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Background and Purpose: The aim of this study was to compare the abilities of cannabidiolic acid methyl ester (HU-580) and cannabidiolic acid (CBDA) to enhance 5-HT 1A receptor activation in vitro and produce 5-HT 1A -mediated reductions in nausea and anxiety in vivo., Experimental Approach: We investigated the effects of HU-580 and CBDA on (i) activation by 8-hydroxy-2-(di-n-propylamino)tetralin of human 5-HT 1A receptors in CHO cell membranes, using [ 35 S]-GTPγS binding assays, (ii) gaping by rats in acute and anticipatory nausea models, and (iii) stress-induced anxiety-like behaviour, as indicated by exit time from the light compartment of a light-dark box of rats subjected 24 h earlier to six tone-paired foot shocks., Key Results: HU-580 and CBDA increased the E max of 8-hydroxy-2-(di-n-propylamino) tetralin in vitro at 0.01-10 and 0.1-10 nM, respectively, and reduced signs of (i) acute nausea at 0.1 and 1 μg·kg -1 i.p. and at 1 μg·kg -1 i.p., respectively, and (ii) anticipatory nausea at 0.01 and 0.1 μg·kg -1 , and at 0.1 μg·kg -1 i.p. respectively. At 0.01 μg·kg -1 , HU-580, but not CBDA, increased the time foot-shocked rats spent in the light compartment of a light-dark box. The anti-nausea and anti-anxiety effects of 0.01 or 0.1 μg·kg -1 HU-580 were opposed by the 5-HT 1A antagonist, WAY100635 (0.1 mg·kg -1 i.p.)., Conclusions and Implications: HU-580 is more potent than CBDA at enhancing 5-HT 1A receptor activation, and inhibiting signs of acute and anticipatory nausea, and anxiety. Consequently, HU-580 is a potential medicine for treating some nausea and anxiety disorders and possibly other disorders ameliorated by enhancement of 5-HT 1A receptor activation., (© 2017 The British Pharmacological Society.)

Background and Purpose: Treatment of Parkinson's disease (PD) with L-DOPA eventually causes abnormal involuntary movements known as dyskinesias in most patients. Dyskinesia can be reduced using compounds that act as direct or indirect agonists of the 5-HT1 A receptor, but these drugs have been reported to worsen PD features and are known to produce '5-HT syndrome', symptoms of which include tremor, myoclonus, rigidity and hyper-reflexia., Experimental Approach: Sprague-Dawley rats were given unilateral nigrostriatal dopamine lesions with 6-hydroxydopamine. Each of the following three purportedly anti-dyskinetic 5-HT compounds were administered 15 min before L-DOPA: the full 5-HT1 A agonist ±-8-hydroxy-2-dipropylaminotetralin (±8-OH-DPAT), the partial 5-HT1 A agonist buspirone or the 5-HT transporter inhibitor citalopram. After these injections, animals were monitored for dyskinesia, 5-HT syndrome, motor activity and PD akinesia., Key Results: Each 5-HT drug dose-dependently reduced dyskinesia by relatively equal amounts (±8-OH-DPAT ≥ citalopram ≥ buspirone), but 5-HT syndrome was higher with ±8-OH-DPAT, lower with buspirone and not present with citalopram. Importantly, with or without L-DOPA, all three compounds provided an additional improvement of PD akinesia. All drugs tempered the locomotor response to L-DOPA suggesting dyskinesia reduction, but vertical rearing was reduced with 5-HT drugs, potentially reflecting features of 5-HT syndrome., Conclusions and Implications: The results suggest that compounds that indirectly facilitate 5-HT1 A receptor activation, such as citalopram, may be more effective therapeutics than direct 5-HT1 A receptor agonists because they exhibit similar anti-dyskinesia efficacy, while possessing a reduced side effect profile., (© 2014 The British Pharmacological Society.)

