Loss of Adult 5-HT1A Autoreceptors Results in a Paradoxical Anxiogenic Response to Antidepressant Treatment.

Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are first-line antidepressants but require several weeks to elicit their actions. Chronic SSRI treatment induces desensitization of 5-HT1A autoreceptors to enhance 5-HT neurotransmission. Mice (both sexes) with gene deletion of 5-HT1A autoreceptors in adult 5-HT neurons (1AcKO) were tested for response to SSRIs. Tamoxifen-induced recombination in adult 1AcKO mice specifically reduced 5-HT1A autoreceptor levels. The 1AcKO mice showed a loss of 5-HT1A autoreceptor-mediated hypothermia and electrophysiological responses, but no changes in anxiety- or depression-like behavior. Subchronic fluoxetine (FLX) treatment induced an unexpected anxiogenic effect in 1AcKO mice in the novelty suppressed feeding and elevated plus maze tests, as did escitalopram in the novelty suppressed feeding test. No effect was seen in wild-type (WT) mice. Subchronic FLX increased 5-HT metabolism in prefrontal cortex, hippocampus, and raphe of 1AcKO but not WT mice, suggesting hyperactivation of 5-HT release. To detect chronic cellular activation, FosB+ cells were quantified. FosB+ cells were reduced in entorhinal cortex and hippocampus (CA2/3) and increased in dorsal raphe 5-HT cells of 1AcKO mice, suggesting increased raphe activation. In WT but not 1AcKO mice, FLX reduced FosB+ cells in the median raphe, hippocampus, entorhinal cortex, and median septum, which receive rich 5-HT projections. Thus, in the absence of 5-HT1A autoreceptors, SSRIs induce a paradoxical anxiogenic response. This may involve imbalance in activation of dorsal and median raphe to regulate septohippocampal or fimbria-fornix pathways. These results suggest that markedly reduced 5-HT1A autoreceptors may provide a marker for aberrant response to SSRI treatment.SIGNIFICANCE STATEMENT Serotonin-selective reuptake inhibitors (SSRIs) are effective in treating anxiety and depression in humans and mouse models. However, in some cases, SSRIs can increase anxiety, but the mechanisms involved are unclear. Here we show that, rather than enhancing SSRI benefits, adulthood knockout (KO) of the 5-HT1A autoreceptor, a critical negative regulator of 5-HT activity, results in an SSRI-induced anxiety effect that appears to involve a hyperactivation of the 5-HT system in certain brain areas. Thus, subjects with very low levels of 5-HT1A autoreceptors, such as during childhood or adolescence, may be at risk for an SSRI-induced anxiety response.

Suppression of serotonin neuron firing increases aggression in mice.

Numerous studies link decreased serotonin metabolites with increased impulsive and aggressive traits. However, although pharmacological depletion of serotonin is associated with increased aggression, interventions aimed at directly decreasing serotonin neuron activity have supported the opposite association. Furthermore, it is not clear if altered serotonin activity during development may contribute to some of the observed associations. Here, we used two pharmacogenetic approaches in transgenic mice to selectively and reversibly reduce the firing of serotonin neurons in behaving animals. Conditional overexpression of the serotonin 1A receptor (Htr1a) in serotonin neurons showed that a chronic reduction in serotonin neuron firing was associated with heightened aggression. Overexpression of Htr1a in adulthood, but not during development, was sufficient to increase aggression. Rapid suppression of serotonin neuron firing by agonist treatment of mice expressing Htr1a exclusively in serotonin neurons also led to increased aggression. These data confirm a role of serotonin activity in setting thresholds for aggressive behavior and support a direct association between low levels of serotonin homeostasis and increased aggression.

Quinpirole and 8-OH-DPAT induce compulsive checking behavior in male rats by acting on different functional parts of an OCD neurocircuit.

