The effects of a low tryptophan diet on brain 5 -HT metabolism and 5-HT-mediated neuroendocrine responses in the male rat

The study was undertaken to assess the effects of periods of dietary tryptophan (TRP) depletion on (i) plasma total and free TRP together with brain TRP, 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5- HIAA) and (ii) the prolactin (PRL) responses to the 5-HT releasing agent, D-fenfluramine (FEN), and the 5-HT agonist, m-chlorophenylpiperazine (mCPP). The TRP-deficient diet caused significant reductions in plasma total and free TRP for a short-lived period; however, it caused longer lasting and significant reductions in brain TRP, 5-HT and 5-HIAA content. Following periods of dietary TRP depletion, plasma PRL responses to FEN were significantly reduced for 14 days but had normalised by day 21. In contrast, the PRL responses to mCPP were significantly enhanced after 6 and 21 days, the response at 14 days being similar to control. The result suggests that periods of dietary invoked TRP depletion cause a deficiency of brain TRP content which subsequently leads to a fall in brain 5-HT. This is associated with a reduced PRL response to FEN and an enhanced PRL response to mCPP, the latter possibly resulting from functional up-regulation of post-synaptic 5-HT receptors.     

Effect of reserpine on behavioural responses to agonists at 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C receptor subtypes.

Rats were given a single dose of reserpine (5 mg/kg s.c.) and behavioural responses to agonists at 5-HT receptor subtypes compared with those of control animals 21 days later. The following effects of activating postsynaptic 5-HT1A receptors by the agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) were significantly increased: tail-flick, reciprocal forepaw treading, flat body posture. The hyperphagic effect of activating presynaptic 5-HT1A receptors by 8-OH-DPAT tended to increase and hypothermia on activating postsynaptic 5-HT1A sites tended to decrease. The hyperlocomotor effect of activating 5-HT1A sites also tended to decrease possibly as a result of a dependence of this response on the known depletion of catecholamines by reserpine. Head shakes on activating 5-HT2A receptors by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and two effects of activating 5-HT2C receptors by 1-(3-chlorophenyl) piperazine (mCPP) were significantly increased (hypophagia, anxiety) and a third effect, hypolocomotion tended to increase but hypophagia on activating postsynaptic 5-HT1B receptors by CP-94, 253 was significantly attenuated. The results are discussed with particular reference to altered 5-HT function in depression.     

Effect of castration and castration with hormone replacement on the plasma prolactin responses to neuroendocrine challenge with i.v. mCPP in the male rat following a low tryptophan diet

Previous studies have shown that castration increased brain 5-HT synthesis and that sex steroid hormone treatment can reverse this effect. Tryptophan (TRP) depletion has been shown to reduce brain 5-HT synthesis and to cause the post-synaptic 5-HT receptors to up-regulate. We have studied the effects of castration and hormone replacement on the prolactin responses to neuroendocrine challenge with the post-synaptic 5-HT agonist, m-chlorophenylpiperazine (m-CPP) in male rats on a low TRP diet. Intact rats on a low TRP diet for 6 days showed significantly enhanced PRL reponses to mCPP as compared to intact rats on a complementary control diet. Animals castrated 20 days prior to neuroendocrine testing and on a low TRP diet demonstrated a loss of the enhanced PRL response to mCPP. The enhanced PRL response was restored by treatment with 25 mg/ kg of testosterone proprionate (TP) 24 h prior to testing. Rats treated with oestradiol benzoate (OB) from initial castration, showed significantly raised basal PRL concentrations but did not show enhanced PRL responses to mCPP in animals on either a low TRP diet or on a control diet as compared to castrated controls. It is suggested that castration increases brain 5-HT in these animals which leads to a down-regulation of post-synaptic 5-HT receptors. When the animals are then subjected to a low TRP diet for 6 days, a reduction in brain 5-HT synthesis occurs, causing a rebound up-regulation of the 5-HT receptors and therefore the end effect is a stalemate between the two initial effects resulting in the loss of the enhanced response. TP but not OB treatment in these animals restores the enhanced PRL response to mCPP by reducing brain 5 -HT synthesis and returning the post synaptic 5-HT receptors to a state of up-regulation.     