The parvalbumin (PV)-positive neurons in the medial septum-diagonal band of Broca complex (MS-DB) play an important role in the generation of hippocampal theta rhythm involved in cognitive functions. These neurons in this region express a high density of 5-HT1A receptors which regulate the neuronal activity and consequently affect the theta rhythm. In this study, we examined changes in the theta-related firing activity of PV-positive neurons in the MS-DB, their response to 5-HT1A receptor stimulation and the corresponding hippocampal theta rhythm, and the density of PV-positive neurons and their co-localization with 5-HT1A receptors in rats with 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc). The lesion of the SNc decreased the rhythmically bursting activity of PV-positive neurons and the peak frequency of hippocampal theta rhythm. Systemic administration of 5-HT1A receptor agonist 8-OH-DPAT (0.5-128 µg/kg, i.v.) inhibited the firing rate of PV-positive neurons and disrupted rhythmically bursting activity of the neurons and the theta rhythm in sham-operated and the lesioned rats, respectively. The cumulative doses producing inhibition and disruption in the lesioned rats were higher than that of sham-operated rats. Furthermore, local application of 8-OH-DPAT (0.005 μg) in the MS-DB also inhibited the firing rate of PV-positive neurons and disrupted their rhythmically bursting activity in sham-operated rats, while having no effect on PV-positive neurons in the lesioned rats. The lesion of the SNc decreased the density of PV-positive neurons in the MS-DB, and percentage of PV-positive neurons expressing 5-HT1A receptors. These results indicate that the lesion of the SNc leads to suppression of PV-positive neurons in the MS-DB and hippocampal theta rhythm. Furthermore, the lesion decreases the response of these neurons to 5-HT1A receptor stimulation, which attributes to dysfunction and/or down-regulation of 5-HT1A receptor expression on these neurons. These changes may be involved in cognitive impairments of Parkinson's disease., (Copyright © 2013 Wiley Periodicals, Inc.)

Background and Purpose: The antidepressant efficacy of selective 5-HT reuptake inhibitors (SSRI) and other 5-HT-enhancing drugs is compromised by a negative feedback mechanism involving 5-HT(1A) autoreceptor activation by the excess 5-HT produced by these drugs in the somatodendritic region of 5-HT neurones. 5-HT(1A) receptor antagonists augment antidepressant-like effects in rodents by preventing this negative feedback, and the mixed β-adrenoceptor/5-HT(1A) receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5-HT(1A) autoreceptors. However, it is unclear whether 5-HT(1A) receptor antagonists not discriminating between pre- and post-synaptic 5-HT(1A) receptors would be clinically effective., Experimental Approach: We characterized the pharmacological properties of the 5-HT(1A) receptor antagonist DU-125530 using receptor autoradiography, intracerebral microdialysis and electrophysiological recordings. Its capacity to accelerate/enhance the clinical effects of fluoxetine was assessed in a double-blind, randomized, 6 week placebo-controlled trial in 50 patients with major depression (clinicaltrials.gov identifier NCT01119430)., Key Results: DU-125530 showed equal (low nM) potency to displace agonist and antagonist binding to pre- and post-synaptic 5-HT(1A) receptors in rat and human brain. It antagonized suppression of 5-hydroxytryptaminergic activity evoked by 8-OH-DPAT and SSRIs in vivo. DU-125530 augmented SSRI-induced increases in extracellular 5-HT as effectively as in mice lacking 5-HT(1A) receptors, indicating a silent, maximal occupancy of pre-synaptic 5-HT(1A) receptors at the dose used. However, DU-125530 addition to fluoxetine did not accelerate nor augment its antidepressant effects., Conclusions and Implications: DU-125530 is an excellent pre- and post-synaptic 5-HT(1A) receptor antagonist. However, blockade of post-synaptic 5- HT(1A) receptors by DU-125530 cancels benefits obtained by enhancing pre-synaptic 5-hydroxytryptaminergic function., (© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.)