This study investigated whether the serotonin 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) can induce compulsive checking in a large open field, as does the dopamine D2/D3 receptor agonist quinpirole. To induce compulsive checking, male rats were exposed to eight injections of either 8-OH-DPAT (1 mg/kg), quinpirole (0.2 mg/kg), or saline. Subsequently, to assess cross-sensitization, rats received an acute challenge of 8-OH-DPAT or quinpirole. The results showed that treatment with 8-OH-DPAT induces compulsive checking and may have a stronger effect on this behavior compared with quinpirole. However, there was no cross-sensitization between 8-OH-DPAT and quinpirole on measures of compulsive checking and locomotion. Moreover, the spatial distribution of locomotor paths in 8-OH-DPAT animals was more confined and invariant than in quinpirole rats; their rate of locomotor sensitization was also faster than that in quinpirole animals. Thus, although 8-OH-DPAT and quinpirole can induce compulsive checking in a large open field, the results suggest that they do so differently. It is suggested that 8-OH-DPAT and quinpirole probably produce compulsive behavior by acting on different parts of a security motivation circuit underlying obsessive-compulsive disorder. Quinpirole may induce compulsive checking behavior by directly driving dopaminergic activity mediating the motivational drive to check. Conversely, 8-OH-DPAT may perpetuate the activated motivational state by inhibiting the serotonergic-negative feedback signals that normally deactivate the obsessive-compulsive disorder circuit.

Serotonin 1A receptor agonist modulation of motor deficits and cortical oscillations by NMDA receptor interaction in parkinsonian rats.

Although serotonin 1A (5-HT1A) receptor agonists are widely used as the additive compound to reduce l-dopa-induced dyskinesia in Parkinson's disease (PD), few studies focused on the effect and mechanism of 5-HT1A receptor agonist on the motor symptoms of PD. Unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats were used and implantation of electrodes was performed in the motor cortex of these rats. So the effect of 5-HT1A receptor agonist 8-OH-DPAT on motor behaviors and oscillatory activities were evaluated. In addition, 8-OH-DPAT combined with D2 receptor antagonist raclopride, NMDA receptor antagonist MK-801, or its agonist d-cycloserine (DCS) were co-administrated. 8-OH-DPAT administration significantly improved spontaneous locomotor activity and asymmetric forepaw function in 6-OHDA-lesioned rats. Meanwhile, 8-OH-DPAT identified selective modulation of the abnormal high beta oscillations (25-40 Hz) in the motor cortex of 6-OHDA-lesioned rats, without inducing pathological finely tuned gamma around 80 Hz. Different from 8-OH-DPAT, l-dopa treatment produced a prolonged improvement on motor performances and differential regulation of high beta and gamma oscillations. However, dopamine D2 receptor antagonist had no influence on the 8-OH-DPAT-mediated-motor behaviors and beta oscillations in 6-OHDA-lesioned rats. In contrast, subthreshold NMDA receptor antagonist MK-801 obviously elevated the 8-OH-DPAT-mediated-motor behaviors, while NMDA receptor agonist DCS partially impaired the 8-OH-DPAT-mediated symptoms in 6-OHDA-lesioned rats. This study suggests that 5-HT1A receptor agonist 8-OH-DPAT improves motor activity and modulates the oscillations in the motor cortex of parkinsonian rats. Different from l-dopa, 8-OH-DPAT administration ameliorates motor symptoms of PD through glutamatergic rather than the dopaminergic pathway.

Estrogen treatment blocks 8-hydroxy-2-dipropylaminotetralin- and apomorphine-induced disruptions of prepulse inhibition: involvement of dopamine D1 or D2 or serotonin 5-HT1A, 5-HT2A, or 5-HT7 receptors.

Prepulse inhibition (PPI) is a measure of sensorimotor gating and an endophenotype of schizophrenia. We have shown previously in rats that estrogen treatment prevents disruption of PPI by the 5-HT(1A)/5-HT(7) receptor agonist 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT). The aim of the present study was to examine the role of dopamine D(1) and D(2) and serotonin 5-HT(1A), 5-HT(2A), and 5-HT(7) receptors in these effects. Part 1 of this study investigated the ability of estrogen treatment to reverse PPI disruption induced by 8-OH-DPAT or the dopamine D(1)/D(2) receptor agonist apomorphine. Part 2 of this study compared these effects to the ability of various antagonists in reversing the action of 8-OH-DPAT and apomorphine on PPI. Female Sprague-Dawley rats were ovariectomized (OVX), and, where appropriate, they received silastic implants containing either a low (E20) or high dose (E100) of estrogen. Two weeks later, PPI was assessed using automated startle boxes. The disruption of PPI by either treatment with 8-OH-DPAT (0.5 mg/kg) or apomorphine (0.3 mg/kg) was similarly prevented by E100 treatment. 8-OH-DPAT-induced PPI disruption was reversed by pretreatment with the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt (WAY 100,635; 1 mg/kg) and the typical antipsychotic and dopamine D(2) receptor antagonist haloperidol (0.25 mg/kg), but it was not reversed by pretreatment with the dopamine D(1) receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390; 0.1 mg/kg), the 5-HT(2A/2C) receptor antagonist ketanserin (2 mg/kg), or the 5-HT(7) receptor antagonist SB-269970 (10 mg/kg). Apomorphine-induced disruptions of PPI were reversed by haloperidol and SCH 23390 only. Estrogen may prevent disruptions of PPI induced by both 8-OH-DPAT and apomorphine by an action on dopamine D(2) receptors downstream of 5-HT(1A) receptors.