5-HT1A, 5-HT1B and 5-HT2 receptor agonists induce differential behavioral responses in neonatal rat pups

Sprague-Dawley rat pups at 3–4 days prenatally were tested in both the absence and presence of milk following administration of various doses of either the 5-HT_1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT), the 5-HT_1B agonist 1-(3-chlorophenyl)piperazine (mCPP), or the 5-HT₂ agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Administration of 8-OHDPAT decreased mouthing, increased probing and increased behavioral activation. Conversely, the 5-HT₂ agonist DOI and the 5-HT_1B agonist mCPP increased mouthing and decreased probing. mCPP and DOI differed in their effects on behavioral activation, with mCPP decreasing and DOI increasing this composite behavioral score. mCPP increased grooming, whereas DOI elicited a characteristic unusual positioning of the limbs. Thus it appears that 5-HT_1A, 5-HT_1B and 5-HT₂ receptor subtypes are present in the neonate and elicit differential behavioral responses upon stimulation with selective agonists. Ontogenetic variations in the balance among these receptor subtypes during development may be related to the ontogenetic reversal that has been previously reported in the impact of serotonin manipulations on mouthing and suckling behavior during the neonatal to weanling age period.     

5-HT1A, 5-HT1B and 5-HT2 receptor agonists induce differential behavioral responses in preweanling rat pups

Preweanling (postnatal day 17-18) Sprague-Dawley rat pups were tested in both the absence and presence of milk following administration of various doses of the 5-HT1A agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) or ipsapirone, the 5-HT1B agonist 1-(3-chlorophenyl)piperazine (mCPP) or the 5-HT2 agonist 1-(2,5-dimethoxy-4-iodo-phenyl)-2-aminopropane (DOI). 8-OH-DPAT decreased mouthing while ipsapirone, mCPP and DOI had no effect upon this behavior. However, all four agonists significantly decreased grooming. Both 8-OH-DPAT and mCPP produced alterations in limb positioning, with 8-OH-DPAT administration resulting in a poor control of the hindlimbs and mCPP inducing a hindlimb straddle position. These functional responses to 5-HT1A, 5-HT1B and 5-HT2 agonists in preweanling pups vary from those observed previously in neonates. For instance, whereas inhibitory effects of 5-HT1A stimulation on mouthing are observed in both neonatal and preweanling pups, facilitory effects of 5-HT1B and 5-HT2 stimulation are only seen in neonates. These ontogenetic alterations may be related to the previously reported ontogenetic reversal in the effect of serotonergic activation upon mouthing and suckling that occurs during the neonatal to weanling age period.     

Behavioral and biochemical effects of the 5-HT1A receptor agonists flesinoxan and 8-OH-DPAT in the rat.

The 5-HT_1A receptor agonists flesinoxan (0.2–3.2 mg kg⁻¹ s.c.) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.025–0.4 mg kg⁻¹ s.c.) produced (1) a dose-dependent facilitation of male rat ejaculatory behavior and (2) characteristic, dose-dependent effects on spontaneous motor activity. Thus, total locomotor activity and rearing activity were decreased. However, forward locomotion and peripheral locomotion were increased relative to the total horizontal activity. Furthermore, (3) 5-HTP accumulation, after inhibition of cerebral decarboxylase, was dose dependency decreased by both compounds in the ventral striatum and in the prefrontal cortex. There was a statistically significant decrease in DOPA accumulation in the ventral striatum after administration of a high dose of flesinoxan (3.2 mg kg⁻¹), and a tendency for 8-OH-DPAT to produce the same effect. The efficacy of the compounds to affect male rat sexual behavior, spontaneous motor activity in the open-field and forebrain 5-HT synthesis was approximately the same, whereas flesinoxan was about an order of magnitude less potent than 8-OH-DPAT.     

Effect of chronic treatment with 5-HT1 agonist (8-OH-DPAT and RU 24969) and antagonist (isapirone) drugs on the behavioural responses of mice to 5-HT1 and 5-HT2 agonists.

