Strain differences in the response to the 5-HT1A receptor agonist, 8-OH-DPAT

Fischer and Sprague-Dawley ovariectomized rats were hormonally primed with estradiol benzoate (EB) and progesterone, and the ability of the 5-HT(1A) receptor agonist, (+/-) 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), to inhibit lordosis behavior was examined. Both strains showed rapid inhibition of lordosis behavior following either intraperitoneal or subcutaneous treatment with 8-OH-DPAT. Similarly, in both strains, pretreatment with EB (1 week prior to estrogen and progesterone priming) attenuated the lordosis-inhibiting effects of 8-OH-DPAT. However, Sprague-Dawley females showed a greater decline in lordosis behavior with a lower dose of 8-OH-DPAT than did Fischer females. The strain difference was present in females that had been preprimed with EB as well as in females receiving a single estrogen and progesterone priming. Moreover, strain differences were present across different priming doses of EB. Sprague-Dawley females were also more likely to show flat body posture after injection with 8-OH-DPAT so that the greater sensitivity of this strain to the 5-HT(1A) receptor agonist was not restricted to the drug's effect on lordosis behavior. These findings lead to the suggestion that, relative to Fischer rats, Sprague-Dawley females are more responsive to the 5-HT(1A) receptor agonist. Possible explanations for this strain difference are discussed.     

Factors elevating cAMP attenuate the effects of 8-OH-DPAT on lordosis behavior

The effects of a soluble derivative of forskolin and of two membrane-permeable analogs of cAMP, dibutyryl cAMP, and 8-bromo-cAMP, on the ability of a serotonin (5-HT)(1A) receptor agonist to inhibit lordosis behavior were examined. Sexually receptive, proestrous rats received a bilateral infusion into the ventromedial nucleus of the hypothalamus (VMN) with 68 ng of the forskolin derivative 1, 1.5, 2, or 2.5 h prior to infusion with 200 ng of the 5-HT(1A) receptor agonist, (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Proestrous rats and ovariectomized rats, hormonally primed with 25 microg estradiol benzoate and 500 microg progesterone, were coinfused with 200 ng 8-OH-DPAT and either 50 microg dibutyryl cAMP or 5 microg 8-bromo-cAMP. In proestrous rats, prior infusion with the forskolin derivative reduced the effects of the 5-HT(1A) receptor agonist on lordosis behavior. The best protection occurred at 2 h; by 2.5 h after the preinfusion, any protective effect had disappeared. Coinfusion with either dibutyryl-cAMP or 8-bromo-cAMP reduced the effects of 8-OH-DPAT in proestrous rats. In hormone-primed, ovariectomized rats, dibutyryl cAMP offered significant protection against the effects of 8-OH-DPAT, but there was no protection with 8-bromo-cAMP. These findings are consistent with the speculation that 8-OH-DPAT's inhibition of lordosis behavior results, in part, from an inhibition of adenylyl cyclase, resulting from agonist activation of 5-HT(1A) receptors in the VMN. The findings are also consistent with our earlier observations for differences between proestrous rats and hormone-primed, ovariectomized rats in their response to 5-HT receptor-active compounds.     

Estrogen desensitizes 5-HT(1A) receptors and reduces levels of G(z), G(i1) and G(i3) proteins in the hypothalamus

The present study investigated whether estrogen would desensitize hypothalamic serotonin(1A) (5-HT(1A)) receptors by examining the neuroendocrine response to 8-OH-DPAT, a 5-HT(1A) agonist. Rats were ovariectomized, allowed to recover for 5 days, then given 2 daily injections of estradiol benzoate or vehicle (10 microg/day, s.c.). Twenty-four hours after the second injection, rats were challenged with a sub-maximal dose of 8-OH-DPAT (50 microg/kg, sc) or saline 15 min prior to sacrifice. 8-OH-DPAT produced a significant increase in plasma oxytocin, ACTH and corticosterone levels in ovariectomized rats. While estrogen treatment for 2 days did not alter basal hormone levels, it did significantly reduce the magnitude of oxytocin, ACTH and corticosterone responses to 8-OH-DPAT. The reduction in hormone responses was accompanied by a significant reduction in hypothalamic levels of G(z), G(i1) and G(i3) proteins (by 50%, 30% and 50%, respectively). These findings suggest that a reduction in these G proteins may contribute to the mechanisms underlying estrogen-induced desensitization of 5-HT(1A) receptors. The desensitization of 5-HT(1A) receptors has been suggested to underlie the therapeutic effects of antidepressant 5-HT uptake inhibitors (SSRIs). Thus, the present results suggest that estrogen or estrogen-like substances in combination with SSRIs may prove effective in developing novel therapeutic strategies for neuropsychiatric disorders in women.     