Differences in 5-HT1A receptor-mediated hypothermia in rats with low or high exploratory activity.

Alterations in the serotonin (5-HT) system and the 5-HT1A receptor function have a significant role in anxiety-related and depression-related states. This study investigated the stress-induced hyperthermia (SIH) response and sensitivity to the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetraline in rats with persistently low or high levels of exploratory activity (LE and HE, respectively), of which the LE rats show more anxiety-like and depressive-like phenotypes. No differences in the SIH in response to novel cage or injection stress were found using rectal temperature measurements. However, the LE rats had significantly less pronounced decreases in SIH in response to the 0.3 mg/kg dose of 8-hydroxy-2-(di-n-propylamino)-tetraline. Exploratory behaviour correlated significantly and positively with the magnitude of change in body temperature in response to the 5-HT1A receptor agonist. This finding suggests a less effective 5-HT1A function in the LE rats and implicates the 5-HT1A receptor in the anxiety component of passive behaviour in novel surroundings.

The role of prior stressor controllability and the dorsal raphé nucleus in sucrose preference and social exploration.

Research investigating how control over stressors affects behavior often utilizes freezing and shuttle escape learning as the behavioral endpoints. These endpoints have been argued to reflect anxious or depressed states, but these descriptions are problematic. The present study sought to determine the impact of stressor controllability and the dorsal raphé nucleus (DRN) on sucrose preference and juvenile social exploration, putative measures of anhedonia and anxiety that are commonly used in studies of stress per se. In Experiment 1 rats were exposed to escapable stress (ES) or yoked-inescapable stress (IS) tailshocks. In Experiment 2 ES or IS was given 7 days before all rats received IS. In Experiment 3 the DRN was inactivated during IS by microinjection of 8-OH-DPAT. Sucrose preference and social exploration were tested for several days after stress. A fourth experiment confirmed that juvenile social exploration is sensitive to traditional beta-carboline and benzodiazepine manipulations. Both ES and IS reduced sucrose preference, but only IS reduced social exploration. Prior treatment with ES prevented the effect of IS on social exploration but did not prevent the effect of IS on sucrose preference and inactivation of the DRN prevented the effect of IS on social exploration but did not change sucrose preference. The present results indicate that social exploration but not sucrose preference is sensitive to prior stressor controllability, and that DRN activation mediates the effect of IS on social exploration. We argue that DRN-5-HT activation mediates a state of generalized anxiety produced by uncontrollable stress and that juvenile social exploration is a useful behavioral endpoint in stressor controllability studies.

The effect of sertraline and 8-OH-DPAT on the PTZ_induced seizure threshold: Role of the nitrergic system.