Background and Purpose: To evaluate the hypothesis that activation of somatodendritic 5-HT(1A) autoreceptors in the dorsal raphe nucleus (DRN) produces the anti-emetic/anti-nausea effects of cannabidiol (CBD), a primary non-psychoactive cannabinoid found in cannabis., Experimental Approach: The potential of systemic and intra-DRN administration of 5-HT(1A) receptor antagonists, WAY100135 or WAY100635, to prevent the anti-emetic effect of CBD in shrews (Suncus murinus) and the anti-nausea-like effects of CBD (conditioned gaping) in rats were evaluated. Also, the ability of intra-DRN administration of CBD to produce anti-nausea-like effects (and reversal by systemic WAY100635) was assessed. In vitro studies evaluated the potential of CBD to directly target 5-HT(1A) receptors and to modify the ability of the 5-HT(1A) agonist, 8-OH-DPAT, to stimulate [(35) S]GTPγS binding in rat brainstem membranes., Key Results: CBD suppressed nicotine-, lithium chloride (LiCl)- and cisplatin (20 mg·kg(-1) , but not 40 mg·kg(-1) )-induced vomiting in the S. murinus and LiCl-induced conditioned gaping in rats. Anti-emetic and anti-nausea-like effects of CBD were suppressed by WAY100135 and the latter by WAY100635. When administered to the DRN: (i) WAY100635 reversed anti-nausea-like effects of systemic CBD, and (ii) CBD suppressed nausea-like effects, an effect that was reversed by systemic WAY100635. CBD also displayed significant potency (in a bell-shaped dose-response curve) at enhancing the ability of 8-OH-DPAT to stimulate [(35) S]GTPγS binding to rat brainstem membranes in vitro. Systemically administered CBD and 8-OH-DPAT synergistically suppressed LiCl-induced conditioned gaping., Conclusions and Implications: These results suggest that CBD produced its anti-emetic/anti-nausea effects by indirect activation of the somatodendritic 5-HT(1A) autoreceptors in the DRN., Linked Articles: This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7., (© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.)

We have studied the effects of 5-HT(1A) and 5-HT(7) serotonin receptor activation in hippocampal CA3-CA1 synaptic transmission using patch clamp on mouse brain slices. Application of either 5-HT or 8-OH DPAT, a mixed 5-HT(1A)/5-HT(7) receptor agonist, inhibited AMPA receptor-mediated excitatory post synaptic currents (EPSCs); this effect was mimicked by the 5-HT(1A) receptor agonist 8-OH PIPAT and blocked by the 5-HT(1A) antagonist NAN-190. 8-OH DPAT increased paired-pulse facilitation and reduced the frequency of mEPSCs, indicating a presynaptic reduction of glutamate release probability. In another group of neurons, 8-OH DPAT enhanced EPSC amplitude but did not alter paired-pulse facilitation, suggesting a postsynaptic action; this effect persisted in the presence of NAN-190 and was blocked by the 5-HT(7) receptor antagonist SB-269970. To confirm that EPSC enhancement was mediated by 5-HT(7) receptors, we used the compound LP-44, which is considered a selective 5-HT(7) agonist. However, LP-44 reduced EPSC amplitude in most cells and instead increased EPSC amplitude in a subset of neurons, similarly to 8-OH DPAT. These effects were respectively antagonized by NAN-190 and by SB-269970, indicating that under our experimental condition LP-44 behaved as a mixed agonist. 8-OH DPAT also modulated the current evoked by exogenously applied AMPA, inducing either a reduction or an increase of amplitude in distinct neurons; these effects were respectively blocked by 5-HT(1A) and 5-HT(7) receptor antagonists, indicating that both receptors exert a postsynaptic action. Our results show that 5-HT(1A) receptors inhibit CA3-CA1 synaptic transmission acting both pre- and postsynaptically, whereas 5-HT(7) receptors enhance CA3-CA1 synaptic transmission acting exclusively at a postsynaptic site. We suggest that a selective pharmacological targeting of either subtype may be envisaged in pathological loss of hippocampal-dependent cognitive functions. In this respect, we underline the need for new selective agonists of 5-HT(7) receptors., (Copyright © 2011 Wiley Periodicals, Inc.)