Differential effects of the serotonin1A agonist, 8-OH-DPAT,on masculine and feminine sexual behavior of the ferret

Administration of the serotonin (5-HT)_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) facilitates the expression of masculine sexual behavior in male and female rats as well as in male rhesus monkeys and inhibits lordosis behavior in female rats. In the present study the effects of 8-OH-DPAT on masculine coital and feminine proceptive and receptive behaviors were evaluated in the ferret, a carnivore. Doses of 8-OH-DPAT (0.1 or 0.2 mg/kg) that facilitate masculine sexual behavior in rats inhibited masculine sexual behavior in castrated, estradiol benzoate (EB)-treated male ferrets. Lower doses of 8-OH-DPAT (5 or 10 µg/kg) had no effect on the expression of masculine sexual behavior in either males or females. In contrast to the female rat, administration of 8-OH-DPAT significantly facilitated receptive behaviors in ovariectomized, EB-treated female ferrets. None of the doses of 8-OH-DPAT tested modified proceptive behaviors of gonadectomized, EB-treated male or female ferrets, as assessed in a T-maze in which the subjects could choose to approach either a castrated, sexually inactive male or a castrated, testosterone-primed stud male. Thus whereas the 5-HT_1A receptor agonist 8-OH-DPAT facilitates masculine sexual behavior and inhibits lordosis in the rat, it inhibits masculine sexual behavior and facilitates receptivity in the ferret. The different effects of 8-OH-DPAT observed in these two species may reflect differences in the neural control of their masculine coital and feminine receptive responses, respectively.     

A role for serotonin in lipopolysaccharide-induced anorexia in rats

Rats consistently reduce their food intake following injection of bacterial lipopolysaccharides (LPS). Because LPS increases CNS serotonin (5-HT) turnover, and because increases in CNS 5-HT turnover are associated with a decrease in food intake, we conducted a series of studies to examine 5-HT's potential role in LPS-induced anorexia. Chronic CNS 5-HT depletion by cisterna magna (CM) administration of 5,7-dihydroxytryptamine (5,7-DHT) failed to attenuate LPS-induced (100 microg/kg, ip) anorexia. In subsequent experiments, LPS was injected at lights out (hour 0) and [8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT)] or N-CBZ-[(8beta)-1,6-dimethylergolin-8-yl]methylamine (metergoline) was injected at hour 5 - the time when LPS-treated rats become anorectic. Food intake was measured during the subsequent 2 h. In LPS-treated rats, 8-OH-DPAT (62.5, 125, or 250 microg/kg, sc) injection increased food intake. In a 2 x 2 factorial arrangement of LPS and 8-OH-DPAT, 125 microg/kg 8-OH-DPAT increased food intake significantly more in LPS-treated rats than in non-LPS-treated rats (significant LPS x 8-OH-DPAT interaction). In LPS-treated rats, 1 and 5 mg/kg metergoline significantly enhanced food intake. However, in a 2 x 2 arrangement of LPS and metergoline, 1 mg/kg metergoline failed to increase food intake in LPS and non-LPS-treated rats in two separate trials. The ability of the 5-HT(1A) receptor agonist 8-OH-DPAT to attenuate LPS-induced anorexia in rats supports a role of 5-HT in LPS-induced anorexia.     

