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Opioids are well-known to cause respiratory depression, but despite clinical evidence of dysphagia, the effects of opioids on swallow excitability and motor pattern are unknown. We tested the effects of the clinically relevant opioid buprenorphine on pharyngeal swallow and respiratory drive in male and female rats. We also evaluated the utility of 5-HT 1A agonists (8-OH-DPAT and buspirone) to improve swallowing and breathing following buprenorphine administration. Experiments were performed on 44 freely breathing Sprague-Dawley rats anesthetized with sodium pentobarbital. Bipolar fine wire electrodes were inserted into the mylohyoid, thyroarytenoid, posterior cricoarytenoid, thyropharyngeus, and diaphragm muscles to measure electromyographic (EMG) activity of swallowing and breathing. We evaluated the hypotheses that swallowing varies by stimulus, opioids depress swallowing and breathing, and that 5-HT 1A agonists improve these depressions. Our results largely confirmed the following hypotheses: 1 ) swallow-related EMG activity was larger during swallows elicited by esophageal distension plus oral water infusion than by either stimulus alone. 2 ) Buprenorphine depressed swallow in both sexes, but females were more susceptible to total swallow suppression. 3 ) Female animals were also more vulnerable to opioid-induced respiratory depression. 4 ) 8-OH-DPAT rescued breathing following buprenorphine-induced respiratory arrest, and pretreatment with the partial 5-HT 1A agonist buspirone prevented buprenorphine-induced respiratory arrest in female animals. 5 ) 8-OH-DPAT enhanced mylohyoid and thyropharyngeus EMG amplitude during swallow but did not restore excitability of the swallow pattern generator following total suppression by buprenorphine. Our results highlight sex-specific and behavior-specific effects of buprenorphine and provide preclinical evidence of a 5HT 1A agonist for the treatment of respiratory depression and dysphagia. NEW & NOTEWORTHY This is the first study, to our knowledge, to evaluate sex-specific effects of opioid administration on pharyngeal swallow. We expand on a small but growing number of studies that report a lower threshold for opioid-induced respiratory depression in females compared with males, and we are the first to produce this effect with the partial μ-opioid-receptor agonist buprenorphine. This is the first demonstration, to our knowledge, that activation of 5-HT 1A receptors can improve swallow and breathing outcomes following systemic buprenorphine administration.

Obsessive-compulsive disorder (OCD) is a neuropsychiatric condition characterized by intrusive, repetitive thoughts and behaviors. Our study uses a validated 8-OH-DPAT-induced experimental model of OCD in rodents. We focus on the modulatory effects of Insulin-like growth factor-1 (IGF-1) and glucagon-like peptide-1 (GLP-1), which are linked to neurodevelopment and survival. Current research investigates melatonin, a molecule with neuroprotective properties and multiple functions. Melatonin has beneficial effects on various illnesses, including Alzheimer's, Parkinson's, and depression, indicating its potential efficacy in treating OCD. In the present study, we employed two doses of melatonin, 5 mg/kg and 10 mg/kg, demonstrating a dose-dependent effect on 8-OH-DPAT-induced rat changes. In addition, the melatonin antagonist luzindole 5 mg/kg was utilized to compare and validate the efficacy of melatonin. In-silico studies alsocontribute to understanding the activation of IGF-1/GLP-1 pathways by melatonin. Current research indicates restoring neurochemical measurements on various biological samples (brain homogenates, CSF, and blood plasma) and morphological and histological analyses. In addition, the current research seeks to increase understanding of OCD and investigate potential new treatment strategies. Therefore, it is evident from the aforementioned research that the protective effect of melatonin can serve as a strong basis for developing a new OCD treatment by upregulating IGF-1 and GLP-1 levels. The primary focus of current study revolves around the examination of melatonin as an activator of IGF-1/GLP-1, with the aim of potentially mitigating behavioral, neurochemical, and histopathological abnormalities in an experimental model of obsessive-compulsive disorder caused by 8-OH-DPAT in adult Wistar rats., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Obsessive-Compulsive disorder (OCD) is a long-term and persistent mental illness characterised by obsessive thoughts and compulsive behaviours. Numerous factors can contribute to the development or progression of OCD. These factors may result from the dysregulation of multiple intrinsic cellular pathways, including SIRT-1, Nrf2, and HO-1. Inhibitors of selective serotonin reuptake (SSRIs) are effective first-line treatments for OCD. In our ongoing research, we have investigated the role of SIRT-1, Nrf2, and HO-1, as well as the neuroprotective potential of Acetyl-11-keto-beta boswellic acid (AKBA) against behavioural and neurochemical changes in rodents treated with 8-OH-DPAT. In addition, the effects of AKBA were compared to those of fluvoxamine (FLX), a standard OCD medication. Injections of 8-OH-DPAT into the intra-dorso raphe nuclei (IDRN) of rats for seven days induced repetitive and compulsive behaviour accompanied by elevated oxidative stress, inflammatory processes, apoptosis, and neurotransmitter imbalances in CSF, blood plasma, and brain samples. Chronic administration of AKBA at 50 mg/kg and 100 mg/kg p.o. restored histopathological alterations in the cortico-striatal-thalamo-cortical (CSTC) pathway, including the cerebral cortex, striatum, and hippocampal regions. Our investigation revealed that when AKBA and fluvoxamine were administered together, the alterations were restored to a greater degree than when administered separately. These findings demonstrate that the neuroprotective effect of AKBA can serve as an effective basis for developing a novel OCD treatment., Competing Interests: Disclosure of potential conflicts of interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Preliminary clinical findings, supported by preclinical studies employing behavioral paradigms such as marble burying, suggest that psilocybin may be effective in treating obsessive-compulsive disorder. However, the receptor mechanisms implicated in the putative anti-obsessional effect are not clear. On this background, we set out to explore (1) the role of serotonin 2A (5-HT2A) and serotonin 1A (5-HT1A) receptors in the effect of psilocybin on marble burying; (2) the effect of staggered versus bolus psilocybin administration and persistence of the effect; (3) the effect of the 5-HT1A partial agonist, buspirone, on marble-burying and the head twitch response (HTR) induced by psilocybin, a rodent correlate of psychedelic effects. Male ICR mice were administered psilocybin 4.4 mg/kg, escitalopram 5 mg/kg, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) 2 mg/kg, M100907 2 mg/kg, buspirone 5 mg/kg, WAY100635 2 mg/kg or combinations, intraperitoneally, and were tested on the marble burying test. HTR was examined in a magnetometer-based assay. The results show that (1) Psilocybin and escitalopram significantly reduced marble burying. The effect of psilocybin was not attenuated by the 5-HT2A antagonist, M100907. The 5-HT1A agonist, 8-OH-DPAT, reduced marble burying as did the 5-HT1A partial agonist, buspirone. The effect of 8-OH-DPAT was additive to that of psilocybin, but that of buspirone was not. The 5-HT1A antagonist, WAY100635, attenuated the effect of 8-OH-DPAT and buspirone but not the effect of psilocybin. (2) Psilocybin injections over 3.5 h had no effect on marble burying and the effect of bolus injection was not persistent. (3) Co-administration of buspirone with psilocybin blocked its effect on HTR. These data suggest that neither 5-HT2A nor 5-HT1A receptors are pivotally implicated in the effect of psilocybin on marble burying. Co-administration with buspirone may block the psychedelic effects of psilocybin without impeding its anti-obsessional effects., (© 2023. The Author(s).)

Psoriasis pain is a common symptom underestimated and rarely evaluated in psoriasis clinical trials. This work aimed to investigate whether the development of secondary chronic allodynia and hyperalgesia in the imiquimod (IMQ)-induced psoriasis mice model could be modulated by anti-inflammatory agents and compound 48/80 (C48/80) and to determine whether the activation of 5-HT 1A receptor modulates these nociceptive behaviours. C57BL/6 male mice were treated with 5% IMQ for 7 days. The paw withdrawal responses to von Frey filaments (10 and 250 mN) were used to assess the allodynia and hyperalgesia. Nociceptive behaviours were also evaluated using ketorolac 15 mg/kg s.c., adalimumab 10 mg/kg s.c. and C48/80 10 mg/kg i.p. Then, the serum serotonin and the impact of 8-OH-DPAT (1 mg/kg s.c), a 5-HT 1A receptor agonist, on long-lasting pain were examined. Mice receiving IMQ showed enhanced nociception, which decreased with all tested compounds. The serum serotonin in the IMQ group showed a significant decrease (947.042 ng/ml) regarding the control group (1143.68 ng/ml). The pretreatment with 8-OH-DPAT alleviated pain-related behaviours. These results suggest that the long-lasting pain resulting from psoriasis inflammation is also associated with the serotonergic system. The 5-HT1A receptor should be further explored as a potential therapeutic target for psoriasis pain modulation., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