PURPOSE: Serotonin is a key regulatory neurotransmitter in the CNS which plays an important role in seizure through different receptors, especially the 5HT1A subtype. The role of sertraline through the 5HT1A receptor and nitric oxide interaction on the PTZ-induced seizure threshold was investigated in this study. METHOD: In this study, 70 white male mice were randomly divided into 10 groups including intact control, sham-control and eight experimental groups which received sertraline, 8-OH-DPAT, WAY100635, WAY100635+sertraline, WAY100635+8-OH-DPAT, L-NAME, L-NAME+sertraline and L-NAME+8-OH-DPAT. After 14days of treatment in different groups, the PTZ-induced seizure threshold was assessed and the measurement of nitric oxide metabolites in the brain tissue was done with the Greiss method. RESULTS: The seizure threshold was significantly increased in the sertraline and 8OH-DPAT receiving groups compared to the sham group (P<0.001). In the presence of WAY100635, the effect of both sertraline and 8-OH-DPAT in raising the seizure threshold was more prominent (P<0.001) but on the other hand, in the presence of L-NAME, an increase in the anticonvulsant effect of 8-OH-DPAT was observed, while L-NAME alone had no effect on the seizure threshold (P<0.001). The NOX concentration was significantly decreased in the 8-OH-DPAT_treated group (P<0.01), while the WAY100657 reversed it and the combination of 8-OH-DPAT with L-NAME reduced the NOX levels (P<0.001). CONCLUSIONS: These findings support the anticonvulsant effect of SSRIs and selective 5HT1A receptors, although serotonin receptors other than 5HT1A subtype may be involved and also it is probable that some anticonvulsant effects of the sertraline and 8-OH-DPAT are through the modulation of nitrergic system.

Effects of long term consumption of sugar as part of meal on serotonin 1-a receptor dependent responses.

In view of an effect of high intake of sugar on brain serotonin (5-hydroxytryptamine, 5-HT) and a role of serotonin in the regulation of appetite, the present study concerns pre and postsynaptic responses to a selective 5-HT-1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) following long term consumption of sugar as part of meal in rats. Sugar diet was prepared by mixing standard rodent diet and table sugar in ratio of 3:1 (w/w) and rats were fed freely on this diet for five weeks. Control rats were fed freely on standard rodent diet. After five weeks 8-OH-DPAT at a dose of 0.5mg/kg/ml was injected to both the groups to compare effectiveness of the drug to elicit hyperphagia (presynaptic response) and elicited hyperactivity syndrome (postsynaptic response). Results showed that 8-OH-DPAT-induced forepaw treading and flatbody posture were smaller in sugar than normal diet treated rats. Conversely 8-OH-DPAT-induced hyperlocomotion was greater in sugar than normal diet treated rats. 4h Food consumption was greater in sugar than normal diet treated rats while 8-OH-DPAT-induced hyperphagia significant in normal diet treated rats was not observed in sugar diet treated rats. The results show a decrease in the effectiveness of pre as well as postsynaptic 5-HT-1A receptor dependent responses following long term consumption of sugar diet. Role of serotonin receptor responsiveness on mood and impaired adaptation to stress is discussed.

Involvement of central serotonergic systems in dextromethorphan-induced behavioural syndrome in rats.

Dextromethorphan, a noncompetitive blocker of the N-methyl-D-aspartate (NMDA) type of glutamate receptor, at 45, 60 and 75 mg/kg, ip doses induced a behavioural syndrome characterised by reciprocal forepaw treading, lateral head-weaving, hind-limb abduction and flat body posture. Such type of behavioural syndrome is induced by 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT) by directly stimulating the central postsynaptic 5-hydroxytryptamine (5-HT, serotonin) receptors of the 5-HT1A type. Pretreatment with buspirone (5, 10 mg/kg, ip) and l-propranolol (10, 20 mg/kg, ip) antagonised the behavioural syndrome induced by 8-OH-DPAT and dextromethorphan. Pretreatment with p-chlorophenylalanine (100 mg/kg/day x 4 days) antagonised the behavioural syndrome induced by dextromethorphan and dexfenfluramine but had no significant effect on 8-OH-DPAT induced behavioural syndrome. This indicates that dextromethorphan induces the behavioural syndrome by releasing 5-HT from serotonergic neurons with resultant activation of the postsynaptic 5-HT1A receptors by the released 5-HT. Pretreatment with fluoxetine (10 mg/kg, ip) significantly potentiated the behavioural syndrome induced by dextromethorphan and 5-hydroxytryptophan but significantly antagonised dexfenfluramine induced behavioural syndrome. This indicates that dextromethorphan releases 5-HT by a mechanism which differs from that of dexfenfluramine. Dextromethorphan may be releasing 5-HT by blocking the NMDA receptors and thereby counteracting the inhibitory influence of l-glutamate on 5-HT release.

Activation of 5-HT1A receptors in the preBötzinger region has little impact on the respiratory pattern.