Restraint accentuates the effects of 5-HT2 receptor antagonists and a 5-HT1A receptor agonist on lordosis behavior

The effect of restraint on lordosis behavior was examined in proestrous and ovariectomized, hormone-primed rats. Restraint durations from 5 to 60 min had no effect on lordosis behavior of proestrous rats. There was also no effect of 5 min restraint on lordosis behavior of ovariectomized rats hormonally primed with 10 microg estradiol benzoate and 500 microg progesterone. However, after intraperitoneal treatment with 1.0 mg/kg ketanserin tartrate (ketanserin), 5 min of restraint significantly reduced lordosis behavior of both groups of rats. The 5-min restraint combined with 0.50 or 0.75 mg/kg ketanserin reduced lordosis to mount (L/M) ratios of ovariectomized rats, while L/M ratios of proestrous rats were inhibited only by the 1.0 mg/kg dose. Increasing the restraint duration (10 or 15 min) reduced the dose of ketanserin necessary to reduce the L/M ratios of proestrous rats. Treatment with the selective serotonin (5-HT)(2C) receptor antagonist, SB206553 (2.5 or 5.0 mg/kg), in combination with 5 min of restraint, also reduced L/M ratios of hormonally primed, ovariectomized rats. The neural sites responsible for ketanserin's additivity with restraint are unknown, but infusion of the drug into the ventromedial nucleus of the hypothalamus (VMN) did not mimic the systemic treatment. However, 5 min of restraint did enhance the effects of VMN infusion with the 5-HT(1A) receptor agonist, 8-OH-DPAT. In contrast, 8-OH-DPAT's systemic potency was not enhanced by restraint. These findings support the hypothesis that a mild stressor increases the lordosis-inhibiting effects of 5-HT(1A) receptor agonists and that 5-HT(2) receptors may protect against such disruption of lordosis behavior.     

Effects of 5-HT1A-receptor agonist, 8-OH-DPAT, and GABAB-receptor agonist, baclofen, on lordosis in female rats with lesions in either the dorsal raphe nucleus or septum

The inhibitory effects of 8-OH-DPAT, a 5-HT1A-receptor agonist, and baclofen, a GABAB-receptor agonist, on lordosis were examined in estrogen and progesterone-treated ovariectomized rats with lesions in either the dorsal raphe nucleus (DRN) or septum and in rats with either sham lesions or no lesions. The first behavior test series was carried out 6 days after implantation of the rats with silicon tubes containing estradiol. Four hours after injection with 0.5 mg progesterone, behavioral tests were performed before and 30 min after an injection with 1 mg/kg body weight 8-OH-DPAT. As a result, the mean lordosis quotient (LQ)s were changed from 100 to less than 20 before and after the injection in all groups. These results suggest that 8-OH-DPAT acts on areas other than the DRN and the septum, leading to a decrease in lordosis. Two weeks after implantation with estradiol, the next behavioral test series was carried out after injection with progesterone. Behavioral tests were performed before and after an injection with 10 mg baclofen. The results showed that the mean LQs decreased after the injection in all groups, but the mean LQ in the DRN lesion group was higher than that in the sham groups. These results indicate that baclofen may act partially on the DRN in inhibiting lordosis in female rats.     

Serotonin receptor involvement in effects of restraint on female rat lordosis behavior

Ovariectomized Fischer (CDF-344) rats, with bilateral cannulae in the mediobasal hypothalamus (MBH) near the ventromedial nucleus of the hypothalamus (VMN), were used to test the hypothesis that serotonin receptors in the VMN contribute to the lordosis-inhibiting effects of mild restraint. Rats were hormonally primed with 10 microg estradiol benzoate (EB) followed 48 h later with sesame seed oil. Four to six hours later (during the dark portion of the light-dark cycle), rats were pretested for sexual behavior. Thereafter, they were infused with saline, 2 microg of the serotonin (5-HT) 2 receptor agonist, (+/-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane HCl (DOI), or 1 microg of the 5-HT(1A) receptor antagonist, N-{2[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY100635). After a 5 min restraint, rats were tested for sexual receptivity. Rats infused with saline showed a significant decline in lordosis behavior after restraint. Infusion with either DOI or WAY100635 attenuated these effects of restraint. These findings extend earlier observations that the lordosis-disruptive effects of mild restraint include activation of 5-HT(1A) receptors in the VMN and are the first to implicate VMN 5-HT(2) receptors in protection against mild restraint.     