Background and Purpose: Xaliproden (SR57746A) is a 5-HT(1A) receptor agonist and neurotrophic agent that reduces oxaliplatin-mediated neuropathy in clinical trials. The present study investigated its profile on in vitro transduction, neurochemical responses and acute nociceptive pain tests in rats., Experimental Approach: Xaliproden was tested on models associated with 5-HT(1A) receptor activation including G-protein activation, extracellular dopamine and 5-HT levels measured by microdialysis and formalin-induced pain. Activation of 5-HT(1A) receptors was confirmed by antagonism with WAY100635., Key Results: Xaliproden exhibited high affinity for rat (r) and human (h) 5-HT(1A) receptors (pK(i)= 8.84 and 9.00). In [(35)S]GTPgammaS (guanosine 5'-O-(3-[(35)S]thio)triphosphate) assays it activated both hippocampal r5-HT(1A)[pEC(50)/E(MAX) of 7.58/61% (%5-HT)] and recombinant h5-HT(1A) receptors (glioma C6-h5-HT(1A): 7.39/62%; HeLa-h5-HT(1A): 7.24/93%). In functional [(35)S]GTPgammaS autoradiography, xaliproden induced labelling in structures enriched with 5-HT(1A) receptors (hippocampus, lateral septum, prefrontal and entorhinal cortices). Xaliproden inhibited in vivo binding of [(3)H]WAY100635 to 5-HT(1A) receptors in mouse frontal cortex and hippocampus (ID(50): 3.5 and 3.3 mg x kg(-1), p.o. respectively). In rat, it increased extracellular dopamine levels in frontal cortex and reduced hippocampal 5-HT levels (ED(50): 1.2 and 0.7 mg x kg(-1), i.p. respectively). In a rat pain model, xaliproden inhibited paw licking and elevation (ED(50): 1 and 3 mg x kg(-1), i.p. respectively) following formalin injection in the paw. All effects were reversed by pretreatment with WAY100635., Conclusions and Implications: These results indicate that activation of 5-HT(1A) receptors is the principal mechanism of action of xaliproden and provide further support for the utility of 5-HT(1A) receptor activation as an anti-nociceptive strategy.

Background and Purpose: Activation of post-synaptic 5-HT(1A) receptors may provide enhanced therapy against depression. We describe the signal transduction profile of F15599, a novel 5-HT(1A) receptor agonist., Experimental Approach: F15599 was compared with a chemical congener, F13714, and with (+)8-OH-DPAT in models of signal transduction in vitro and ex vivo., Key Results: F15599 was highly selective for 5-HT(1A) receptors in binding experiments and in [(35)S]-GTPgammaS autoradiography of rat brain, where F15599 increased labelling in regions expressing 5-HT(1A) receptors. In cell lines expressing h5-HT(1A) receptors, F15599 more potently stimulated extracellular signal-regulated kinase (ERK1/2) phosphorylation, compared with G-protein activation, internalization of h5-HT(1A) receptors or inhibition of cAMP accumulation. F13714, (+)8-OH-DPAT and 5-HT displayed a different rank order of potency for these responses. F15599 stimulated [(35)S]-GTPgammaS binding more potently in frontal cortex than raphe. F15599, unlike 5-HT, more potently and efficaciously stimulated G(alphai) than G(alphao) activation. In rat prefrontal cortex (a region expressing post-synaptic 5-HT(1A) receptors), F15599 potently activated ERK1/2 phosphorylation and strongly induced c-fos mRNA expression. In contrast, in raphe regions (expressing pre-synaptic 5-HT(1A) receptors) F15599 only weakly or did not induce c-fos mRNA expression. Finally, despite its more modest affinity in vitro, F15599 bound to 5-HT(1A) receptors in vivo almost as potently as F13714., Conclusions and Implications: F15599 showed a distinctive activation profiles for 5-HT(1A) receptor-mediated signalling pathways, unlike those of reference agonists and consistent with functional selectivity at 5-HT(1A) receptors. In rat, F15599 potently activated signalling in prefrontal cortex, a feature likely to underlie its beneficial effects in models of depression and cognition.