The preBötzinger (preBötC) complex has been suggested as the primary site where systemically administered selective serotonin agonists have been shown to reduce or prevent opioid-induced depression of breathing. However, this hypothesis has not been tested pharmacologically in vivo. This study sought to determine whether 5-HT1A receptors within the preBötC and ventral respiratory column (VRC) mediate the tachypneic response induced by intravenous (IV) (±)-8-Hydroxy-2-diproplyaminotetralin hydrobromide (8-OH-DPAT) in a decerebrated dog model. IV 8-OH-DPAT (19 ± 2 µg/kg) reduced both inspiratory (I) and expiratory (E) durations by ∼ 40%, but had no effect on peak phrenic activity (PPA). Picoejection of 1, 10, and 100 µM 8-OH-DPAT on I and E preBötC neurons produced dose-dependent decreases up to ∼ 40% in peak discharge. Surprisingly, microinjections of 8-OH-DPAT and 5-HT within the VRC from the obex to 9 mm rostral had no effect on timing and PPA. These results suggest that the tachypneic effects of IV 8-OH-DPAT are due to receptors located outside of the areas we studied.

Voltammetric study of 8-OH-DPAT effect on the raphe-trigeminal 5-HT system.

The effect of i.p. administration of the selective 5-HT1A agonist 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT) (100 micrograms kg-1) has been investigated by in vivo 5-hydroxyindole electrochemical (peak 3) detection in the nucleus raphe magnus (NRM) and medullary dorsal horn (MDH) of acute anaesthetized and unanaesthetized freely moving rats. 8-OH-DPAT induced a small but significant decrease in peak 3 in the NRM and MDH of anaesthetized rats. In freely moving animals, a similar small effect was observed at both NRM and MDH levels. With reference to similar in vivo studies demonstrating differential responsiveness of ascending serotonergic systems to 8-OH-DPAT, it is concluded that the serotonergic NRM-dorsal horn system is slightly affected by this 5-HT1A agonist.

Differential regulation of the expression of contextual freezing and fear-potentiated startle by 5-HT mechanisms of the median raphe nucleus.

It has previously been shown that the median raphe nucleus (MR) is one of the main sources of projections to the septum and hippocampus. 5-HT projections from this nucleus to the hippocampus are implicated in the acquisition and expression of contextual fear (background stimuli), as assessed by freezing. It has also been reported that amygdala is involved in the acquisition of conditioned fear to foreground cues such as light, used as CS. As the MR projects to the hippocampus and amygdala, the role of this raphe nucleus in fear conditioning to contextual and classical fear conditioning remains to be elucidated. The present study examined the involvement of the MR serotonergic mechanisms in the expression of two distinct types of conditioned fear responses: contextual freezing and fear conditioning to explicit cue (light) measured in a fear-potentiated startle (FPS) procedure. Animals received MR electrolytic lesions of or microinjections of 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino tetralin) (1 microg/0.2 microl) into the MR, 1 or 7 days after two consecutive training sessions in which they received 10 pairings of the CS (light, 4 s)-US (foot-shocks 0.6 mA, 1s) and were tested in a contextual fear paradigm and in a FPS procedure. The startle was clearly potentiated in the presence of light-CS in animals bearing lesions of or microinjected with 8-OH-DPAT into MR at 1 or 7 days post-training. However, animals bearing MR electrolytic lesions or microinjections of 8-OH-DPAT into the MR at 1 day, but not at 7 days post-training, showed a significant decrease in time spent in freezing than control ones. Thus, the memory for contextual conditioned fear seems to be formed during a time-window shorter than 1 week. As FPS may be produced in lesioned rats unable to freeze to fear contextual stimuli, dissociable systems seem to be recruited in each condition. Thus, the production of contextual freezing and fear-potentiated startle are conveyed by distinct 5-HT-mediated circuits of the MRN.

Working memory deficits induced by intrahippocampal administration of 8-OH-DPAT, a 5-HT1A receptor agonist, in the rat.

In a test of working memory using a three-panel runway task, the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), at 1.0 mg/kg i.p. significantly increased the number of errors (attempts to pass through two incorrect panels of the three panel gates at four choice points), but it had no effect on errors in a test of reference memory. Intrahippocampal injection of 8-OH-DPAT at 10 micrograms/side also significantly increased the number of working memory errors, without affecting that of reference memory errors. The effect of intrahippocampal 8-OH-DPAT (10 micrograms/side) on working memory was blocked by the 5-HT1A receptor antagonist, (-)-propranolol, at 5 mg/kg i.p. These results suggest that activation of hippocampal 5-HT1A receptors impairs working memory, but does not affect retention of reference memory.