Separation of dopaminergic and serotonergic inhibitory mechanisms in the mediation of estrogen-induced lordosis behaviour in the rat

The administration of the putative 5-hydroxytryptamine1 (5-HT1) agonist 8-hydroxy-2(di-n-propylamino) tetralin (8-OH-DPAT) (0.0625-1.0 mg X kg-1) suppresses lordosis behaviour induced in ovariectomized female rats by daily treatment for 3-5 days with estradiol benzoate (1.25 micrograms/rat). A similar suppressive effect on the lordosis behaviour can be obtained by administration of the dopamine/serotonin agonist, lisuride (0.1-0.4 mg X kg-1), or after the administration of the dopamine (DA) agonists, apomorphine (0.2-0.8 mg X kg-1) or quinpirole (0.75-2.50 mg X kg-1). The suppressive effects on the lordosis behaviour by 8-OH-DPAT cannot be antagonized by the DA receptor antagonist haloperidol (0.2 mg X kg-1) neither with methiotepin (0.5 mg X kg-1), which is assumed to be a non-selective 5-HT receptor blocking agent, nor with pirenperone (0.25 mg X kg-1) which is assumed to be a 5-HT2 receptor blocking agent. However, a partial blockade of the lordosis suppressive effects of 8-OH-DPAT was obtained by treatment with (-)-pindolol, which is thought to be a partial 5-HT1 blocking agent, suggesting that 8-OH-DPAT exerts its suppressive effects on the lordosis behaviour through the 5-HT system. Haloperidol causes a complete blockade of the suppressive effects of apomorphine and quinpirole suggesting that these drugs exert their inhibitory effects on the lordosis behaviour by activating the DA system.(ABSTRACT TRUNCATED AT 250 WORDS)     

Suppression of lordosis behavior by the putative 5-HT receptor agonist 8-OH-DPAT in the rat

The administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), inhibited the lordosis induced by estradiol benzoate or estradiol benzoate plus progesterone in ovariectomized rats. There was no facilitation of lordosis by 8-OH-DPAT in animals pretreated with a threshold dose of estradiol benzoate. The results are consistent with the view that 8-OH-DPAT is an agonist at 5-HT receptors and provide further support for an inhibition role of central 5-HT in the mediation of lordosis behavior.     

Treatment of cycling female rats with fluoxetine induces desensitization of hypothalamic 5-HT(1A) receptors with no change in 5-HT(2A) receptors

Although women constitute the majority of patients who receive treatment with selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, most animal studies of SSRIs are conducted on males. The present study investigated whether long-term treatment of cycling female rats with fluoxetine alters their estrous cycle and the sensitivity of hypothalamic serotonin (5-HT) 5-HT(1A) and 5-HT(2A) receptor systems. Adult female rats received daily injections of fluoxetine (10 mg/kg, i.p.) for three consecutive estrous cycles (15.2+/-0.2 days) with the first injection beginning on metestrus (when circulating estrogen levels are low and stable). Fluoxetine did not alter basal plasma estradiol levels at metestrus, nor did it alter the pattern of estrous cyclicity. Rats treated with fluoxetine showed a loss in body weight. On the morning of metestrus of the fourth cycle (18 h after the last fluoxetine injection), the rats were injected with a sub-maximal dose of the 5-HT(1A) agonist (+/-)-8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT, 50 MICRO/kg, s.c.) or a maximal dose of the 5-HT(2A) agonist [(+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl] (DOI). Plasma levels of oxytocin, ACTH and corticosterone were measured as peripheral indicators of hypothalamic 5-HT(1A) and 5-HT(2A) receptor sensitivity. Injecting 8-OH-DPAT to saline pretreated rats produced a significant increase in plasma oxytocin (299%), ACTH (1456%) and corticosterone (170%) levels but not in plasma prolactin or renin concentrations. Greater increases in plasma levels of these hormones were observed after injecting DOI. Fluoxetine treatment completely blocked the oxytocin, ACTH and corticosterone responses to 8-OH-DPAT, but did not inhibit the effect of DOI on any hormone, thus confirming that fluoxetine treatment did not produce a deficit in the functioning of corticotropin releasing hormone or oxytocin containing neurons. These results indicate that in cycling female rats, fluoxetine treatment desensitizes hypothalamic post-synaptic 5-HT(1A) receptor signaling. Understanding the pharmacological effects of fluoxetine in females may lead to more effective treatment of women with mood disorders.     

