 8-OH-DPAT inhibited EEDQ inactivation of cortical and hippocampal 5-HT1A receptors in a concentration dependent manner. The synthesis and turnover of 5-HT1A receptors differ in cortex and hippocampus, as evident by earlier recovery in the cortex. [ABSTRACT FROM AUTHOR]

We investigated the effects of the novel 5-HT1A receptor agonist BAY x 3702 on the serotonergic function in rat brain using single unit recordings in the dorsal raphe nucleus (DR) of anesthetized rats and in vivo microdialysis in freely moving rats. The administration of BAY x 3702 (0.25–4 µg/kg i.v.) suppressed the firing activity of 5-HT neurones. This effect was antagonized by a low dose of the selective 5-HT1A receptor antagonist WAY 100635 (5 µg/kg i.v.). In microdialysis experiments, BAY x 3702 (10–100 µg/kg s.c.) reduced dose-dependently the 5-HT output in the dorsal and median raphe (MnR) nucleus, dorsal hippocampus (DHPC) and medial prefrontal cortex (mPFC) in a regionally selective manner. Maximal effects were observed in the MnR and mPFC, with reductions to ~15% of baseline at a dose of 0.1 mg/kg s.c. The decrease in 5-HT output produced in the DR and DHPC was more moderate, to 45% of baseline at 0.1 mg/kg s.c. BAY x 3702. WAY 100635 (0.3 mg/kg s.c.) completely antagonized the effect of BAY x 3702 (30 µg/kg s.c.). The application of BAY x 3702 in the DR (1–100 µM) reduced the local 5-HT output to 25% of baseline. In rats implanted with two dialysis probes (in DR and mPFC) the application of BAY x 3702 (30 µM) in the DR reduced the 5-HT output in the DR and that in mPFC. These effects were significantly antagonized by the co-perfusion of WAY 100635 (100 µM) in the DR. Overall, these results indicate that the systemic administration of BAY x 3702 reduces the 5-HT release with high potency through the activation of midbrain 5-HT1A receptors. [ABSTRACT FROM AUTHOR]

LB50016 was characterized as a selective and potent 5-HT1A receptor agonist and evaluate its anxiolytic and antidepressant activities. It shows high affinity for 5-HT1A receptor, moderate affinity for α2 adrenergic and 5-HT2A receptors and no significant affinity for other receptors tested. Hypothermia and increased serum corticosterone level were observed in LB50016-treated rats, which are mediated mostly by post synaptic 5-HT1A receptor activation. In the mouse forced swim model for depression, LB50016-elicited dose-dependent reductions in immobility time, showing ED50 of approximately 3 mg/kg i.p., which was blocked by pretreatment of NAN-190, 5-HT1A antagonist. In face-to-face test for anxiolytic activity in mice, estimated ED50 was 2 mg/kg, i.p.. In isolation-induced aggression test with mice, fifty-fold increases in latency to attack were observed at 30 min and last up to 4 h after LB50016 treatment (3 mg/kg i.p.). Taken together, LB50016-induced pharmacological activities are mediated by activation of 5-HT1A receptors, offering an effective therapeutic candidate in the management of anxiety and depression in humans. [ABSTRACT FROM AUTHOR]

1.Rat hypothalamic 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) concentrations are transiently sexually differentiated in the second week postpartum (pp), with higher levels in the female. In this report we investigate the possibility that 5-HT receptors may also exhibit sexual dimorphism in the neonatal period. 2.5-HT1A and 5-HT2A receptors were quantitated by radioligand binding of [3H]ketanserin and [3H]8-OH DPAT, respectively, in hypothalamus and amygdala from male and female rats at days 8–16 pp. 3.There was no sexual dimorphism or change in the density of 5-HT2A binding in hypothalamus or amygdala over days 8–16 pp. There was also no sexual dimorphism of 5-HT1A receptors. 4.There was an increase in 5-HT1A receptor density in both the hypothalamus and the amygdala. In the hypothalamus, but not the amygdala, this increase was interrupted on day 14 by a decrease in 5-HT1A receptors, which we suggest may be of physiological significance in modifying the eventual pattern of adult agonistic activity. 5.The results suggest that the sexual dimorphism in 5-HT turnover is predominantly presynaptic, relating to altered synthesis and/or release, and is not of sufficient magnitude or duration to produce adaptive responses in postsynaptic 5-HT1A or 5-HT2A receptors. [ABSTRACT FROM AUTHOR]