Background and Purpose: Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa which induces anxiolytic- and antipsychotic-like effects in rodents. These effects could be mediated by facilitation of the endocannabinoid system or by the activation of 5-HT(1A) receptors. As either of these mechanisms could promote adaptation to inescapable stress, the aim of the present work was to test the hypothesis that CBD would attenuate the autonomic and behavioural consequences of restraint stress (RS). We also investigated if the responses to CBD depended on activation of 5-HT(1A) receptors., Experimental Approach: Male Wistar rats received i.p. injections of vehicle or CBD (1, 10 or 20 mg kg(-1)) and 30 min later were submitted to 60 min of restraint where their cardiovascular responses were recorded. The protocol of the second experiment was similar to the first one except that animals received i.p. injections of the 5-HT(1A) receptor antagonist WAY100635 (0.1 mg kg(-1)) before CBD treatment and exposure to restraint. 24 h later they were also tested in the elevated plus-maze (EPM), an animal model of anxiety., Key Results: Exposure to RS increased blood pressure and heart rate and induced an anxiogenic response in the EPM 24 h later. These effects were attenuated by CBD. WAY100635 by itself did not change the cardiovascular and anxiogenic response to RS, but blocked the effects of CBD., Conclusion and Implications: The results suggest that CBD can attenuate acute autonomic responses to stress and its delayed emotional consequences by facilitating 5-HT(1A) receptor-mediated neurotransmission.

Reasons for Performing Study: Prokinetic drugs used to treat gastrointestinal ileus in man have equivocal results in horses. In man, prokinetic drugs have 5-hydroxytryptamine4(5-HT4) receptors as their target, but little is known about the 5-HT-receptor subtypes in the equine small intestine., Objective: Functional and immunohistochemical identification of the serotonin receptor subtype(s) responsible for the 5-HT induced contractile response in the equine circular jejunum., Methods: Isometric organ-bath recordings were carried out to assess spontaneous and drug-evoked contractile activity of equine circular jejunum. Histological investigations by immunofluorescence analyses were performed to check for presence and localisation of this functionally identified 5-HT receptor subtype., Results: Tonic contractions were induced by 5-HT in horse jejunal circular muscle. Tetrodotoxin, atropine and NG-nitro L-arginine did not modify this response. A set of 5-HT receptor subtype selective antagonists excluded interaction with 5-HT1B, 1D, 2A, 3, 4 and 7 receptors. The selective 5-HT1A receptor antagonists WAY 100635 and NAN 190 caused a clear rightward shift of the concentration-response curve to 5-HT. The contractile effect of 5-CT, that can interact with 5-HT1A, 1B, 1D, 5 and 7 receptors was also antagonised by WAY 100635, identifying the targeted 5-HT receptor as a 5-HT1A-like receptor. Immunohistology performed with rabbit polyclonal anti-5-HT1A receptor antibodies confirmed the presence of muscular 5-HT1A receptors in the muscularis mucosae, and both longitudinal and circular smooth muscle layers of the equine jejunum., Conclusions: Contractile responses in equine jejunal circular smooth muscle induced by 5-HT involves 5-HT1A-like receptors.

Background and Purpose: Prepulse inhibition (PPI) of the acoustic startle response is a model of sensorimotor gating which is disrupted in schizophrenia and other mental illnesses. We and others have shown that treatment with the 5-hydroxytryptamine-1A (5-HT(1A)) receptor agonist, 8-OH-DPAT, disrupts PPI in rats. In the present study, we highlight the importance of baseline levels on the effect of 8-OH-DPAT on PPI., Experimental Approach: Adult male and female Sprague-Dawley rats were gonadectomised. These rats were treated with saline, 0.02 and 0.5 mg kg(-1) of 8-OH-DPAT using a random-sequence, repeated-measures protocol. The rats were allocated into high and low baseline groups depending on their baseline PPI observed after saline treatment., Key Results: Treatment with 0.5 mg kg(-1) of 8-OH-DPAT significantly disrupted PPI in both male and female rats. In male rats only, 0.02 mg kg(-1) 8-OH-DPAT caused a small, but significant, increase in PPI. When these male rats were allocated to either a high or low baseline PPI group, 0.5 mg kg(-1) 8-OH-DPAT disrupted PPI in the high baseline group only. In contrast, treatment with 0.02 mg kg(-1) 8-OH-DPAT increased PPI only in the low baseline PPI group. There were no changes in the effect of 8-OH-DPAT administration in female rats when they were divided into high and low baseline PPI groups., Conclusions and Implications: The level of baseline PPI is an important variable that can influence the direction of drug effects induced by 8-OH-DPAT. The explanation for this phenomenon could be differential activation of pre- and postsynaptic 5-HT(1A) receptors.

