5HT-2 mediation of acute behavioral effects of hallucinogens in rats

In rats tested during their first exposure to a Behavioral Pattern Monitor chamber, acute injections of the 5HT-2 agonists mescaline, quipazine, 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-methylamphetamine (DOM), or 2,5-dimethoxy-4-ethylamphetamine (DOET) produced an inhibition of locomotor and investigatory behavior during the first 30 min of the test session. This suppression of exploratory behavior was attenuated when rats were familiarized with the testing chamber prior to the administration of DOI. Hence, as previously observed with both LSD and DOM, 5HT-2 agonists appear to potentiate the normal neophobic reaction to a novel environment. The mixed 5HT-1 and 5HT-2 agonist 5-methoxy-N,N-dimethyltryptamine (5MeODMT) also produced a decrease in activity when animals were tested in the novel environment. However, as previously found with 5HT-1A agonists, this effect was unchanged when animals were tested in the familiar environment and may therefore reflect a generalized sedation. The receptor specificity of these differential effects of 5HT-1 and 5HT-2 agonists in this paradigm was tested by assessing the ability of selective 5HT-2 antagonists to block the effects of the agonists. A dose of the 5HT-2 antagonist ketanserin which had no effect by itself significantly reduced the behavioral effects of mescaline, DOM, and quipazine. Similarly, the selective 5HT-2 antagonist ritanserin blocked the effect of quipazine. In contrast, ketanserin had no significant effect on the suppression of activity produced by the 5HT-1A agonist 8-hydroxy-2(di-n-propylamino)tetralin (8OHDPAT). These results demonstrate that the behavioral effects of 5HT-1 and 5HT-2 agonists can be differentiated both phenomenologically and pharmacologically within a single paradigm. The findings provide further support for the hypothesis that the potentiation of neophobia produced by hallucinogens in rats is attributable to their agonist actions at 5HT-2 receptors.     

Dissociation of multiple effects of acute LSD on exploratory behavior in rats by ritanserin and propranolol

Rats tested for 1 h in the Behavioral Pattern Monitor (BPM) after injection of the mixed serotonergic agonistd-lysergic acid diethylamide (LSD) exhibit a behavioral profile similar to that produced by various hallucinogenic 5HT-2 agonists. The characteristic effects of the hallucinogens include suppression of locomotor and exploratory behavior and a preferential decrease in entries into the center of the BPM during the initial half of the test session. After LSD, the initial suppression of responding is followed by a subsequent increase in locomotor activity that is not observed with other serotonergic agonists. In the present studies, the 5HT-1 andβ-adrenergic antagonistd,1-propranolol and the 5HT-2 antagonist ritanserin were administered individually or in combination prior to the acute administration of LSD to test for the involvement of these receptor subtypes in the mediation of the effects of LSD in the BPM paradigm. Propranolol (20 mg/kg) abolished the initial suppression of activity induced by 60 μg/kg LSD without affecting the subsequent increase in locomotion. Conversely, 2.0 mg/kg ritanserin failed to block the initial suppressive effects of 60 or 120 μg/kg LSD, but attenuated the LSD-induced increases in activity during the second half of the session. The combination of propranolol and ritanserin prevented both these effects of LSD. By contrast, the more selective 5HT-2 agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) (0.27 mg/kg) produced an initial suppression of activity in the BPM that was blocked by 2.0 mg/kg ritanserin and was not followed by a subsequent increase in activity. These findings suggest that the initial suppressive effects of LSD in the BPM paradigm are dissociable from the subsequent increases in locomotion and that the two effects are mediated via different serotonergic orβ-adrenergic receptors.     