Comparison of relative potencies of i.v. and i.c.v. administered 8-OH-DPAT gives evidence of different sites of action for hypothermia, lower lip retraction and tail flicks.

8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)-induced temperature reduction, lower lip retraction and tail flick responses are widely used models of 5-HT1A receptor function. To obtain information about the sites of receptors mediating these effects we measured these responses, parallel over wide dose ranges after intracerebroventricular (i.c.v., 0.6-67 micrograms/kg) and intravenous (i.v., 3-500 micrograms/kg) administration. Analysis of the dose-response curves provided evidence for a 9.8-fold ratio of the potency of 8-OH-DPAT following i.c.v. compared to i.v. administration on body temperature reduction (ED50 values are 5.1 and 50 micrograms/kg, after i.c.v and i.v. administration, respectively) and a 2.9-fold ratio in potency for lower lip retraction (ED50 values are 29 and 86 micrograms/kg, after i.c.v. and i.v. administration, respectively). 8-OH-DPAT was less potent in the induction of tail flicks than of the other responses and had a lower potency after i.c.v. than after i.v. administration (ED50 values, the first one extrapolated, are 526 and 246 micrograms/kg, after i.c.v. and i.v. administration, respectively). In addition, the i.c.v. ED50 for temperature reduction was significantly lower than those for lower lip retraction or tail flick responses. The relative potency, that is, the ratio of i.v. and i.c.v. ED50, was significantly higher for temperature reduction than for lower lip retraction or tail flick responses (ED50 i.v./ED50 i.c.v. values are 9.8, 2.9, and 0.47, respectively). These data provide evidence that distinct sites of action are involved in these models. Temperature reduction is mediated mainly by postsynaptic receptors in the close vicinity of the lateral ventricle. Receptors that mediate lower lip retraction are located more distantly in the brain, supporting previous evidence that they are somatodendritic autoreceptors, and receptors in the spinal cord are probably responsible for tail flick responses.

Role of dorsal and median raphe nuclei in lower lip retraction in rats.

Induction of lower lip retraction after local infusion of the selective 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in the dorsal and median raphe nuclei was measured. Infusion of 8-OH-DPAT (2.5, 5 and 10 micrograms/rat) into the median raphe nucleus caused an immediate and dose-dependent lower lip retraction. After infusion into the dorsal raphe nucleus a higher dose was needed. The lowest dose of 8-OH-DPAT that induced lower lip retraction was 10 micrograms/rat. Infusion of 8-OH-DPAT (10 micrograms/rat) into the pontine reticular nucleus induced the same degree of lower lip retraction as seen after infusion of the compound into the dorsal raphe nucleus. 8-OH-DPAT-induced lower lip retraction was attenuated by s.c. injection of the preferential 5-HT2C receptor agonist m-chlorophenyl-piperazine. The results suggest that lower lip retraction is mediated by 5-HT1A receptors in the median rather than in the dorsal raphe nucleus.

A neuronal nitric oxide synthase inhibitor 7-nitroindazole reduces the 5-HT1A receptor against 8-OH-DPAT-elicited hyperphagia in rats.

The effects of the neuronal nitric oxide (NO) synthase inhibitor 7-nitroindazole on 8-hydroxy-2-di-n-(propylamino)tetralin (8-OH-DPAT)-induced hyperphagia, which is mediated by the 5-HT1A autoreceptor, were investigated in rats. 7-Nitroindazole suppressed 8-OH-DPAT-elicited increases in food intake. The inhibitory effects of 7-nitroindazole on 8-OH-DPAT-induced feeding were prevented by the NO precursor L-arginine. Although 8-OH-DPAT decreases 5-hydroxytryptamine (5-HT) synthesis, 7-nitroindazole did not reverse the 8-OH-DPAT-elicited decrease in 5-HT synthesis. Therefore, these results indicate that NO formed in the brain is involved in 8-OH-DPAT-induced hyperphagia and that the hypophagic effects of 7-nitroindazole are not dependent on 5-HT synthesis.

Modulation of the behavioral effects of 8-OH-DPAT by estrogen and DOI.