Background and Purpose: The serotonergic system within the spinal cord have been proposed to play an important role in the analgesic effects of systemic morphine. Currently, seven groups of 5-HT receptors (5-HT1-7) have been characterized. One of the most recently identified subtypes of 5 HT receptor is the 5-HT7 receptor. We aimed to examine the role of spinal 5-HT7 receptors in the antinociceptive effects of systemic morphine., Experimental Approach: The involvement of spinal 5-HT7 receptor in systemic morphine antinociception was compared to that of the 5-HT1A and 5-HT2 receptors by using the selective 5-HT7 receptor antagonist, SB-269970, the selective 5-HT1A receptor antagonist, WAY 100635, the selective 5-HT2 antagonist ketanserin as well as the non-selective 5-HT1,2,7 receptor antagonist, metergoline. Nociception was evaluated by the radiant heat tail-flick test., Key Results: I.t. administration of SB-269970 (10 microg) and metergoline (20 microg) completely blocked the s.c. administered morphine-induced (1, 3, 5 and 10 mg kg(-1)) antinociception in a time-dependent manner. Additionally, i.t. administration of SB-269970 (1, 3, 10 and 20 microg) and metergoline (1, 5, 10 and 20 microg) dose dependently inhibited the antinociceptive effects of a maximal dose of morphine (10 mg kg(-1), s.c.). I.t. administration of WAY 100635 (20 microg) or ketanserine (20 microg) did not alter morphine-induced (1, 3, 5 and 10 mg kg(-1), s.c.) antinociception., Conclusion and Implications: These findings indicate that the involvement of spinal 5-HT7, but not of 5-HT1A or of 5-HT2 receptors in the antinociceptive effects of systemic morphine.

Although previous reports have suggested that the sigma 1 (sigma(1)) receptor may be involved in pain sensation, its specific site of action has not been elucidated. The aim of present study was to determine the role of the spinal sigma(1) receptor in formalin-induced pain behavior, spinal cord Fos expression and phosphorylation of N-methyl-D-aspartate receptor subunit 1 (pNR1). Intrathecal (i.t.) pretreatment with the selective sigma(1) receptor antagonist, BD-1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide) (10-100 nmol) dose dependently reduced formalin-induced pain behaviors in second phase, but not first phase, of the formalin test. I.t. injection of BD-1047 also reduced formalin-evoked Fos expression and pNR1 at the protein kinase C-dependent site, serine-896 (Ser896) and the protein kinase A-dependent site, serine-897 (Ser897) in spinal dorsal horn.i.t. BMY-14802 ((alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol hydrochloride) (10-100 nmol, sigma(1) receptor antagonist and 5-HT(1A) receptor agonist) dose dependently reduced formalin-induced pain behaviors in both phases. However, the 5-HT(1A) receptor might not be involved in the antinociceptive effect of BMY-14802 on the second phase, since i.t. pretreatment with the 5-HT(1A) receptor antagonist propranolol ((S)-1-isopropylamino-3-(1-naphthyloxy)-2-propanol hydrochloride) (injected 10 min prior to i.t. BMY-14802) partially blocked the effect of BMY-14802 on the first phase of the formalin test but did not affect the inhibitory effect of BMY-14802 on the second phase. In addition, i.t. BMY-14802 significantly reduced formalin-evoked Fos expression and pNR1 (Ser896 and Ser897) expression in spinal dorsal horn. The results of this study suggest that selective blockage of spinal sigma(1) receptors can reduce pain behaviors, spinal cord Fos expression and pNR1 (Ser896 and Ser897) expression associated with the second phase of the formalin test.