The effects of chronic (14 day) administration to mice of the 5-HT1 agonists 8-hydroxy 2-(di-n-propylamino) tetralin (8-OH-DPAT) and 5-methoxy-3 (1,2,3,6-tetrahydropyridin-4-yl) IH indole (RU 24969) on the hypothermic response to 8-OH-DPAT and the locomotor response to RU 24969 have been examined. Chronic administration of 8-OH-DPAT (5 mg kg-1, s.c.) resulted in an attenuated hypothermic response to this drug given subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) but did not alter the locomotor response to RU 24969. Chronic injection of RU 24969 (3 mg kg-1, i.p.) produced an attenuated locomotor response to this drug given i.p. or i.c.v. but not the hypothermic response to 8-OH-DPAT (0.5 mg kg-1, s.c.). Chronic administration of the putative presynaptic 5-HT1 antagonist isapirone (10 mg kg-1, i.p.) decreased the hypothermic response following 8-OH-DPAT injection but did not alter RU 24969-induced locomotion. Chronic treatment with 8-OH-DPAT (5 mg kg-1, s.c.) produced a modest enhancement of the 5-HT2 receptor-mediated head-twitch behaviour initiated by 5-hydroxytryptophan injection while chronic isapirone decreased this behavioural response. 5-HT2 receptor number in frontal cortex was unaltered by isapirone treatment but markedly decreased (34%) by chronic 8-OH-DPAT. These data suggest that chronic administration of the 5-HT1 agonists induces tolerance in their respective responses but not cross-tolerance, while chronic isapirone may down-regulate the 5-HT1A site in a matter analogous to that seen by 5-HT2 receptors following 5-HT2 receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)     

Single-dose 8-OH-DPAT pretreatment does not induce tachyphylaxis to the 5-HT release-reducing effect of 5-HT1A autoreceptor agonists.

It has recently been suggested that central 5-HT1A autoreceptors are already desensitised after single-dose 5-HT1A agonist treatment. In turn, this would lead to an attenuated feedback suppression of transmitter release from 5-HT neurones, and thus to enhanced 5-HT synaptic transmission. In the present study in vivo brain microdialysis techniques were used in an attempt to test this hypothesis. The results show that single-dose pretreatment with the reference 5-HT1A receptor agonist 8-hydroxy-2-(din-propylamino)tetralin, 8-OH-DPAT, (i) did not significantly alter the baseline output of 5-HT in the rat ventral hippocampus 24 h later, and (ii) did not alter the release-reducing response to 5-HT1A agonist (8-OH-DPAT, ipsapirone or BMY 7378) challenge under the same conditions. These observations indicate that the functional responsiveness of the 5-HT release-controlling 5-HT1A autoreceptors is maintained after bolus 8-OH-DPAT pretreatment. When related to the acute 8-OH-DPAT-induced reduction in raphe 5-HT1A radioligand binding density recently reported by others, the present results are consistent with a large functional overcapacity of this 5-HT1A receptor population. The mechanism by which 5-HT1A receptor-mediated hypothermia and hyperphagia are rapidly attenuated by a previous large single dose of a 5-HT1A receptor agonist remains to be explained.     

The 5-HT1A agonists 8-OH-DPAT, buspirone and ipsapirone attenuate stress-induced anorexia in rats

The effects of 5-HT agonists and antagonists, benzodiazepine anxiolytics and tricyclic antidepressants on restraint stress-induced anorexia in rats were examined. The selective 5-HT(1A) agonists 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT), buspirone and ipsapirone, when injected 2 h after the termination of stress, attenuated stress-induced anor exia and body weight loss. The effects of 8-OH-DPAT on stress-induced anorexia were blocked by the 5-HT(1A) antagonist spiperone but not by the 5-HT(2) antagonist ketanserin. The preferential 5-HT(1B) agonists RU-24969 and quipazine induced anorexia in unstressed rats and tended to supplement the anorectic effects of stress. The benzodiazepines chlordiazepoxide and diazepam and the 5-HT antagonist cyproheptadine had no effect on stress-induced anorexia, when given (like the 5-HT(1A) agonists) 2 h after the stress. Similarly, daily injection for 2 weeks of the tricyclic antidepressants desipramine and sertraline had no beneficial effect. The data suggest that 8-OH-DPAT, buspirone and ipsapirone attenuate stress-induced anorexia in rodents by a hyperphagic action on 5-HT(1A) receptors.     

Role of 5-HT1B, 5-HT2A and 5-HT2C receptors in the generalization of 5-HT receptor agonists to the ethanol cue in the rat