When placed in an unfamiliar and brightly lit open-field, two adult male rats that have not previously interacted display a low level of social interaction (SI) attributed to an anxiety-like state. The SI test has therefore been used to explore anxiolytic/antistress activity. Here, we investigated the effects of serotonin 5-HT 1A receptor agonists displaying various activity profiles, i.e. partial vs full agonist efficacy and pre- versus postsynaptic 5-HT 1A receptor preferential activation by "biased agonists". Adult male Sprague-Dawley rats were housed singly before starting the social interaction session. At 30 min before being placed in an open-field, both rats of the dyad were injected (i.p or s.c.) with either vehicle, diazepam (as a reference compound), or one of six 5-HT 1A receptor agonists: NLX-101 (a.k.a. F15599), F13714, S15535, flesinoxan, 8-OH-DPAT, and buspirone. Time spent in SI (following, sniffing, playing) was recorded for 10 min. Time spent in SI was inversely correlated with light intensity, with values dropping nearly by half (212.6 ± 18.8 vs 113.7 ± 7.0 s) between 10 and 300 lx (measured at floor level). Under the high light intensity conditions (300 lx), diazepam showed a bell-shaped curve, significantly increasing SI (78% increase in interaction time above control) at 1 mg/kg i.p. only. In the case of 5-HT 1A receptor ligands, full agonists, whether nonpreferential (flesinoxan, (±)8-OH-DPAT) or preferential for presynaptic receptors (F13714), showed the strongest activity in this model. The preferential presynaptic receptor partial agonist, S15535, was also active over a wide dose-range, although with lower efficacy than F13714. In contrast, NLX-101, a high-efficacy biased agonist that preferentially activates postsynaptic 5-HT 1A receptors, exhibited little activity. The clinical anxiolytic, buspirone, showed a marked effect likely due to its partial agonist activity at 5-HT 1A presynaptic receptors. These data support the hypothesis that enhancement of SI in this model is mediated by preferential agonist activation of presynaptic 5-HT 1A receptors, and confirm previous studies using local microinjections of (±)8-OH-DPAT. They further support the utility of noninvasive administration of biased agonists for exploring the activity of 5-HT 1A receptor subpopulations.

Deep brain stimulation (DBS) is known to be a promising treatment for resistant depression, which acts via the serotonin (5-hydroxytryptamine, 5-HT) system in the infralimbic prefrontal cortex (ILPFC). Previous study revealed that dysfunction of brain 5-HT homeostasis is related to a valproate (VPA)-induced rat autism spectrum disorder (ASD) model. Whether ILPFC DBS rescues deficits in VPA-induced offspring through the 5-HT system is not known. Using VPA-induced offspring, we therefore explored the effect of DBS in autistic phenotypes and further investigated the underlying mechanism. Using combined behavioral and molecular approaches, we observed that applying DBS and 5-HT 1A receptor agonist treatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) reversed sociability deficits, anxiety and hyperactivity in the VPA-exposed offspring. We then administered the selective 5-HT 1A receptor antagonist N -[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]- N -2-pyridinylcyclohexanecarboxamide maleate (WAY 100635), following which the effect of DBS in terms of improving autistic behaviors was blocked in the VPA-exposed offspring. Furthermore, we found that both 8-OH-DPAT and DBS treatment rescued autistic behaviors by decreasing the expressions of NR2B subunit of N -methyl- D -aspartate receptors (NMDARs) and the β₃ subunit of γ-aminobutyric acid type A receptors (GABA A R) in the PFC region. These results provided the first evidence of characteristic behavioral changes in VPA-induced offspring caused by DBS via the 5-HT system in the ILPFC.

This study was designed to examine an anxiety-like behavior in the adult gonadectomized (GDX) male rats subjected to testosterone propionate (TP) treatment alone or in combination with 8-OH-DPAT, a 5-HT 1A receptor agonist, or with NAN-190, 5-HT 1A receptor antagonist. Two weeks after gonadectomy, GDX rats were subjected by treatments with the solvent, TP (0.5mg/kg, s.c.), 8-OH-DPAT (0.05mg/kg, s.c.), NAN-190 (0.1mg/kg, i.p.), TP in combination with 8-OH-DPAT or NAN-190 during 14days. Anxiety behavior was assessed in the elevated plus maze (EPM) and the open field test (OFT). 8-OH-DPAT treatment failed to modify the anxiety-like behavior of GDX rats in the EPM as compared to the GDX rats given with oil solvent. NAN-190 injected alone or in combination with TP to GDX rats resulted in a significant anxiolytic-like effect as compared to the GDX given with oil solvent or TP application. Our data indicate that the combination of NAN-190 and TP is more effective than TP alone in GDX rats inducing a more profound anxiolytic-like effect in the EPM. Thus, the results of this study suggest that effects of 5-HT 1A receptor agonist/antagonist can modify anxiety level in opposite direction in male rats after gonadectomy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We previously demonstrated that nicotine elicited kinetic tremor by elevating the neural activity of the inferior olive via α7 nicotinic acetylcholine (nACh) receptors. Since α7 nACh receptors reportedly facilitate synaptic monoamine release, we explored the role of 5-HT receptors in induction and/or modulation of nicotine tremor. Treatment of mice with nicotine induced kinetic tremor that normally appeared during movement. The 5-HT 1A agonist, 8-hydroxydipropylaminotetraline (8-OH-DPAT), significantly enhanced nicotine-induced tremor and the action of 8-OH-DPAT was antagonized by WAY-100135 (5-HT 1A antagonist). In addition, the cerebral 5-HT depletion by repeated treatment with p-chlorophenylalanine did not reduce, but rather potentiated the facilitatory effects of 8-OH-DPAT. In contrast, the 5-HT 2 agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), significantly attenuated nicotine tremor, which was antagonized by ritanserin (5-HT 2 antagonist). The 5-HT 3 agonist SR-57227 did not affect nicotine-induced tremor. Furthermore, when testing the direct actions of 5-HT antagonists, nicotine tremor was inhibited by WAY-100135, but was unaffected by ritanserin, ondansetron (5-HT 3 antagonist) or SB-258585 (5-HT 6 antagonist). These results suggest that postsynaptic 5-HT 1A receptors are involved in induction of nicotine tremor mediated by α7 nACh receptors. In addition, 5-HT 2 receptors have an inhibitory modulatory role in induction of nicotine tremor., (Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Rationale: Orexin knockout (KO) mice exhibit a phenotype that is similar to human narcolepsy, and monoamine-related compounds, such as psychostimulants and 5-HT uptake inhibitors, have been used for the treatment of narcoleptic disorders. However, little information is available regarding the pathophysiological features of orexin KO mice, particularly with respect to their narcoleptic-like disorder and how it is affected by monoamine-related compounds., Objectives: The present study was designed to investigate both the nature of the neuronal changes in orexin KO mice and the therapeutic effects of monoamine-related compounds on the sleep disorder in orexin KO mice., Results: A decrease in locomotor activity in the dark phase was observed in orexin KO mice, and psychostimulants and 5-HT-related compounds, such as 8-OH-DPAT (5-HT1A receptor agonist) and DOI (5-HT2 receptor agonist), inhibited this hypolocomotion. We also found that 5-HT1A receptor mRNA levels, but not those for 5-HT2 or dopamine receptors, were significantly decreased in the prefrontal cortex of orexin KO mice in the dark period and were accompanied by compromising the increase in 5-HT metabolite levels. In addition, the sleep disorder in orexin KO mice, as analyzed by a polysomnography during the dark period, was completely normalized by 8-OH-DPAT., Conclusion: These results suggest that a dysfunction of 5-HT1A receptors is involved in the narcoleptic-like sleep dysfunction in orexin KO mice, and such dysfunction may participate in orexin deficiency-induced sleep disorders. Further, the use of 5-HT1A receptor agonist could be useful for treating the sleep disorder under a deficiency of orexin.