Evidence for the involvement of central 5-HT1A receptors in the mediation of lordosis behavior in the female rat

5-Hydroxy-L-tryptophan (5-HTP), 25 mg kg^-1 IP, in combination with the peripheral 5-HTP decarboxylase inhibitor benserazide, 25 mg kg^-1 IP, and the selective inhibitor of neuronal 5-hydroxytryptamine (5-HT) re-uptake, zimeldine, 10 mg kg^-1 IP, suppressed lordosis in ovariectomized female rats, treated with estradiol benzoate (EB) or with EB plus progesterone (P). The suppression of lordosis produced by 5-HTP was antagonized by the -receptor blocker (-)pindolol, which also is a selective 5-HT₁ receptor antagonist, but not by the 5-HT₂ receptor antagonists metitepine or pirenperone, nor by the -receptor blocker betaxolol. The EB-or EB plus P-activated lordosis was also suppressed by administration of the selective 5-HT_1a receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Together, these observations indicate an important role of central 5-HT_1a receptors in the mediation of lordosis behavior in the female rat.     

Diabetes-induced changes in 5-hydroxytryptamine modulation of vagally-induced bradycardia in rat heart

1. In the present study, we investigated how alloxan-induced diabetes affects the ability of 5-hydroxytryptamine (5-HT) to modulate bradycardia induced in vivo by electrical stimulation of the vagus nerve in pithed rats. We also analysed the type and/or subtype of 5-HT receptors involved. 2. Diabetes was induced in male Wistar rats with a single injection of alloxan (150 mg/kg, s.c.). Four weeks later, rats were anaesthetized, pretreated with atenolol and pithed. Electrical stimulation (3, 6 and 9 Hz) of the vagus nerve resulted in frequency dependent decreases in heart rate (HR). 3. In diabetic rats, intravenous bolus administration of high doses of 5-HT (100 and 200 microg/kg) increased the bradycardia induced by vagal electrical stimulation. Similarly, low doses (10 microg/kg) of the 5-HT(1/7) receptor agonist 5-carboxamidotryptamine (5-CT), increased vagally induced bradycardia. However, at high doses (50, 100 and 150 microg/kg), 5-CT reduced the bradycardia. Attenuation of the vagally induced bradycardia evoked by the higher doses of 5-CT was reproduced by L-694,247 (50 microg/kg), a selective agonist for the non-rodent 5-HT(1B) and 5-HT(1D) receptors. Enhancement of the vagally induced bradycardia elicited by low doses of 5-CT was reproduced by the selective 5-HT(1A) receptor agonist 8-hydroxydipropylaminotretalin hydrobromide (8-OH-DPAT; 50 microg/kg). These stimulatory and inhibitory actions on vagal stimulation-induced bradycardia in diabetic rats were also observed after administration of exogenous acetylcholine. 4. Vagally induced bradycardia in diabetic rats was not affected by administration of the selective 5-HT(2) receptor agonist alpha-methyl-5-HT (150 microg/kg), the selective 5-HT(3) receptor agonist 1-phenylbiguanide (150 microg/kg) or the selective 5-HT(1B) receptor agonist CGS-12066B (50 microg/kg). 5. Enhancement of the electrical stimulation-induced bradycardia in diabetic rats caused by 5-CT (10 microg/kg) or 8-OH-DPAT (50 microg/kg) was abolished by the selective 5-HT(2/7) receptor antagonist mesulergine (1 mg/kg) and the selective 5-HT(1A) receptor antagonist WAY-100,635 (100 microg/kg), respectively. Similarly, pretreatment with the non-selective 5-HT(1) receptor antagonist methiothepin (0.1 mg/kg) blocked the inhibitory effect of 5-CT (50 microg/kg) on the bradycardia induced by vagal electrical stimulation in diabetic rats. BRL-15572 (2 microg/kg), a selective 5-HT(1D) receptor antagonist, inhibited the action of L-694,247 (50 microg/kg), a selective agonist for the non-rodent 5-HT(1B) and 5-HT(1D) receptors, on the vagally induced bradycardia. 6. In conclusion, in the present study, experimental diabetes evoked changes in both the nature and 5-HT receptor types/subtypes involved in vagally induced bradycardia.     