Although accumulating evidence suggests that serotonergic drugs are able to substitute for the ethanol (EtOH) cue in rats, it is still unclear which 5-HT receptor subtypes are responsible for this phenomenon, and whether these receptors are critically involved in the EtOH cue. In the present study, rats were trained to discriminate EtOH (1000 mg/kg, i.p., t-15 min) from saline in a two-lever food-reinforced procedure, and it was investigated to which extent serotonergic compounds with a certain level of specificity for either 5-HT1B, 5-HT2A or 5-HT2C receptors generalized to the EtOH cue. Subsequently, the involvement of these receptor subtypes was ascertained by the use of selected 5-HT receptor antagonists. The 5-HT1B receptor agonist CP 94,253 (0.3-5 mg/kg, i.p.) and the mixed 5-HT(2C/1B) receptor agonist mCPP (0.1-1 mg/kg, i.p.), but not the preferential 5-HT2A receptor agonist DOI (0.3-1 mg/kg, i.p.), completely generalized to the EtOH cue. Complete generalization of the former two compounds coincided with a decrease in response rate. In antagonism studies, it was shown that the 5-HT1B receptor antagonist GR 127935 (10 mg/kg, i.p.) completely blocked generalization of CP 94,253 to the EtOH cue, suggesting that stimulation of 5-HT1B receptors produces discriminative stimulus effects which are similar to those of EtOH. GR 127935 (10 mg/kg, i.p.), as well as the mixed 5-HT(1B/2C) receptor antagonist metergoline (1 mg/kg, i.p.), and the 5-HT2C receptor antagonist SB 206,553 (1 mg/kg, i.p.) completely blocked generalization of mCPP to the EtOH cue. This suggests that 5-HT1B and 5-HT2C receptors are required for the generalization of mCPP to the EtOH cue. The present findings indicate that activation of 5-HT1B and 5-HT2C, but not of 5-HT2A receptors, mimics the EtOH cue. However, the finding that neither metergoline, nor the 5-HT2A receptor antagonist MDL 100,907 blocked the EtOH cue, suggests that these receptors play only a minor role in the discriminative stimulus effects of a moderately low dose of EtOH.     

Hypothermia induced by the putative 5-HT1A agonists LY165163 and 8-OH-DPAT is not prevented by 5-HT depletion

The putative 5-HT1A agonist 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)piperazine (LY165163, PAPP) (1, 2, 4, 10 mg/kg s.c.) caused a significant and dose-dependent hypothermia in rats, 30 and 60 min after injection. The decreases of temperature were less marked than that caused by 8-OH-DPAT 1 mg/kg s.c.). Depletion of brain serotonin (5-HT) by 91% following pretreatment with p-chlorophenylalanine (pCPA) (150 mg/kg i.p. on three successive days) significantly enhanced the hypothermic effects of both 8-OH-DPAT (0.25 mg/kg s.c.) and LY165163 (4 mg/kg s.c.). LY165163-induced hypothermia was also somewhat enhanced following depletion of hypothalamic 5-HT by 76% after infusion of 5,7-dihydroxytryptamine (5,7-DHT) (150 micrograms) into the third ventricle. Results indicate that the hypothermia induced by the putative 5-HT1A agonists LY165163 and 8-OH-DPAT in the rat is not dependent on presynaptic 5-HT stores and is therefore probably mediated by postsynaptic 5-HT receptors.     

Effect of the 5-HT1A agonist, 8-OH-DPAT on instrumental performance in rats

These experiments assessed whether reported increases in food consumption and food-reinforced instrumental performance in undeprived rats by the 5-HT_1A agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) are due to an increment in the incentive value of foods. Against this hypothesis, we found that when undeprived rats were trained to lever press for the food pellets and then allowed to consume the pellets under 8-OH-DPAT, this reexposure decreased subsequent instrumental extinction performance regardless of test drug condition relative to reexposure under vehicle. Although both food consumption and reinforced lever press performance were incremented, 8-OH-DPAT was found generally to reduce instrumental extinction performance and lever pressing during a period when the reinforcer was delivered non-contingently. Rats injected with 8-OH-DPAT were, however, more sensitive to delay of reinforcement, and increased their lever press performance at a 3-s delay but decreased performance at 6-s and 12-s delays relative to animals injected with vehicle. These results are consistent with the hypothesis that 8-OH-DPAT modifies arousal processes in a manner similar to mild stress, thereby acting both to elevate rewarded instrumental performance and to increase sensitivity to the effects of non-reward.     