The current study assessed whether antidepressant and/or antinociceptive drugs, duloxetine, fluoxetine as well as (±)-8-hydroxy-2-[di-n-propylamino] tetralin (8-OH-DPAT), are able to reverse depression-like behaviour in animals with chronic neuropathic pain. Chronic constriction injury (CCI) of the sciatic nerve in rats was selected as neuropathic pain model. Mechanical hypersensitivity and depression-like behaviour were evaluated 4 weeks after surgery by "electronic algometer" and forced swimming test (FST), which measured the time of immobility, and active behaviours climbing and swimming. The selective noradrenergic and serotonergic uptake blocker duloxetine (20mg/kg) and the selective 5-HT1A agonist 8-OH-DPAT (0.5mg/kg) significantly reversed both mechanical hypersensitivity and depression-like behaviour in CCI animals. Duloxetine significantly reversed depression-like behaviour in CCI rats by increasing the time of climbing and swimming, while 8-OH-DPAT attenuated depression-like behaviour mainly by increasing the time of swimming. However, the selective serotonergic uptake blocker fluoxetine (20mg/kg) failed to attenuate mechanical hypersensitivity and depression-like behaviour, possibly due to confounding pro-nociceptive actions at 5-HT3 receptors. These data suggest to target noradrenergic and 5-HT1A receptors for treatment of chronic pain and its comorbidity depression., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Chronic oxidative stress contributes to age related diseases including age related macular degeneration (AMD). Earlier work showed that the 5-hydroxy-tryptamine 1a (5HT1a) receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) protects retinal pigment epithelium (RPE) cells from hydrogen peroxide treatment and mouse retinas from oxidative insults including light injury. In our current experiments, RPE derived cells subjected to mitochondrial oxidative stress were protected from cell death by the up-regulation of anti-oxidant enzymes and of the metal ion chaperone metallothionein. Differentiated RPE cells were resistant to oxidative stress, and the expression of genes for protective proteins was highly increased by oxidative stress plus drug treatment. In mice treated with 8-OH-DPAT, the same genes (MT1, HO1, NqO1, Cat, Sod1) were induced in the neural retina, but the drug did not affect the expression of Sod2, the gene for manganese superoxide dismutase. We used a mouse strain deleted for Sod2 in the RPE to accelerate age-related oxidative stress in the retina and to test the impact of 8-OH-DPAT on the photoreceptor and RPE degeneration developed in these mice. Treatment of mice with daily injections of the drug led to increased electroretinogram (ERG) amplitudes in dark-adapted mice and to a slight improvement in visual acuity. Most strikingly, in mice treated with a high dose of the drug (5 mg/kg) the structure of the RPE and Bruch's membrane and the normal architecture of photoreceptor outer segments were preserved. These results suggest that systemic treatment with this class of drugs may be useful in preventing geographic atrophy, the advanced form of dry AMD, which is characterized by RPE degeneration., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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.)

There is considerable evidence from research in neonatal and adult rat and mouse preparations to warrant the conclusion that activation of 5-HT2 and 5-HT1A/7 receptors leads to activation of the spinal cord circuitry for locomotion. These receptors are involved in control of locomotor movements, but it is not clear how they are implicated in the responses to 5-HT agonists observed after spinal cord injury. Here we used agonists that are efficient in promoting locomotor recovery in paraplegic rats, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OHDPAT) (acting on 5-HT1A/7 receptors) and quipazine (acting on 5-HT2 receptors), to examine this issue. Analysis of intra- and interlimb coordination confirmed that the locomotor performance was significantly improved by either drug, but the data revealed marked differences in their mode of action. Interlimb coordination was significantly better after 8-OHDPAT application, and the activity of the extensor soleus muscle was significantly longer during the stance phase of locomotor movements enhanced by quipazine. Our results show that activation of both receptors facilitates locomotion, but their effects are likely exerted on different populations of spinal neurons. Activation of 5-HT2 receptors facilitates the output stage of the locomotor system, in part by directly activating motoneurons, and also through activation of interneurons of the locomotor central pattern generator (CPG). Activation of 5-HT7/1A receptors facilitates the activity of the locomotor CPG, without direct actions on the output components of the locomotor system, including motoneurons. Although our findings show that the combined use of these two drugs results in production of well-coordinated weight supported locomotion with a reduced need for exteroceptive stimulation, they also indicate that there might be some limitations to the utility of combined treatment. Sensory feedback and some intraspinal circuitry recruited by the drugs can conflict with the locomotor activation.

In the present study, we describe how a nonstoichiometric ratio of the isomers of 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT) produce a broad-spectrum of antiemetic effects in cats and shrews. Determination of the receptor profile of the isomers and testing them separately in cats revealed superior antiemetic effects but severe defensive behavior with the R isomer compared with the S isomer. Differing ratios yielded the best results with the 1:8 (R-S) ratio producing a drug more potent than DPAT and with negligible defensive behavior side effects. Studies with selective 5-HT1D ligands led to the conclusion that this site contributes antiemetic efficacy but is not related to defensive behavior, which is most likely a consequence of 5-HT7 receptor activation. ETI-385 was effective in preventing emetic responses to provocative motion, drugs acting at the chemical trigger zone and cisplatin in both cats and shrews. The results support a clinical trial of this drug for antiemetic effects.

In the present study, we examined the effect of ACTH on the immobilization of rats in the forced swim test and hippocampal cell proliferation after administration of the 5-HT1A receptor agonist, R-(+)-8-hydroxy-2-di-n-propylamino tetralin ((+)-8-OH-DPAT). Chronic treatment with (+)-8-OH-DPAT (0.01-0.1 mg/kg, s.c.) significantly decreased the duration of immobility in saline- and ACTH-treated rats. Chronic administration of ACTH caused a significant decrease in hippocampal cell proliferation. However, (+)-8-OH-DPAT significantly normalized cell proliferation in ACTH-treated rats. We then investigated the effects of (+)-8-OH-DPAT on the expression of brain-derived neurotrophic factor (BDNF) and cyclin D1 (elements of cyclic adenosine monophosphate response element-binding protein (CREB)-BDNF and Wnt signaling pathways, respectively) in the hippocampus of saline- and ACTH-treated rats. ACTH treatment significantly decreased the expression of cyclin D1, while treatment with (+)-8-OH-DPAT normalized the expression of cyclin D1 in ACTH-treated rats. However, the expression of BDNF did not change in either saline- or ACTH-treated rats. These findings suggest that the antidepressant effects of (+)-8-OH-DPAT in treatment-resistant animals may be attributed to an enhancement of hippocampal cell proliferation, at least in part due to an enhancement of cyclin D1 expression., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Haemorrhagic shock is a life threatening condition, and, as such, it is important to understand the mechanisms taking part in its reversal. In the 1990s, it was shown that activation of serotonin 1A receptors is responsible for the circulatory decompensation and development of the sympathoinhibitory phase. In previous reports, it was demonstrated that activation of serotonin 1A receptors induces resuscitative effects in haemorrhaged rats. However, the effectory mechanisms still require further investigation. The aim of the present study was to determine whether the sympathetic nervous system participates in the effects of serotonin through central serotonin 1A receptors in haemorrhagic shock in rats. In order to determine the role of the sympathetic nervous system alpha-1-, alpha-2-, and beta-adrenergic receptor agonists - prazosin, yohimbine and propranolol, respectively, were used. We found that stimulation of the central serotonin 1A receptors by the administration of a selective agonist - 8-hydroxy-2-(di-n-propylamino)tetralin, 1-(2,5-dimethoxy-4-iodophenyl)-aminopropane (8-OH-DPAT) into the lateral brain ventricle is connected with the activation of compensation mechanisms leading to the increase in the heart rate and blood pressure. The current results demonstrate that the stimulation of peripheral alpha-1-, alpha-2- and beta-adrenergic receptors plays an essential role in the resuscitative effect triggered by the stimulation of central serotonin 1A receptors., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Previous studies have shown that depressed patients as well as animal models of depression exhibit decreased sensitivity to evoked pain stimuli, and serotonin is indicated to be involved in depression-induced hypoalgesia. The purpose of this study was to investigate the potential role of 5-HT1A receptor in the depression-induced hypoalgesia. Acute or chronic administration of 5-HT1A receptor agonist, 8-OH-DPAT, was performed in olfactory bulbectomy (OB) and sham-operated rats. The depression-like behavior and pain thresholds were measured using open-field test and radiant heat thermal pain test, respectively. We found that acute administration of 8-OH-DPAT increased locomotor activity and pain thresholds in the sham rats but had no effect on the OB rats. In contrast, chronic administration of 8-OH-DPAT reduced locomotor activity and pain thresholds and restored them to normal level. Increased pain thresholds were also observed in the sham rats after the chronic administration. These results demonstrated that chronic administration of 8-OH-DPAT reversed the depression-induced decrease in pain sensitivity in rats, suggesting that 5-HT1A receptor may play a role in the depression-associated hypoalgesia.