Recent investigations in neurogenomics have opened up new lines of research into a crucial genetic problem-the pathway from genes to behavior. This paper concentrates on the involvement of protein elements in the brain neurotransmitter serotonin (5-HT) system in the genetic control of aggressive behavior. Specifically, it describes: (1) the effect of the knockout of MAO A, the principal enzyme in 5-HT degradation, (2) the association of intermale aggression with the polymorphism in the Tph2 gene encoding the key enzyme in 5-HT synthesis in the brain, tryptophan hydroxylase (TPH), and (3) the effect of selective breeding for nonaggressive behavior on 5-HT metabolism, TPH activity and 5-HT(1A) receptors in the brain. The review provides converging lines of evidence that: (1) brain 5-HT contributes to a critical mechanism underlying genetically defined individual differences in aggressiveness, and (2) genes encoding pivotal enzymes in 5-HT metabolism (TPH and MAO A), 5-HT-transporter, 5-HT(1A) and 5-HT(1B) receptors belong to a group of genes that modulate aggressive behavior., (2006 Wiley Periodicals, Inc.)

1. Experiments were carried out to characterize the possible adrenergic properties of the 5-HT(1A) antagonists WAY 100635 and MM-77 using the mouse isolated vasa deferentia preparation. 2. When vasa deferentia were preincubated for 10 min in the presence of MM-77 (10(-8)-10(-6) m) or WAY100635 (10(-8)-7 x 10(-7) m), a concentration-dependent inhibition of the contractile response to submaximal electrical field stimulation (10 Hz, 50 V, 50 ms) was observed with pIC(50) values of 7.05 +/- 0.01 and 6.85 +/- 0.1 respectively. 3. MM-77 (10(-8)-10(-6) m) antagonized the contractile responses of the vasa deferentia to phenylephrine (PE) (10(-6)-10(-3) m) in a concentration-dependent manner. Schild plots of these data were linear and yielded a mean rhoA(2) value of 6.81 +/- 0.084. The mean slope was 1.42 +/- 0.22. 4. WAY100635 (10(-8)-10(-6) m) antagonized the contractile responses of the vasa deferentia to PE (10(-6)-10(-3) m) in a concentration-dependent manner. Schild plots of these data were linear and yielded a mean rhoA(2) value of 7.05 +/- 0.08. The mean slope was 0.97 +/- 0.1. 5. The results suggest that while WAY100635 acts as a competitive antagonist at alpha(1)-adrenoceptors, MM-77 displays non-competitive antagonist characteristics at this receptor subtype. 6. These results may have important implications for the use of these compounds as 5-HT(1A) receptor antagonists in in vivo studies.

This study examines the activity of hippocampal CA, pyramidal neurons during conditioned fear stress (CFS)-induced freezing behavior in unanesthetized, unrestrained rats. The firing frequency of hippocampal CA1 pyramidal neurons was significantly decreased when conditioned rats exhibited freezing behavior. Firing frequency returned to the baseline after freezing behavior disappeared. The selective 5-hydroxytryptamine (5-HT)1A antagonists, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY-100635), and N-tert-butyl-3-[4-(2-methoxyphenyl)piperazine-1-yl]-2-phenylpropamide (WAY-100135) and 5-HT depletion with parachlorophenylalanine (PCPA) completely abolished the decrease in firing frequency during CFS-induced freezing behavior. These results suggested that endogenous 5-HT inhibited the firing activity of hippocampal CA1 pyramidal neurons during CFS-induced freezing behavior mainly through stimulating 5-HT1A receptors.