Effects of fenfluramine on free-operant timing behaviour: evidence for involvement of 5-HT2A receptors

RATIONALE: Temporal differentiation in the free-operant psychophysical procedure is sensitive to the 5-hydroxytryptamine (5-HT)1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and the 5-HT2 receptor agonist 2,5-dimethoxy-4-iodo-amphetamine (DOI); both drugs shift the psychophysical curve leftwards, reducing the indifference point, T50. We have examined the effect of the 5-HT releasing agent fenfluramine on temporal differentiation. OBJECTIVE: We examined whether fenfluramine's effect on temporal differentiation can be antagonised by the 5-HT1A receptor antagonist N-[2-(4-[2-methoxy-phenyl]-1-piperazinyl)ethyl]-N-2-pyridinylcyclohexane-carboxamide (WAY-100635) and the 5-HT2A receptor antagonist ketanserin, and compared the effects of fenfluramine, DOI and 8-OH-DPAT in intact rats and rats whose 5-HTergic pathways had been destroyed by 5,7-dihydroxytryptamine. METHODS: Rats were trained under the free-operant psychophysical procedure to press levers A and B in 50-s trials in which reinforcers were provided intermittently for responding on A in the first half, and B in the second half of the trial. Percent responding on B (%B) was recorded in successive 5-s epochs of the trials; logistic psychophysical curves were fitted to the data for derivation of timing indices (T50, time corresponding to %B=50%, and Weber fraction). Experiment 1 examined the effects of acute treatment with fenfluramine, and the interaction between fenfluramine and the 5-HT1A and 5-HT2A receptor antagonists WAY-100635 and ketanserin; experiment 2 compared the effects of fenfluramine, 8-OH-DPAT and DOI in intact rats and rats whose 5-HTergic pathways had been destroyed by intra-raphe injection of 5,7-dihydroxytryptamine. Concentrations of 5-HT and catecholamines in the brain were measured by high-performance liquid chromatography. RESULTS: Experiment 1: fenfluramine (2 mg/kg) reduced T50; this effect was attenuated by ketanserin (1.0 mg/kg) but not by WAY-100635 (100 microg/kg). Experiment 2: 8-OH-DPAT (100 microg/kg) and DOI (250 microg/kg) reduced T50 in both groups; fenfluramine reduced T50 only in the sham-lesioned group. Levels of 5-HT were reduced by 80% in the lesioned group; catecholamine levels were not affected. CONCLUSIONS: The results suggest that fenfluramine affects temporal differentiation via the release of endogenous 5-HT which acts mainly on postsynaptic 5-HT2A receptors.     

Stimulation of 5-HT1A receptors in the dorsal hippocampus and inhibition of limbic seizures induced by kainic acid in rats.

1. We studied whether the stimulation of 5-HT1A receptors by 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a specific 5-HT1A receptor agonist, reduced electroencephalographic (EEG) seizures induced by intrahippocampal injection of 0.04 microgram in 0.5 microliter of the glutamate analogue kainic acid in freely-moving rats. 2. Pretreatment with 8-OH-DPAT 15 min earlier at the same site as kainic acid injection, caused a dose-dependent decrease of kainic acid-induced seizure activity. One and 10 micrograms significantly reduced the total time spent in seizures by 72% on average and the total number of seizures by 58% (P < 0.01) and 43% (P < 0.05) respectively. The latency to onset of the first seizure was increased 2.8 times (P < 0.01) only after 1 microgram 8-OH-DPAT; 0.1 microgram was ineffective on all seizure parameters. 3. Systemic administration of 25, 100 and 1000 micrograms kg-1 8-OH-DPAT significantly reduced the total number of seizures and the total time in seizures induced by intrahippocampal kainic acid by 52% and 74% on average. The latency to onset of the first seizure was delayed 1.8 times by 100 and 1000 micrograms kg-1 (P < 0.05). 4. The anticonvulsant action of 8-OH-DPAT given intrahippocampally or systemically was significantly blocked by 5 micrograms, but not 1 microgram WAY 100635, a selective 5-HT1A receptor antagonist, administered in the hippocampus before the agonist. 5. These results indicate that postsynaptic 5-HT1A receptors in the hippocampus mediate the anticonvulsant action of 8-OH-DPAT and that their stimulation has an inhibitory role in the generation of limbic seizures.     