Poisoning by organophosphate nerve agents can induce seizures which rapidly become refractory to treatment and result in brain damage. Current therapies have only a narrow time frame for effective administration after poisoning. 5-HT1A agonists were tested for efficacy in mice against a seizure-producing combination of the carboxylesterase inhibitor 2-(o-cresyl)-4H-1:3:2-benzodioxaphosphorin-2-oxide (CBDP) and sarin, producing an LD20-40. Administration of the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) decreased glial fibrillary acidic protein (GFAP) staining in mice when administered 1min after CBDP and sarin while other 5-HT1A agonists buspirone and S-14506 were not effective. The reduction in GFAP staining by 8-OH-DPAT remained significant when a single dose was administered 2h after the toxic challenge. In addition, 8-OH-DPAT reversed the increase in the inflammatory factor IL-1β in the dentate gyrus and amygdala but did not reduce positive TUNEL staining in the dentate gyrus. Due to the failure of the two other agonists to provide protection, the 5-HT1A antagonist WAY-100635 was tested. WAY-100635 was found to neither reverse the neuroprotective effects of 8-OH-DPAT nor worsen the damage when given alone, making a role for this receptor unlikely. The neuroprotective effects of 8-OH-DPAT appear to lie within its secondary pharmacology., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Cortical reorganization plays a significant role in recovery of function after injury of the central nervous system. The neural mechanisms that underlie this reorganization may be the same as those normally responsible for skilled behaviors that accompany extended sensory experience and, if better understood, could provide a basis for further promoting recovery of function after injury. The work presented here extends studies of spontaneous cortical reorganization after spinal cord injury to the role of rehabilitative strategies on cortical reorganization. We use a complete spinal transection model to focus on cortical reorganization in response to serotonergic (5-HT) pharmacotherapy without any confounding effects from spared fibers left after partial lesions. 5-HT pharmacotherapy has previously been shown to improve behavioral outcome after SCI but the effect on cortical organization is unknown. After a complete spinal transection in the adult rat, 5-HT pharmacotherapy produced more reorganization in the sensorimotor cortex than would be expected by transection alone. This reorganization was dose dependent, extended into intact (forelimb) motor cortex, and, at least in the hindlimb sensorimotor cortex, followed a somatotopic arrangement. Animals with the greatest behavioral outcome showed the greatest extent of cortical reorganization suggesting that the reorganization is likely to be in response to both direct effects of 5-HT on cortical circuits and indirect effects in response to the behavioral improvement below the level of the lesion., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Trauma to the thoracolumbar spine commonly results in injuries to the cauda equina and the lumbosacral portion of the spinal cord. Both complete and partial injury syndromes may follow. Here, we tested the hypothesis that serotonergic modulation may improve voiding function after an incomplete cauda equina/conus medullaris injury. For this purpose, we used a unilateral L5-S2 ventral root avulsion (VRA) injury model in the rat to mimic a partial lesion to the cauda equina and conus medullaris. Compared to a sham-operated series, comprehensive urodynamic studies demonstrated a markedly reduced voiding efficiency at 12 weeks after the VRA injury. Detailed cystometrogram studies showed injury-induced decreased peak bladder pressures indicative of reduced contractile properties. Concurrent external urethral sphincter (EUS) electromyography demonstrated shortened burst and prolonged silent periods associated with the elimination phase. Next, a 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), was administered intravenously at 12 weeks after the unilateral L5-S2 VRA injury. Both voiding efficiency and maximum intravesical pressure were significantly improved by 8-OH-DPAT (0.3-1.0 mg/kg). 8-OH-DPAT also enhanced the amplitude of EUS tonic and bursting activity as well as duration of EUS bursting and silent period during EUS bursting. The results indicate that 8-OH-DPAT improves voiding efficiency and enhances EUS bursting in rats with unilateral VRA injury. We conclude that serotonergic modulation of the 5-HT(1A) receptor may represent a new strategy to improve lower urinary tract function after incomplete cauda equina/conus medullaris injuries in experimental studies., (Copyright © 2012. Published by Elsevier Inc.)

Intravenous bolus injection of morphine causes a vagal-mediated brief apnea (∼3 s), while continuous injection, via action upon central μ-opioid receptor (MOR), arrests ventilation (>20 s) that is eliminated by stimulating central 5-hydroxytryptamine 1A receptors (5HT(1A)Rs). Bronchopulmonary C-fibers (PCFs) are essential for triggering a brief apnea, and their afferents terminate at the caudomedial region of the nucleus tractus solitarius (mNTS) that densely expresses 5HT(1A)Rs. Thus we asked whether the vagal-mediated apneic response to MOR agonists was PCF dependent, and if so, whether this apnea was abolished by systemic administration of 8-hydroxy-2-(di-n-propylamino)tetral (8-OH-DPAT) largely through action upon mNTS 5HT(1A)Rs. Right atrial bolus injection of fentanyl (5.0 μg/kg, a MOR agonist) was performed in the anesthetized and spontaneously breathing rats before and after: 1) selective blockade of PCFs' conduction and subsequent bivagotomy; 2) intravenous administration of 5HT(1A)R agonist 8-OH-DPAT; 3) intra-mNTS injection of 8-OH-DPAT; and 4) intra-mNTS injection of 5HT(1A)R antagonist WAY-100635 followed by 8-OH-DPAT (iv). We found the following: First, fentanyl evoked an immediate apnea (2.5 ± 0.4 s, ∼6-fold longer than the baseline expiratory duration, T(E)), which was abolished by either blocking PCFs' conduction or bivagotomy. Second, this apnea was prevented by systemic 8-OH-DPAT challenge. Third, intra-mNTS injection of 8-OH-DPAT greatly attenuated the apnea by 64%. Finally, intra-mNTS microinjection of WAY-100635 significantly attenuated (58%) the apneic blockade by 8-OH-DPAT (iv). We conclude that the vagal-mediated apneic response to MOR activation depends on PCFs, which is fully antagonized by systemic 8-OH-DPAT challenge largely via acting on mNTS 5HT(1A)Rs.

Rationale: Existing animal models of impulsivity frequently use food restriction to increase subjects' motivation. In addition, behavioral tasks that assess impulsive choice typically involve the use of reinforcers with dissimilar caloric content. These factors represent energy-homeostasis limitations, which may confound the interpretation of results and limit the applicability of these models., Objectives: This study was aimed at validating face and convergent validities of a modified adjusting delay task, which assesses impulsive choice between isocaloric reinforcers in ad libitum fed rats., Methods: Male Wistar rats (n = 18) were used to assess the preferredness and reinforcing efficacy of a "supersaccharin" solution (1.5% glucose/0.4% saccharin) over a 1.5% glucose solution. A separate group of rats (n = 24) was trained in a modified adjusting delay task, which involved repeated choice between the glucose solution delivered immediately and the supersaccharin solution delivered after a variable delay. To pharmacologically validate the task, the effects of the 5-HT(2A/C) receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(±)-DOI] and the 5-HT(1A) receptor agonist (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide [(±)-8-OH-DPAT] on impulsive choice were then evaluated., Results: Supersaccharin was highly reinforcing and uniformly preferred over the glucose solution by all subjects. Rats quickly learned the task, and impulsivity was a very stable and consistent trait. DOI and 8-OH-DPAT significantly and dose dependently increased impulsive choice in this modified adjusting delay task., Conclusions: We validated a rodent task of impulsive choice, which eliminates typical energy-homeostasis limitations and, therefore, opens new avenues in the study of impulsivity in preclinical feeding and obesity research.