Accumulating data have been published emphasizing the important role of 5-hydroxytryptamine (5-HT) receptors in proximal stomach relaxation. However, a proper in vivo characterization of 5-HT receptors mediating gastric relaxation is still missing. In the current study, we focus on the in vivo characterization of 5-HT1A receptors mediating relaxation of the proximal stomach in conscious dogs. Beagle dogs were equipped with a gastric fistula. In the conscious state, volume changes within an intragastric bag were measured at constant pressure by means of a barostat. Results are presented as the maximum volume increase after treatment (mean+/-s.e.m.). All drugs were injected intravenously. The 5-HT1A receptor agonist flesinoxan (10, 50, 100 and 150 microg kg-1) induced a dose-dependent relaxation of the canine proximal stomach (50+/-10, 230+/-51, 290+/-38 and 275+/-33 ml, respectively; n=9-11). The selective 5-HT1A receptor antagonist WAY-100635 dose-dependently inhibited the flesinoxan-induced relaxation. NG-nitro-l-arginine methyl ester did not affect this relaxation, suggesting that nitrergic nerves are not involved. After supradiaphragmatic vagotomy, the baseline of the intragastric volume was larger compared to that before vagotomy (317+/-50 vs 142+/-28 ml, respectively; n=5). Compensation for this by either reduction of the intraballoon pressure or infusion of a contractile dose of bethanechol did not establish a condition in which flesinoxan was able to relax the stomach. In contrast, nitroprusside induced a significant gastric relaxation when tone was increased by bethanechol. It is concluded that flesinoxan induces proximal gastric relaxation in conscious dogs via 5-HT1A receptors. The response is mediated through a vagal pathway without involvement of nitrergic nerves.

(1) Using in vivo intracerebral microdialysis in conscious, freely moving rats, we examined the effect of flibanserin, a potential antidepressant drug with high affinity for human 5-HT(1A) receptors and four-50-fold lower affinity for 5-HT(2A) and D(4) receptors, on basal extracellular concentrations of serotonin (5-hydroxytryptamine, 5-HT), dopamine (DA) and noradrenaline (NA) in selected regions of the rat brain. (2) Flibanserin at 3 and 10 mg kg(-1) significantly reduced extracellular 5-HT in the prefrontal cortex (by 30 and 45%) and dorsal raphe (35 and 44%), but had no effect on extracellular 5-HT in the ventral hippocampus. The 3 and 10 mg kg(-1) doses raised extracellular NA to a similar extent in the prefrontal cortex (47 and 50%). In all, 10 mg kg(-1) raised extracellular DA in the prefrontal cortex (63%) whereas 3 mg kg(-1) had no significant effect. (3) Pretreatment with the selective 5-HT(1A) receptor antagonist WAY100,635 (0.3 mg kg(-1)) 30 min before 10 mg kg(-1) flibanserin completely antagonized the latter's effects on extracellular 5-HT, DA and NA in the prefrontal cortex. WAY100,635 by itself had no effect on cortical extracellular monoamines. (4) The results show that the stimulation of 5-HT(1A) receptors plays a major role in the effect of flibanserin on brain extracellular 5-HT, DA and NA.

1. Factors influencing agonist affinity and relative efficacy have been studied for the 5-HT(1A) serotonin receptor using membranes of CHO cells expressing the human form of the receptor and a series of R-and S-2-(dipropylamino)tetralins (nonhydroxylated and monohydroxylated (5-OH, 6-OH, 7-OH, 8-OH) species). 2. Ligand binding studies were used to determine dissociation constants for agonist binding to the 5-HT(1A) receptor: (a) K(i) values for agonists were determined in competition versus the binding of the agonist [(3)H]-8-OH DPAT. Competition data were all fitted best by a one-binding site model. (b) K(i) values for agonists were also determined in competition versus the binding of the antagonist [(3)H]-NAD-199. Competition data were all fitted best by a two-binding site model, and agonist affinities for the higher (K(h)) and lower affinity (K(l)) sites were determined. 3. The ability of the agonists to activate the 5-HT(1A) receptor was determined using stimulation of [(35)S]-GTPgammaS binding. Maximal effects of agonists (E(max)) and their potencies (EC(50)) were determined from concentration/response curves for stimulation of [(35)S]-GTPgammaS binding. 4. K(l)/K(h) determined from ligand binding assays correlated with the relative efficacy (relative E(max)) of agonists determined in [(35)S]-GTPgammaS binding assays. There was also a correlation between K(l)/K(h) and K(l)/EC(50) for agonists determined from ligand binding and [(35)S]-GTPgammaS binding assays. 5. Simulations of agonist binding and effect data were performed using the Ternary Complex Model in order to assess the use of K(l)/K(h) for predicting the relative efficacy of agonists.