Diabetes-induced changes in the 5-hydroxytryptamine inhibitory receptors involved in the pressor effect elicited by sympathetic stimulation in the pithed rat

1. We investigated the effect of alloxan-induced diabetes on the inhibitory mechanisms of 5-hydroxytryptamine (5-HT) in the pressor responses induced by stimulation of sympathetic vasopressor outflow in pithed rats, and analysed the type and/or subtype of 5-HT receptors involved. 2. Diabetes was induced in male Wistar rats by a single s.c. injection of alloxan, then 4 weeks later, they were anaesthetized, pretreated with atropine and pithed. Electrical stimulation of the sympathetic outflow from the spinal cord (0.1, 0.5, 1 and 5 Hz) resulted in frequency-dependent increases in blood pressure. 3. Intravenous infusions of 5-HT (1-80 microg kg(-1) min(-1)) reduced the pressor effects obtained by electrical stimulation. The 5-HT(1) receptor agonist 5-carboxamidotryptamine, 5-CT (5 microg kg(-1) min(-1)), caused an inhibition of the pressor response, whereas the selective 5-HT(2) receptor agonist, alpha-methyl-5-HT (5 microg kg(-1) min(-1)) and the selective 5-HT(3) receptor agonist, 1-phenylbiguanide (40 microg kg(-1) min(-1)), did not modify the sympathetic pressor responses. 5-HT had no effect on exogenous noradrenaline (NA)-induced pressor responses. 4. The inhibition of electrically induced pressor responses by 5-HT (10 microg kg(-1) min(-1)) was unable to be elicited after i.v. treatment with methiothepin (100 microg kg(-1)) because of the marked inhibition produced by methiothepin alone. The 5-HT-induced inhibition was blocked after i.v. administration of WAY-100,635 (100 microg kg(-1)) and not affected by ritanserin (1 mg kg(-1)), MDL 72222 (2 mg kg(-1)). 5. The selective 5-HT(1A) receptor agonist, 8-hydroxydipropylaminotretalin hydrobromide (8-OH-DPAT) (5-20 microg kg(-1) min(-1)) but neither the rodent 5-HT(1B) receptor agonist, CGS-12066B (5 microg kg(-1) min(-1)), nor the selective nonrodent 5-HT(1B) and 5-HT(1D) receptor agonist, L-694,247 (5 and 40 microg kg(-1) min(-1)), inhibited the electrically induced pressor response. The selective 5-HT(1A) receptor antagonist, WAY-100,635 (100 microg kg(-1)), blocked the inhibition induced by 8-OH-DPAT (10 microg kg(-1) min(-1)). 8-OH-DPAT had no effect on exogenous NA-induced pressor responses. 6. Experimental diabetes produces changes in the inhibitory effect induced by 5-HT on electrically induced sympathetic pressor responses, such that the inhibitory action induced by 5-HT in diabetic pithed rats is mediated by prejunctional 5-HT(1A) receptors.     