While serotonin 5-HT1A receptor (5-HT1AR) agonists reduce L-DOPA-induced dyskinesias (LID) by normalizing activity in the basal ganglia neurocircuitry, recent evidence suggests putative 5-HT1AR within the primary motor cortex (M1) may also contribute. To better characterize this possible mechanism, c-fos immunohistochemistry was first used to determine the effects of systemic administration of the full 5-HT1AR agonist ±8-OH-DPAT on L-Dopa-induced immediate early gene expression within M1 and the prefrontal cortex (PFC) of rats with unilateral medial forebrain bundle (MFB) dopamine (DA) lesions. Next, in order to determine if direct stimulation of 5-HT1AR within M1 attenuates the onset of LID, rats with MFB lesions were tested for L-Dopa-induced abnormal involuntary movements (AIMs) and rotations following M1 microinfusions of ±8-OH-DPAT with or without coadministration of the 5-HT1AR antagonist WAY100635. Finally, ±8-OH-DPAT was infused into M1 at peak dyskinesia to determine if 5-HT1AR stimulation attenuates established L-Dopa-induced AIMs and rotations. While no treatment effects were seen within the PFC, systemic ±8-OH-DPAT suppressed L-Dopa-induced c-fos within M1. Intra-M1 5-HT1AR stimulation diminished the onset of AIMs and this effect was reversed by WAY100635 indicating receptor specific effects. Finally, continuous infusion of ±8-OH-DPAT into M1 at peak dyskinesia alleviated L-Dopa-induced AIMs. Collectively, these findings support an integral role for M1 in LID and its modulation by local 5-HT1AR., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The Japanese Suncus murinus, the house musk shrew, is a small insectivore commonly used in emetic research. The Guamanian S. murinus has not had extensive testing as an emetic model, but it is readily available for use in emetic experiments in the United States, unlike the Japanese Suncus. This study determined that Guamanian S. murinus is an acceptable model for emesis research and its differences from the Japanese strain were examined. Motion and nicotine were used as emetic stimuli and comparable doses of 8-OH-DPAT were used to compare emetic susceptibility to the Japanese strain. The Guamanian strain had decreased susceptibility to motion and increased susceptibility to nicotine as compared to the Japanese, as well as increased sensitivity to 8-OH-DPAT, with lower doses of the recovery drug eliminating retching episodes. The study also determined that Guamanian S. murinus are smaller and more aggressive than the Japanese strain, but just as effective as a model for emetic research., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Cervical incomplete spinal cord injuries often lead to severe and persistent impairments of sensorimotor functions and are clinically the most frequent type of spinal cord injury. Understanding the motor impairments and the possible functional recovery of upper and lower extremities is of great importance. Animal models investigating motor dysfunction following cervical spinal cord injury are rare. We analysed the differential spontaneous recovery of fore- and hindlimb locomotion by detailed kinematic analysis in adult rats with unilateral C4/C5 hemisection, a lesion that leads to the Brown-Séquard syndrome in humans. The results showed disproportionately better performance of hindlimb compared with forelimb locomotion; hindlimb locomotion showed substantial recovery, whereas the ipsilesional forelimb remained in a very poor functional state. Such a differential motor recovery pattern is also known to occur in monkeys and in humans after similar spinal cord lesions. On the lesioned side, cortico-, rubro-, vestibulo- and reticulospinal tracts and the important modulatory serotonergic, dopaminergic and noradrenergic fibre systems were interrupted by the lesion. In an attempt to facilitate locomotion, different monoaminergic agonists were injected intrathecally. Injections of specific serotonergic and noradrenergic agonists in the chronic phase after the spinal cord lesion revealed remarkable, although mostly functionally negative, modulations of particular parameters of hindlimb locomotion. In contrast, forelimb locomotion was mostly unresponsive to these agonists. These results, therefore, show fundamental differences between fore- and hindlimb spinal motor circuitries and their functional dependence on remaining descending inputs and exogenous spinal excitation. Understanding these differences may help to develop future therapeutic strategies to improve upper and lower limb function in patients with incomplete cervical spinal cord injuries.

Although serotonergic agents have been used to treat patients with stress urinary incontinence, the characteristics of the external urethral sphincter (EUS) activity activated by 5-HT receptors have not been extensively studied. This study examined the effects of the 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), on the EUS-electromyography and resistance of the urethra in a rat model with bilateral pudendal nerve injury (BPNI). Two measurements were utilized to assess the effects of the drug on bladder and urethral functions: the simultaneous recordings of transvesical pressure under isovolumetric conditions [isovolumetric intravesical pressure (IVP)] and urethral perfusion pressure, and the simultaneous recordings of IVP during continuously isotonic transvesical infusion with an open urethra (isotonic IVP) and EUS-electromyography. This study also evaluated the urethral continence using leak point pressure testing. The urethral perfusion pressure and leak point pressure measurements of BPNI rats reveal that 8-OH-DPAT significantly increased urethral resistance during the bladder storage phase, yet decreased resistance during the voiding phase. The entire EUS burst period was significantly prolonged, within which the average silent period increased and the frequency of burst discharges decreased. 8-OH-DPAT also improved the voiding efficiency, as evidenced by the detection of decreases in the contraction amplitude and residual volume, with increases in contraction duration and voided volume. These findings suggest that 8-OH-DPAT not only improved continence function, but also elevated the voiding function in a BPNI rat model.

When provided individually, both the serotonin (5-HT(1A))-receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and environmental enrichment (EE) enhance behavioral outcome and reduce histopathology after experimental traumatic brain injury (TBI). The aim of this study was to determine whether combining these therapies would yield greater benefit than either used alone. Anesthetized adult male rats received a cortical impact or sham injury and then were randomly assigned to enriched or standard (STD) housing, where either 8-OH-DPAT (0.1 mg/kg) or vehicle (1.0 mL/kg) was administered intraperitoneally once daily for 3 weeks. Motor and cognitive assessments were conducted on post-injury days 1-5 and 14-19, respectively. CA1/CA3 neurons and choline acetyltransferase-positive (ChAT(+)) medial septal cells were quantified at 3 weeks. 8-OH-DPAT and EE attenuated CA3 and ChAT(+) cell loss. Both therapies also enhanced motor recovery, acquisition of spatial learning, and memory retention, as verified by reduced times to traverse the beam and to locate an escape platform in the water maze, and a greater percentage of time spent searching in the target quadrant during a probe trial in the TBI + STD + 8-OH-DPAT, TBI + EE + 8-OH-DPAT, and TBI + EE + vehicle groups versus the TBI + STD + vehicle group (p ≤ 0.0016). No statistical distinctions were revealed between the TBI + EE + 8-OH-DPAT and TBI + EE + vehicle groups in functional outcome or CA1/CA3 cell survival, but there were significantly more ChAT(+) cells in the former (p = 0.003). These data suggest that a combined therapeutic regimen of 8-OH-DPAT and EE reduces TBI-induced ChAT(+) cell loss, but does not enhance hippocampal cell survival or neurobehavioral performance beyond that of either treatment alone. The findings underscore the complexity of combinational therapies and of elucidating potential targets for TBI.

Receptors for 5-HT(1A) are widely distributed throughout the basal ganglia, and their activation results in an inhibition of dopamine (DA) release. This study aimed to investigate the effect of buspirone, as a partial agonist of 5-HT(1A) receptors, on 6-hydroxydopamine (6-OHDA)-induced catalepsy in male Wistar rats. Catalepsy was induced by unilateral infusion of 6-OH-DA (6 microg/2 microl/rat) into the central region of the substantia nigra pars compacta (SNc) and assayed by the bar-test method 60, 120 and 180 min after drug administration. The results demonstrated that intraperitoneal (ip) injection of buspirone at doses of 5, 7.5 and 10 mg/kg decreased catalepsy compared with the control group. In addition, intra-SNc injection of 8-hydroxy-2-[di-n-propylamino]tetralin (8-OH-DPAT; 10 microg/rat), a 5-HT(1A) receptor agonist, decreased 6-OHDA-induced catalepsy. The effects of buspirone (7.5 mg/kg, ip) and 8-OH-DPAT (10 microg/rat, intra-SNc) were abolished by 1-(2-methoxyphenyl)-4-[4-(2-phthalimido) butyl]piperazine hydrobromide (NAN-190; 10 microg/rat, intra-SNc), a 5-HT(1A) receptor antagonist. Our study indicates that buspirone improves catalepsy in a 6-OHDA-induced animal model of Parkinson's disease through activation of nigral 5-HT(1A) receptors. However, further investigations should be undertaken to clarify the exact mechanism of interaction between 5-HT(1A) and DA receptors.

After complete spinal cord transections that removed all supraspinal inputs in adult rats, combinations of serotonergic agonists and epidural electrical stimulation were able to acutely transform spinal networks from nonfunctional to highly functional and adaptive states as early as 1 week after injury. Using kinematics, physiological and anatomical analyses, we found that these interventions could recruit specific populations of spinal circuits, refine their control via sensory input and functionally remodel these locomotor pathways when combined with training. The emergence of these new functional states enabled full weight-bearing treadmill locomotion in paralyzed rats that was almost indistinguishable from voluntary stepping. We propose that, in the absence of supraspinal input, spinal locomotion can emerge from a combination of central pattern-generating capability and the ability of these spinal circuits to use sensory afferent input to control stepping. These findings provide a strategy by which individuals with spinal cord injuries could regain substantial levels of motor control.

Rationale: The effect of manipulation of the serotonin (5-HT) system on conditioned gaping (presumably reflective of nausea in rats) was evaluated., Objective: The potential of the selective serotonin reuptake inhibitor (SSRI), fluoxetine (which produces nausea in the clinic), to produce conditioned gaping in rats and of the 5-HT(3) antagonists (ondansetron and palonosetron) and the 5-HT(1A) autoreceptor agonist (8-OH-DPAT) to reverse this effect were evaluated., Materials and Methods: In each of four experiments, rats received three pairings of intraorally delivered 17% sucrose solution and fluoxetine (0, 2, 10 or 20 mg/kg) and 72 h later were given a drug-free test trial. In experiment 2, rats were pretreated with the 5-HT(3) antagonists, ondansetron (0, 0.1 or 1.0 mg/kg) or the longer acting palonosetron (0.1 mg/kg), 30 min before each of three sucrose-fluoxetine (20 mg/kg) pairings. In experiment 3, rats were injected with palonosetron (0.1 mg/kg) 2 h before each of three sucrose-fluoxetine (20 mg/kg) or sucrose-lithium chloride (LiCl, 25 mg/kg) pairings. In experiment 4, rats were pretreated with the 5-HT(1A) autoreceptor agonist, 8-OH-DPAT (DPAT, 0.1 mg/kg) 30 min before each of three sucrose-fluoxetine (20 mg/kg) pairings., Results: After two sucrose-fluoxetine pairings, the highest dose of fluoxetine tested (20 mg/kg) produced conditioned gaping reactions. These conditioned gaping reactions were prevented by pretreatment with DPAT, but not with the 5-HT(3) antagonists. On the other hand, palonosetron administered 2 h prior to sucrose-LiCl pairings attenuated conditioned gaping reactions., Conclusions: These results suggest that the conditioned nausea produced by SSRIs, but not LiCl, may be resistant to treatment with 5-HT(3) antagonists, but not 5-HT(1A) autoreceptor agonists.