The effects of female gonadal hormones on 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)-induced flat body posture, hypothermia, and eating behavior were examined. Ovariectomized rats were injected with estradiol benzoate, estradiol benzoate, and progesterone, progesterone or vehicle on each of 2 consecutive weeks. On each week, the behavioral effects of the 5-HT1A receptor agonist, 8-OH-DPAT, or the combination of both 8-OH-DPAT and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), a 5-HT2 receptor agonist, were examined. 8-OH-DPAT produced flat body posture, hypothermia, and eating behavior on each week of the experiment. Female gonadal hormones modulated eating behavior (e.g., rats treated with estradiol benzoate showed less eating after 8-OH-DPAT), but had no effect on either flat body posture or hypothermia. The 5-HT2 receptor agonist, DOI, attenuated 8-OH-DPAT's effect on flat body posture and on hypothermia, but not on eating behavior. 8-OH-DPAT's effect on all behaviors declined during the second week of the experiment.

Serotonin 1A receptor inhibits the status epilepticus induced by lithium-pilocarpine in rats.

Status epilepticus (SE) is a life-threatening neurological emergency associated with a high mortality rate. The serotonin 1A (5-HT1A) receptor is a possible target for the treatment of SE, but its role in animal models and the precise area of brain involved remain controversial. The hippocampus is a candidate site due to its key role in the development of SE and the existence of a high density of 5-HT1A receptors. Therefore, we investigated the effects of subcutaneous and intrahippocampal activation of 5-HT1A receptors in lithium-pilocarpine-induced SE, and tested whether the hippocampus is a true effector site. We developed SE in male Sprague-Dawley rats by giving lithium chloride (LiCl; 3 meq/kg, i.p.) 22-24 h prior to pilocarpine (25 mg/kg, i.p.), and found that 8-OH-DPAT, a 5-HT1A receptor agonist administered subcutaneously (s.c.) at 0.5 or 1.0 mg/kg 1 h before pilocarpine injection increased the latency to the first epileptiform spikes, the electrographic SE, and the behavioral generalized seizures (GS), while reducing the total EEG seizure time (P <0.01). The duration of GS was shortened only by 1.0 mg/kg 8-OH-DPAT s.c. (P <0.05). All these effects were inhibited by combined administration of WAY-100635 (1.0 mg/kg, s.c.) (P <0.05), an antagonist of the 5-HT1A receptor, but WAY-100635 alone and low doses of 8-OHDPAT (0.01 and 0.1 mg/kg) did not alter seizure activity. Furthermore, intrahippocampal 8-OH-DPAT only shortened the GS duration (P <0.05). These findings imply that the 5-HT1A receptor is a promising therapeutic target against the generation and propagation of SE, and hippocampal receptors are involved in reducing the seizure severity.

Dorsomedial hypothalamus serotonin 1A receptors mediate a panic-related response in the elevated T-maze.

The dorsomedial hypothalamus (DMH) has long been associated with the regulation of escape, a panic-related defensive response. Previous evidence has shown that the activation of serotonin (5-HT) 1A and 2A receptors impairs escape behavior induced by the electrical stimulation of the same region. In this study we further explore the relationship of the DMH with defense by investigating the effects of 5-HT1A activation on escape behavior generated in male Wistar rats by an ethologically based aversive stimuli, exposure to one of the open arms of the elevated T-maze (ETM). Aside from escape, the ETM also allows the measurement of inhibitory avoidance, a defensive response associated with generalized anxiety disorder. To evaluate locomotor activity, after ETM measurements animals were submitted to an open field. Results showed that intra-DMH administration of the 5-HT1A receptor agonist 8-OH-DPAT inhibited escape expression. Local administration of the 5-HT1A antagonist WAY-100635 by its own was ineffective, but blocked the panicolytic-like effect of 8-OH-DPAT. Chronic (21 days) systemic treatment with imipramine potentiated the anti-escape effect of 8-OH-DPAT. No significant effects of treatment with 8-OH-DPAT or imipramine on avoidance latencies or the number of lines crossed in the open field were found. These results indicate that 5-HT1A receptors within the DMH may play a phasic inhibitory role on ETM escape expression. As previously proposed, facilitation of 5-HT1A-mediated neurotransmission in the DMH may be involved in the mechanism of action of anti-panic compounds.