Response of cerebellar Purkinje cells to serotonin and the 5-HT1A agonists 8-OH-DPAT and ipsapirone in vitro

These studies were undertaken in an attempt to classify the receptor subtypes mediating the inhibitory effects of serotonin (5-HT) on cerebellar Purkinje cells in the in vitro slice preparation. 5-HT and the 5-HT1A specific agonists 8-hydroxy-2(di-n-propyl-amino)tetralin (8-OH-DPAT) and ipsapirone were iontophoretically applied to Purkinje cells during control periods and periods of concurrent application of the 5-HT1A/5-HT2 antagonist spiperone. 5-HT was found to produce three distinct effects on Purkinje cell spontaneous discharge: inhibition, excitation and a biphasic effect. Iontophoretically applied 8-OH-DPAT and ipsapirone elicited only inhibition of Purkinje cell firing in all cells tested. Purkinje cell inhibitions elicited by 5-HT, 8-OH-DPAT and ipsapirone were all found to be significantly dose-dependent. However, while dose-response curves for 8-OH-DPAT and ipsapirone were found to be identical, they both differed significantly from the 5-HT curve. Spiperone was shown to significantly attenuate Purkinje cell inhibition induced by 5-HT, 8-OH-DPAT and ipsapirone. In several cells 5-HT-induced inhibition of spontaneous discharge was reversed to excitation in the presence of spiperone. This was never observed with either 8-OH-DPAT or ipsapirone. Thus, our results suggest that 5-HT-induced Purkinje cell inhibitions are at least partially mediated by the 5-HT1A receptor subtype, and there also may be additional 5-HT receptor subtypes present mediating other responses. Ultimate Purkinje cell responses to 5-HT may be due to summation of responses induced by activation of several 5-HT receptor subtypes.     

Effects of stereoselective 5-HT1A agonists on male rat sexual behavior

The effects on male rat sexual behavior of some new stereoselective 5-HT agonists, related to 8-OH-DPAT, are presented. It was found that (+)cis-8-hydroxy-1-methyl-2-(di-n-propylamino) tetralin (8-OH-MeDPAT), as well as (-)trans-2-(2-hydroxyphenyl)-N,N-di-n-propylcyclopropylamine (2-OH-DCPA), and its 3-hydroxy-phenyl analog (3-OH-DCPA), stereoselectively facilitated the male rat sexual behavior, as evidenced by a decrease in the number of intromissions preceding ejaculation, and a shortening of the ejaculation latency. For the former two compounds, studied in further detail, the potency and efficacy appear to be of the same magnitude as previously found for 8-OH-DPAT. The results demonstrate specific 5-HT receptor involvement in the mediation of male rat sexual behavior.     

Effect of selective serotonin (5-HT) agonists and 5-HT2 antagonist on prolactin secretion

The present study was undertaken to determine the involvement of serotonergic 5-HT1 and 5-HT2 receptor subtypes in stimulation of the secretion of prolactin. Several 5-HT agonists were administered, in a dose-response fashion, to conscious rats and the effect on the levels of prolactin in plasma was measured. The 5-HT1A + 5-HT1B agonist RU 24969 (5-methoxy-3[1,2,3,6-tetrahydropyridin-4-yl]-1H-indole succinate) and the 5-HT1 + 5-HT2 agonist MK-212 (6-chloro-2-[1-piperazinyl]pirazine) increased levels of prolactin in plasma in a dose-dependent manner. In contrast, the selective 5-HT1A agonists 8-OH-DPAT (8-hydroxy-2-[di-n-propylamino]tetralin) and ipsapirone (2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,2-benzisothiazol-3 -(2H) one-1,1-dioxidehydrochloride) did not increase levels of prolactin in plasma at any dose. The 5-HT-releasing drug, fenfluramine, also increased the concentration of prolactin in plasma. Pretreatment with the selective 5-HT2 antagonist, LY53857 (6-methyl-1-[1-methylethyl]ergoline-8-carboxylic acid, 2-hydroxy-1-methyl propyl ester (Z)-2-butenedioate [1:1]), did not significantly diminish an increase in levels of prolactin in plasma, induced by injection of fenfluramine. The antagonist LY53857 inhibited, but did not block the MK-212- and RU 24969-induced increase in the levels of prolactin in plasma. By deduction, these data suggest that 5-HT1B receptors, or as yet undefined 5-HT receptor subtypes may be involved in the stimulation of the secretion of prolactin by endogenously released 5-HT, and that 5-HT2 receptors may play a minor role in the serotonergic regulation of the secretion of prolactin.     