An early (i.e., 15min) single systemic administration of the 5-HT(1A) receptor agonist 8-OH-DPAT enhances behavioral recovery after experimental traumatic brain injury (TBI). However, acute administration of pharmacotherapies after TBI may be clinically challenging and thus the present study sought to investigate the potential efficacy of a delayed and chronic 8-OH-DPAT treatment regimen. Forty-eight isoflurane-anesthetized adult male rats received either a controlled cortical impact or sham injury and beginning 24h later were administered 8-OH-DPAT (0.1 or 0.5mg/kg) or saline vehicle (1.0mL/kg) intraperitoneally once daily until all behavioral assessments were completed. Neurobehavior was assessed by motor and cognitive tests on post-operative days 1-5 and 14-19, respectively. The lower dose of 8-OH-DPAT (0.1mg/kg) enhanced motor performance, acquisition of spatial learning, and memory retention vs. both the higher dose (0.5mg/kg) and vehicle treatment (p<0.05). These data replicate previous findings from our laboratory showing that 8-OH-DPAT improves neurobehavior after TBI, and extend those results by demonstrating that the benefits can be achieved even when treatment is withheld for 24h. A delayed and chronic treatment regimen may be more clinically feasible.

Appearance of dyskinesia is a common problem of long-term l-DOPA treatment in Parkinson's disease patients and represents a major limitation for the pharmacological management of the motor symptoms in advanced disease stages. We have recently demonstrated that dopamine released from serotonin neurons is responsible for l-DOPA-induced dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats, raising the possibility that blockade of serotonin neuron activity by combination of 5-HT(1A) and 5-HT(1B) agonists could reduce l-DOPA-induced dyskinesia. In the present study, we have investigated the efficacy of 5-HT(1A) and 5-HT(1B) agonists to counteract l-DOPA-induced dyskinesia in 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-treated macaques, the gold standard model of Parkinson's disease. In addition, we have studied the ability of this treatment to prevent development of l-DOPA-induced dyskinesia in 6-OHDA-lesioned rats. The results demonstrate the existence of a potent synergistic effect between 5-HT(1A) and 5-HT(1B) agonists in their ability to dampen l-DOPA-induced dyskinesia in the MPTP-treated macaques. Sub-threshold doses of the drugs, which individually produced no effect, were able to reduce the abnormal involuntary movements by up to 80% when administered in combination, without affecting the anti-parkinsonian properties of l-DOPA. Furthermore, chronic administration of low doses of the 5-HT(1) agonists in combination was able to prevent development of dyskinesia, and reduce the up-regulation of FosB after daily treatment with l-DOPA in the rat 6-OHDA model. Our results support the importance of a clinical investigation of the effect of 5-HT(1A) and 5-HT(1B) agonists, particularly in combination, in dyskinetic l-DOPA-treated Parkinson's disease patients.

To clarify the role and mechanism of the 5-HT1A receptor in modulating extrapyramidal motor disorders, we studied the actions of 5-HT1A agonists in the mouse pole test, a valid model of parkinsonian bradykinesia. Haloperidol markedly delayed pole-descending behavior of mice in the pole test, and this effect was alleviated by the antiparkinsonian agent trihexyphenidyl (a muscarinic antagonist). The selective 5-HT1A agonists, 8-hydroxydipropylaminotetraline (8-OH-DPAT) and tandospirone, significantly attenuated haloperidol-induced bradykinesia in a dose-dependent manner. The alleviation of haloperidol-induced bradykinesia by 8-OH-DPAT was completely antagonized by WAY-100135 (a selective 5-HT1A antagonist), but was unaffected by cerebral 5-HT depletion with p-chlorophenylalanine (PCPA) treatment (300 mg/kg, i.p. for 3 days). These results suggest that 5-HT1A agonists improve extrapyramidal motor disorders associated with antipsychotic treatments by stimulating the postsynaptic 5-HT1A receptor.

Our laboratory has recently observed the development of an anxiogenic response after a short abstinence period ( approximately 10 days) in young adult rats treated repeatedly with cocaine during adolescence. The present study was conducted to determine if this effect persists into adulthood following extended durations of abstinence and whether it could be modulated with the 5-HT(1A) agonist (+/-)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT). Accordingly, 30-day-old rats were injected with either 10mg/kg cocaine or saline for 8 consecutive days. Approximately 8 weeks after the final injection, anxiety levels in subjects were assessed with an elevated zero maze with a second assessment performed 4 weeks thereafter. Shortly prior to each test session, half the subjects in each of the two adolescent drug conditions received injections of 300 microg/kg 8-OH-DPAT while the other half received injections of the vehicle. Based on total time spent in the open areas of the maze, the results obtained at the first abstinent duration indicated that adolescent cocaine treatment did not induce an anxiogenic response. Assessment of maze behavior at the second abstinent duration was aided with a digital tracking and computerized scoring system (LimeLight, Actimetrics). Similar to the results obtained at the first abstinent duration, the amount of time spent in the open areas of the maze was unrelated to prior cocaine treatment. However, cocaine-treated rats did show evidence of an anxiogenic response at this abstinent duration based on more frequent entries into and out of the open and enclosed areas of the maze, more frequent and longer durations of exploratory bouts beyond the perimeter of the maze, excessive number of cautious protrusions into the open areas, and faster running velocities through the open areas. These results were not artifacts of generalized motor activation in that comparable total distance traveled scores were noted for all subjects. Treatment with 8-OH-DPAT shortly prior to elevated zero maze testing normalized these behaviors induced by adolescent cocaine. It is concluded that the anxiogenic response produced by cocaine exposure during adolescence persists 12 weeks beyond cessation of drug treatment and that this effect is reversible with 8-OH-DPAT. In addition, the results underscore the importance of taking multiple measures when assessing anxiety in experimental animals. Implications for the neurobiology of drug abuse and the role of serotonin are discussed.

Monoamines are well known to modulate locomotion in several vertebrate species. Coapplication of dopamine (DA) and serotonin (5-HT) has also been shown to potently induce fictive locomotor rhythms in isolated spinal cord preparations. However, a synergistic contribution of these monoamines to locomotor rhythmogenesis in vivo has never been examined. Here, we characterized the effects induced by selective DA and 5-HT receptor agonists on hindlimb movement induction in completely spinal cord transected (adult) mice. Administration of the lowest effective doses of SKF-81297 (D 1/5 agonist, 1-2 mg/kg, ip) or 8-OH-DPAT (5-HT 1A/7 agonist, 0.5 mg/kg, ip) acutely elicited some locomotor-like movements (LM) (5.85 +/- 1.22 and 3.67 +/- 1.44 LM/min, respectively). Coadministration of the same doses of SKF-81297 and 8-OH-DPAT led to a significant increase (7- to 10-fold) of LM (37.70 +/- 5.01 LM/min). Weight-bearing and plantar foot placement capabilities were also found with the combination treatment only (i.e., with no assistance or other forms of stimulation). These results clearly show that D 1/5 and 5-HT 1A/7 receptor agonists can synergistically activate spinal locomotor networks and thus generate powerful basic stepping movements in complete paraplegic animals. Although previous work from this laboratory has reported the partial rhythmogenic potential of monoamines in vivo, the present study shows that drug combinations such as SKF-81297 and 8-OH-DPAT can elicit weight-bearing stepping.