The septum and the hippocampus differentially mediate anxiolytic effects of R(+)-8-OH-DPAT

Infusing the 5-HT1A receptor agonist R(+)-8-OH-DPAT into the septum or hippocampus reduced the fear responses of rats differentially in the elevated plus-maze and shock-probe burying tests, two rat models of anxiety. Intra-septal infusions of R(+)-8-OH-DPAT (5 and 10 microg) produced dramatic reductions in rat burying behavior in the shock-probe test, whereas it did not alter rat open-arm activity in the plus-maze test, across a wide range of doses (0.1, 0.25, 5 and 10 microg). Conversely, intra-hippocampal infusions of R(+)-8-OH-DPAT (0.1 and 5 microg/side) produced substantial increases in open-arm activity in the plus-maze test, but did not alter rat burying behavior in the shock-probe test. These dissociations suggest that 5-HT1A receptors in the septum and hippocampus exert parallel but distinct control over different fear reactions.     

8-Hydroxy-2-(di-n-propylamino)-tetralin inhibits food intake in fasted rats by an action at 5-HT1A receptors

The effects of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) on food intake were investigated in food-deprived rats. 8-OH-DPAT (25-100 microg/kg) administered subcutaneously immediately prior to the presentation of food produced a dose-related decrease in food intake in rats that had been fasted for 22 h. The hypophagic effect of 8-OH-DPAT (50 microg/kg) was abolished by pretreatment with the selective 5-HT1A receptor antagonist n-[2-(4-2-methoxyphenyl)-1-piperazinyl]-n-(2-pyridyl) cyclohexanecarboxamide (WAY 10063; 0.3 mg/kg). The results of this study show that the acute dose-dependent depressant effect of 8-OH-DPAT on food intake in fasted rats is mediated by an action at 5-HT1A receptors.     

5-HT1A receptor activity disrupts spontaneous alternation behavior in rats

Agonists selective for three different serotonin (5-HT) receptor subtypes were tested for the ability to disrupt spontaneous alternation behavior (SAB) in the CD strain of rats. Rats were scored for alternation or repetition in their choice of arms of a T-maze equally baited with chocolate milk. Compared with vehicle controls, the 5-HT(1A) agonist 8-hydroxy-dipropylaminotetraline (8-OH-DPAT; 2 mg/kg) significantly (P<.0001) increased repetitive choices (disrupted SAB). In contrast, intraperitoneal injections with the 5-HT(2) agonist R-(-)-dimethoxyiodophenylaminoethane (DOI; 1 mg/kg) or the 5-HT(3) agonist N-methyl quipazine (NMQ; 3 mg/kg) had no significant effect on SAB in CD rats. Onset of vicarious trial and error (VTE) behavior prolonged the time required for each rat to select an arm of the T-maze when injected with either 8-OH-DPAT (P<.0001) or buspirone (1-2 mg/kg), a 5-HT(1A) partial agonist. The disruption of SAB and the induction of VTE behavior were reversible with behavioral scores returning to preinjection levels within 48 h after injections. The disruption of SAB by 8-OH-DPAT was also seen with the Long-Evans rat strain. The results extend the use of the SAB model and point to a specific role of 5-HT(1A) receptors in the induction of repetitive behavioral patterns.     

Chronic imipramine enhances 5-HT(1A) and 5-HT(2) receptors-mediated inhibition of panic-like behavior in the rat dorsal periaqueductal gray

Electrical stimulation of the dorsal periaqueductal gray (DPAG) has been used to induce panic-like behavior in rats. In the present study, we investigated the effect of chronic imipramine treatment on the sensitivity of different 5-HT receptor subtypes in inhibiting aversion induced by electrical stimulation of this brain area. For that, the effects of intra-DPAG administration of the endogenous agonist 5-HT (20 nmol), the 5-HT(1A) receptor agonist 8-OH-DPAT (8 nmol) and the 5-HT(2A/2C) receptor agonist DOI (16 nmol) were measured in female Wistar rats given either chronic injection of imipramine (15 mg/kg, 3 weeks, ip) or saline. The results showed that the three receptor agonists raised the threshold of aversive electrical stimulation in both groups of animals, but this antiaversive effect was significantly higher in rats treated with imipramine. Treatment with imipramine did not change the basal threshold of aversive electrical stimulation measured before intra-DPAG injection of the 5-HT agonists. The results suggest that sensitization of both 5-HT(1A) and 5-HT(2) receptors within the DPAG may be involved in the beneficial effect of imipramine in panic disorder (PD).