8-OH-DPAT, a 5-HT1A agonist and ritanserin, a 5-HT2A/C antagonist, reverse haloperidol-induced catalepsy in rats independently of striatal dopamine release

In this study, both catalepsy and changes in extracellular levels of striatal dopamine (DA) and dihydroxyphenyl acetic acid (DOPAC) induced by the typical neuroleptic haloperidol (HAL) were simultaneously assessed, using intracerebral microdialysis in freely moving rats, in the presence of either the 5-HT_1A agonist 8-OH-DPAT or the 5-HT_2A/C antagonist ritanserin. HAL (1 mg/kg, SC) elicited a strong cataleptic state, reaching its maximal intensity (about 240 s) 2 h after the drug administration. This effect was paralleled by a long-lasting enhancement of striatal DA and DOPAC extracellular levels, reaching 230 and 350% of basal values, respectively. 8-OH-DPAT (0.1 mg/kg, SC) given 2.5 h after, and ritanserin (0.63 and 1.25 mg/kg, IP), given 15 min prior to HAL, significantly reduced the neuroleptic-induced catalepsy. However, both 5-HT agents failed to modify basal DA and DOPAC striatal outflow as well as the stimulatory effect of HAL on these parameters. It can thus be concluded that the anticataleptic effect of these compounds is not related to an alteration of DA release within the striatum. Received: 29 August 1996/Final version: 25 November 1996     

8-OH-DPAT acts on both 5-HT1A and 5-HT7 receptors to induce hypothermia in rodents

Studies using selective drugs and knockout mice have demonstrated that the 5-HT(7) receptor plays an instrumental role in serotonin-induced hypothermia. There is also evidence supporting an involvement of the 5-HT(1A) receptor, although mainly from studies using 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT(1A/7) receptor agonist. Here we studied the effects of 8-OH-DPAT and selective antagonists for the 5-HT(1A) and 5-HT(7) receptors on body temperature in rats, wild-type (5-HT(7)(+/+)) mice and knockout (5-HT(7)(-/-)) mice. At lower doses (0.3-0.6 mg/kg, i.p.), 8-OH-DPAT decreased body temperature in 5-HT(7)(+/+) mice but not in 5-HT(7)(-/-) mice. At a higher dose (1 mg/kg, i.p.) 8-OH-DPAT induced hypothermia in both 5-HT(7)(-/-) and 5-HT(7)(+/+) mice. The 5-HT(1A) receptor antagonist (S)-N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide (WAY-100135) (10 mg/kg, i.p.) inhibited the effect of 8-OH-DPAT at all doses in rats and mice. In 5-HT(7)(+/+) mice the selective 5-HT(7) receptor antagonist (R)-3-(2-(2-(4-methylpiperidin-1-yl)-ethyl)pyrrolidine-1-sulfonyl)phenol (SB-269970) (10 mg/kg, i.p.) fully inhibited the hypothermia induced by 0.3 mg/kg 8-OH-DPAT, but not that of higher doses. In rats, SB-269970 caused a 60% inhibition of the hypothermia induced by 0.3 mg/kg 8-OH-DPAT. Thus, both 5-HT(7) and 5-HT(1A) receptors are involved in a complex manner in thermoregulation, with the 5-HT(7) receptor being more important at lower, possibly more physiological, concentrations.     

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.     

Intracerebral actions of the 5-HT1A agonists, 8-OH-DPAT and buspirone and of the 5-HT1A partial agonist/antagonist, NAN-190, on female sexual behavior.

Proestrous rats were infused intracerebrally with 50-1000 ng 8-OH-DPAT, 500 or 2000 ng buspirone or 125-500 ng NAN-190. For each drug, bilateral infusions into the mediobasal hypothalamus inhibited female lordosis behavior and proceptivity and initiated resistive behavior. The effects of the drugs were evident within 5-20 min of infusion and generally lasted for 1-2 hr. The effective sites for 5-HT1A-mediated inhibition of sexual behavior were most concentrated in the ventromedial nucleus of the hypothalamus. Cannulae sites anterior, posterior or dorsal to the ventromedial nucleus or clearly within the IIIrd ventricle were less effective at disrupting lordosis behavior. The inhibition of sexual behavior, following 8-OH-DPAT occurred in a dose-dependent manner and appeared to include the loss of motivation of the female to mate. Buspirone produced similar, but quantitatively smaller, effects on lordosis behavior. NAN-190 slightly, but significantly, suppressed lordosis behavior after either intracerebral or intraperitoneal injection and substantially increased resistive behavior. These results suggest that the inhibition of lordosis behavior, following treatment with 5-HT1A agonists, include an action within the ventromedial nucleus. Moreover, 5-HT1A receptors in this area appear to play a functionally important role in the modulation of the female's "willingness" to mate.