Clinical trials in obstructive sleep apnea syndrome patients reported moderate effects of serotoninergic drugs on oropharyngeal apneas, although numerous specific 5-HT ligands highly modulate the genioglossus muscle (GG) activity in experiments performed in anesthetized animals. The purpose of this study was to investigate time- and dose-related effects of central and systemic injections of 8-OHDPAT (5-HT1A agonist), SB224289 (5-HT1B antagonist), and DOI (5-HT2A/2C agonist) on the GG activity in anesthetized and conscious rats. Electromyographic recordings of the GG activity (GGemg) were analyzed after central and systemic injections of each drug in ketamine-xylazine anesthetized rats. Electroencephalograms (EEG), as well as neck and GG muscle activities (Nemg and GGemg), were recorded in 15 additional rats to analyze changes in sleep-wake states before and after systemic injection of the drugs. Central injections of 8-OHDPAT and DOI in anesthetized rats induced clear dose-related increases in phasic and tonic GGemg activities, respectively. The time-responses were inferior to 30 min with 8-OHDPAT and over 50 min with DOI. Moderate increases in phasic GGemg activity were also observed after central, but not peripheral injection of SB and DOI. The total sleep time measured in conscious rats significantly decreased after systemic injections of DOI and 8-OHDPAT, although no change was observed in phasic or tonic GGemg activity. The dose- and time-responses of the DOI in anesthetized rat partly explain the lack of GGemg tonic change in conscious rat. The moderate effect on the GGemg phasic activity of peripheral 5-HT1A ligand injection easily explains the lack of change in conscious rat. The serotonergic modulation of the respiratory component of the GGemg remains complex, but is highly sensitive to 5-HT1A receptors after central injection in rats under anesthesia. Forthcoming therapy in OSAS should be made of mixed profiled neurotransmitters and different routes of administration.

The interaction between the selective sigma (sigma) receptor agonists and 8-OH-DPAT, a serotonin (5-HT)(1A) receptor agonist, was examined in the forced swimming test in rats. The results indicate that joint administration of DTG (5 mg/kg) or SA4503 (3 mg/kg), the selective sigma(1)/sigma(2)- or sigma(1)-receptor agonists, respectively, and 8-OH-DPAT (0.1 or 0.3 mg/kg) induces an antidepressant-like effect. The doses of sigma agonists and 8-OH-DPAT used in the study were inactive per se in this model. The effect of DTG and 8-OH-DPAT co-administration was partly counteracted by WAY 100635 (0.1 mg/kg) as well as by BD 1047 (3 mg/kg), a 5-HT(1A) and sigma(1) receptor antagonists, respectively, suggesting the involvement of both receptor types in the anti-immobility effect in rats.

Purpose: The serotonin 5-hydroxytryptamine(1A/7) receptor agonist (R)-8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) (Sigma) and the 5-hydroxytryptamine(1A/1B/1D) agonist GR-46611 (3-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-N-(4-methoxybenzyl)acrylamide) (Tocris Cookson, Ellisville, Missouri) inhibit bladder activity during saline infusion into the bladder of cats with chronic spinal cord injury (saline infused, spinal cord injured cats), suggesting an effect on mechanosensitive bladder afferent C fibers or their targets. We investigated the effects of (R)-8-OH-DPAT and GR-46611 on bladder activity in chronic spinal cord injured cats during infusion of dilute acetic acid into the bladder to stimulate chemosensitive bladder afferent C fibers (acid infused, spinal cord injured cats)., Materials and Methods: Chloralose anesthetized, spinal cord injured cats were catheterized through the bladder dome for filling cystometry during 0.5% acetic acid infusion. Dose-response curves for (R)-8-OH-DPAT (0.3 to 30 microg/kg intravenously) or GR-46611 (0.03 to 300 microg/kg intravenously) were followed by the 5-hydroxytryptamine(1A) antagonist WAY-100635 (N-tert-butyl-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-2-phenylpropanamide) (Sigma) (300 microg/kg). Threshold volume, bladder capacity, residual volume, micturition volume and arterial pressure were measured and external urethral sphincter electromyogram was recorded., Results: Acid infused, spinal cord injured cats responded to (R)-8-OH-DPAT but not to GR-46611 with dose dependent increases in threshold volume, capacity and residual volume (significant above 3 microg/kg). Effects of (R)-8-OH-DPAT were largely reversed by WAY-100635. Neither (R)-8-OH-DPAT nor GR-46611 augmented external urethral sphincter electromyogram activity., Conclusions: Based on differences in the response to GR-46611 in saline vs acid infused, spinal cord injured animals it is tempting to speculate that 2 distinct populations of bladder afferent C fibers (1 chemosensitive and 1 mechanosensitive) can initiate spinal bladder reflexes. Because 5-hydroxytryptamine(1A) receptor agonists increased bladder capacity under saline or acid infused conditions, they are promising candidates for decreasing bladder hyperactivity and increasing bladder capacity in patients with chronic spinal cord injury.

5-HT1A autoreceptor stimulation can act to attenuate supraphysiological swings in extracellular dopamine levels following long-term levodopa treatment and may be useful in the treatment and prevention of the motor complications. The purpose of this study was to investigate cellular and behavioral effects of 5-HT1A receptor agonist 8-OH-DPAT in a rat model of levodopa-induced motor complications. Two sets of experiments were performed. First, animals were treated with levodopa (50 mg/kg with benserazide 12.5 mg/kg, twice daily), intraperitoneally (i.p.) for 22 days. On day 23, animals received either 8-OH-DPAT (1 mg/kg, i.p.) or 8-OH-DPAT plus WAY-100635 (0.1 mg/kg, i.p) or vehicle with each levodopa dose. In the second set, animals were treated either with levodopa (50 mg/kg, i.p.) plus 8-OH-DPAT (1 mg/kg, i.p.) or levodopa (50 mg/kg, i.p.) plus vehicle, administered twice daily for 22 consecutive days. Our study showed that 8-OH-DPAT plus levodopa both prolonged the duration of the motor response and reduced peak turning. 8-OH-DPAT plus levodopa also decreased the frequency of failures to levodopa. Co-administration of WAY-100635, a 5-HT1A receptor antagonist, with 8-OH-DPAT eliminated the effect of 8-OH-DPAT on motor complications indicating that the observed 8-OH-DPAT responses were probably mediated at the 5-HT1A autoreceptor. Moreover, 8-OH-DPAT plus levodopa significantly reduced hyperphosphorylation of GluR1 at serine 845, which was closely associated with levodopa-induced motor complications.

The introduction of therapeutic mild hypothermia after cardiac arrest allows the neuronal damage caused by global cerebral ischemia to be advantageously influenced for the first time. Currently, hypothermia is induced by external or internal cooling of the patient (forced hypothermia). However, this results in activation of counter-regulation mechanisms which could be possible risk factors for the patient. The aim of this article is to give a review of possible, but at present only experimental, methods which could allow the body temperature set point to be decreased pharmacologically (regulated hypothermia). Various classes of substances will be discussed based on their effect on thermoregulation and their performance in animal experiments on cerebral ischemia.

Adjuvant treatment of hypovolemic shock with vasoconstrictors is controversial due to their propensity to raise arterial resistance and exacerbate ischemia. A more advantageous therapeutic approach would use agents that also promote venoconstriction to augment perfusion pressure through increased venous return. Recent studies indicate that 5-hydroxytryptophan (5-HT)(1A) receptor agonists increase blood pressure by stimulating sympathetic drive when administered after acute hypotensive hemorrhage. Given that venous tone is highly dependent upon sympathetic activation of alpha(2)-adrenergic receptors, we hypothesized that the 5-HT(1A) receptor agonist, (+)8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), would increase venous tone in rats subject to hypovolemic shock through sympathetic activation of alpha(2)-adrenergic receptors. Systemic administration of 8-OH-DPAT produced a sustained rise in blood pressure (+44 +/- 3 mm Hg 35 min after injection, P < 0.01 versus saline) and mean circulatory filling pressure (+4.2 +/- 0.7 mm Hg, P < 0.01 versus saline) in conscious rats subjected to hypovolemic shock. An equipressor infusion of epinephrine failed to influence mean circulatory filling pressure (MCFP). Ganglionic blockade, alpha(1)-, or peripheral alpha(2)-adrenergic receptor blockade prevented the rise in MCFP observed with 8-OH-DPAT, but only alpha(1)-adrenergic receptor blockade diminished the pressor effect of the drug (P < 0.01). 8-OH-DPAT raises blood pressure in rats in hypovolemic shock through both direct vascular activation and sympathetic activation of alpha(1)-adrenergic receptors. The sympathoexcitatory effect of 8-OH-DPAT contributes to elevated venous tone through concurrent activation of both alpha(1)- and alpha(2)-adrenergic receptors. The data suggest that 5-HT(1A) receptor agonists may provide an advantageous alternative to currently therapeutic interventions used to raise perfusion pressure in hypovolemic shock.

The influence of the chronic administration of the 5-HT1A receptor agonist 8-OH-DPAT (0.05 mg/kg, s.c.) and the 5-HT1A receptor antagonist NAN-190 (0.1 mg/kg, i.p.) alone or in combination with 17beta-estradiol (0.5 microg per animal, i.m.) for 14 days on the depression behavior and the monoamine level in hippocampus has been studied in adult ovariectomized (OVX) female rats. The model of depression in rats was realized under the Porsolt test conditions. The levels of monoamine and its metabolites were determined using HPLC. It was established that the chronic administration of 8-OH-DPAT alone produces an antidepressant effect in OVX rats. The chronic administration of 8-OH-DPAT in combination with 17beta-estradiol potentiated the antidepressant action of both preparations. The antidepressant effect of 8-OH-DPAT in OVX rats was correlated with the restoration of noradrenergic, serotoninergic, and dopaminergic neurotransmission in the hippocampus. The obtained data are indicative of a close interaction between the ovarian hormonal system and the cerebral serotoninergic system in the realization of depression mechanisms.

To evaluate the possible role of 5-HT 1A and 5-HT 2A receptors in the anticonvulsant effect of swim stress, mice were pre-treated with agonists and antagonists of these receptors prior to exposure to stress and the intravenous infusion of picrotoxin. 8-OH-DPAT ((+/-)-8-hydroxy-2-(di-n-propylamino) tetralin) and WAY-100635 (a selective agonist and antagonist of 5-HT 1A receptors), DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) and ketanserin (a 5-HT 2A/2C receptor agonist and antagonist) were used. Results demonstrated that 1 and 3 mg/kg of 8-OH-DPAT increased the doses of picrotoxin producing running/bouncing clonus, tonic hindlimb extension and death in stressed and unstressed mice, respectively. Pre-treatment with WAY (0.3 mg/kg) prevented the effect of 8-OH-DPAT (3 mg/kg). DOI (2.5 mg/kg) and ketanserin (1 mg/kg) failed to affect the seizure threshold for picrotoxin. The results show that stimulation of 5-HT 1A receptors exerts anticonvulsant actions in stressed and unstressed mice, while stimulation of 5-HT 2A/2C receptors does not interfere with the effect of stress on picrotoxin-induced convulsions.

Respiratory dysfunction after cervical spinal cord injury (SCI) has not been examined experimentally using conscious animals, although clinical SCI most frequently occurs in midcervical segments. Here, we report a C5 hemicontusion SCI model in rats with abnormalities that emulate human post-SCI pathophysiology, including spontaneous recovery processes. Post-C5 SCI rats demonstrated deficits in minute ventilation (Ve) responses to a 7% CO2 challenge that correlated significantly with lesion severities (no injury or 12.5, 25, or 50 mm x 10 g weight drop; New York University impactor; p < 0.001) and ipsilateral motor neuron loss (p = 0.016). Importantly, C5 SCI resulted in at least 4 weeks of respiratory abnormalities that ultimately recovered afterward. Because serotonin is involved in respiration-related neuroplasticity, we investigated the impact of activating 5-HT1A receptors on post-C5 SCI respiratory dysfunction. Treatment with the 5-HT1A agonist 8-hydroxy-2-(di-n-propylmino)tetralin (8-OH DPAT) (250 microg/kg, i.p.) restored hypercapnic Ve at 2 and 4 weeks after injury (i.e., approximately 39.2% increase vs post-SCI baseline; p < or = 0.033). Improvements in hypercapnic Ve response after single administration of 8-OH DPAT were dose dependent and lasted for approximately 4 h(p < or = 0.038 and p < or = 0.024, respectively). Treatment with another 5-HT1A receptor agonist, buspirone (1.5 mg/kg, i.p.), replicated the results, whereas pretreatment with a 5-HT1A-specific antagonist, 4-iodo-N-[2-[4(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzamide (3 mg/kg, i.p.) given 20 min before 8-OH DPAT negated the effect of 8-OH DPAT. These results imply a potential clinical use of 5-HT1A agonists for post-SCI respiratory disorders.

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-HT(1A) 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-HT(1A) 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.

Published investigations of serotonin-1A (5-hydroxytryptamine1A; 5-HT1A) receptor agonists and serotonin-2A (5-hydroxytryptamine2A; 5-HT2A) receptor antagonists in nonprimate species provide conflicting results with regard to their intraocular pressure-lowering efficacy. Thus, their therapeutic utility in the treatment of human glaucoma has been confusing. We evaluated the effect of selected 5-HT1A agonists and 5-HT2A receptor antagonists on intraocular pressure in a nonhuman primate model, the conscious cynomolgus monkey with laser-induced ocular hypertension. Neither selective 5-HT1A agonists [e.g., R-8-hydroxy-2-(di-n-propylamino)tetralin and flesinoxan] nor selective 5-HT2 receptor antagonists [e.g., R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (M-100907) and 6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxamide (SB-242084)] lowered intraocular pressure in the primate model following topical ocular administration. However, compounds that function as agonists at both the 5-HT1A and 5-HT2 receptors were found to effectively lower intraocular pressure in the model: 5-hydroxy-alpha-methyltryptamine, 5-methoxy-alpha-methyltryptamine, 5-hydroxy-N,N-dimethyltryptamine (bufotenine), and 5-methoxy-N,N-dimethyltryptamine. Furthermore, the selective 5-HT2 receptor agonist R-(-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane lowered intraocular pressure in the primate model, demonstrating a pharmacological response associated with activation of the 5-HT2 receptor. These observations suggest that compounds that function as efficient agonists at 5-HT2 receptors should be considered as potential agents for the control of intraocular pressure in the treatment of ocular hypertension and glaucoma in humans.

Contusion spinal cord injury (SCI) at T8 produces respiratory abnormalities in conscious rats breathing room air and challenged with CO2. In seeking ways to improve respiration after SCI, we tested drugs that stimulate serotonin 1A (5-HT1A) receptors, based on our previous findings that these agents can counteract respiratory depression produced by morphine overdose. Respiratory function was measured with a head-out plethysmograph system in conscious rats. T8 SCI rats (n = 5) showed decreased tidal volume (Vt; 0.90 +/- 0.02-0.66 +/- 0.03 ml; p < 0.05) and increased respiratory rate (f;91 +/- 3.7-132 +/- 5.7 breaths/min; p < 0.05) with room air ventilation at 24 hr after injury. They also exhibited a diminished response to the respiratory stimulating effect of 7% CO2; minute ventilation increased to 250 +/- 17 ml/min before, but only to 162 +/- 15 ml/min at 24 hr after SCI (p < 0.05). Respiratory deficits during room air ventilation were also observed at 7 d after injury (n = 3). Treatment with the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylmino)tetralin (8-OH-DPAT; 250 microg/kg, i.p.) at 24 hr (n = 5) or 7 d (n = 3) after injury normalized Vt, f, and the respiratory response to 7% CO2. Identical results were obtained with another 5-HT1A receptor agonist, buspirone (1.5 mg/kg, i.p.; n = 3). In contrast, intraperitoneal saline vehicle administration (n = 5) showed no beneficial effects on SCI-impaired respiration. Finally, pretreatment with a specific antagonist of 5-HT1A receptors, 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzamide (3 mg/kg, i.p.; n = 3) given 20 min before 8-OH-DPAT, prevented 8-OH-DPAT from restoring respiration to normal. Our results demonstrate that drugs that stimulate 5-HT1A receptors counteract respiratory abnormalities in conscious rats after SCI.

Recent evidence indicates that serotonin (5-HT)1A receptor agonists may abrogate excitotoxic brain damage. We investigated whether a single i.p. injection of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), at a dose of 2.5 mg/kg, protects cholinergic neurons of the rat magnocellular nucleus basalis (MBN) against NMDA excitotoxicity when administered at post-injury intervals ranging from 6 to 96 h. Drug effects on passive avoidance learning and on the density of cortical cholinergic innervation, a measure of neuronal survival in the damaged MBN, were analyzed. Our results demonstrate that 8-OH-DPAT, when administered up to 24 h post-lesion, significantly attenuates both behavioral and neuroanatomical consequences of NMDA excitotoxicity on cholinergic MBN neurons; and support the hypothesis that 5-HT1A receptor agonists may interfere with delayed neuronal death in vivo that is of significance in the pharmacological treatment of neurological disorders associated with excitotoxic neuronal damage., (Copyright 2003 Lippincott Williams & Wilkins)

To further investigate the efficacy of 5-HT(1A) receptor agonism on functional and histological outcome in traumatically-brain injured (TBI) rats, a single intraperitoneal injection of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.1, 0.5, or 1.0 mg/kg) or vehicle was given 15 min after controlled cortical impact or sham injury. Function was assessed by established motor and cognitive tests on post-operative days 1-5 and 14-18, respectively. Cortical lesion volume and hippocampal CA(1)/CA(3) cell survival were quantified at 4 weeks. The administration of 8-OH-DPAT (0.5 mg/kg) attenuated spatial acquisition deficits and reduced hippocampal CA(3) cell loss vs. vehicle (P < 0.05). These data augment published reports that 5-HT(1A) receptor agonists confer neuroprotective effects after experimental TBI., (Copyright 2002 Elsevier Science Ireland Ltd.)