The roles of 5-HT1A and 5-HT2 receptors in the effects of 5-MeO-DMT on locomotor activity and prepulse inhibition in rats

Rationale The hallucinogen 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is structurally similar to other indoleamine hallucinogens such as LSD. The present study examined the effects of 5-MeO-DMT in rats using the Behavioral Pattern Monitor (BPM), which enables analyses of patterns of locomotor activity and exploration, and the prepulse inhibition of startle (PPI) paradigm.Objectives A series of interaction studies using the serotonin (5-HT)_1A antagonist WAY-100635 (1.0 mg/kg), the 5-HT_2A antagonist M100907 (1.0 mg/kg), and the 5-HT_2C antagonist SER-082 (0.5 mg/kg) were performed to assess the respective contributions of these receptors to the behavioral effects of 5-MeO-DMT (0.01, 0.1, and 1.0 mg/kg) in the BPM and PPI paradigms.Results 5-MeO-DMT decreased locomotor activity, investigatory behavior, the time spent in the center of the BPM chamber, and disrupted PPI. All of these effects were antagonized by WAY-100635 pretreatment. M100907 pretreatment failed to attenuate any of these effects, while SER-082 pretreatment only antagonized the PPI disruption produced by 5-MeO-DMT.Conclusions While the prevailing view was that the activation of 5-HT₂ receptors is solely responsible for hallucinogenic drug effects, these results support a role for 5-HT_1A receptors in the effects of the indoleamine hallucinogen 5-MeO-DMT on locomotor activity and PPI in rats.     

Cross-tolerance studies of serotonin receptors involved in behavioral effects of LSD in rats

Like hallucinogenic 5-HT₂ agonists, LSD (d-lysergic acid diethylamide) produces characteristic decreases in locomotor activity and investigatory behaviors of rats tested in a novel environment. Because LSD is an agonist at both 5-HT_1A and 5-HT₂ receptors, however, the respective influences of these different receptors in the behavioral effects of LSD remain unclear. In particular, the paucity of selective 5-HT_1A antagonists has made it difficult to assess the specific contribution of 5-HT_1A receptors to the effects of LSD. An alternative approach to the delineation of receptor-specific effects is the use of cross-tolerance regimens. In the present studies, rats were pretreated with saline, 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) (0.5 mg/kg SC), 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (1.0 mg/kg SC), or LSD (60 µg/kg SC), every 12 h for 5 or 8 days. Thirty-six hours later, rats were tested in a behavioral pattern monitor 10 min after injection of saline, 0.5 mg/kg 8-OH-DPAT, 1.0 mg/kg DOI, or 60 µg/kg LSD. As expected, tolerance to the decreases in locomotor activity produced by acute administrations of 8-OH-DPAT, DOI, or LSD occurred when rats were pretreated chronically with 8-OH-DPAT, DOI, or LSD, respectively. Furthermore, pretreatment with either 8-OH-DPAT or DOI produced cross-tolerance to LSD. These results support the hypothesis that the effects of LSD in this model reflect a combination of 5-HT_1A and 5-HT₂ effects and support the view that there is an interaction between 5-HT_1A and 5-HT₂ receptors.     

The role of 5-HT(1A) receptors in the locomotor-suppressant effects of LSD: WAY-100635 studies of 8-OH-DPAT, DOI and LSD in rats

The selective 5-HT(1A) antagonist WAY-100635 was employed to further clarify the respective contributions of 5-HT(1A) receptors to the effects of the 5-HT(1A) agonist 8-OH-DPAT, the 5-HT(2) agonist DOI, and the mixed 5-HT(1A/2) agonist LSD on exploratory locomotion in rats. In nocturnal studies of well-handled rats during their first exposure to the Behavioral Pattern Monitor, which enables analyses of quantitative and qualitative changes in locomotor activity, locomotor and investigatory responses were reduced by treatment with either 8-OH-DPAT, DOI, or LSD. The hypoactivity produced by 8-OH-DPAT, but not that produced by DOI, was antagonized by pretreatment with WAY-100635. These results substantiate the effectiveness and functional specificity of WAY-100635 as a 5-HT(1A) antagonist. Furthermore, these results are inconsistent with a functional interaction between 5-HT(1A) and 5-HT(2) receptors in the control of locomotor behavior. The decreases in locomotion produced by LSD were attenuated by pretreatment with WAY-100635, indicating that the effects of LSD in this paradigm are due partly to agonist actions at 5-HT(1A) receptors. Therefore, 5-HT(1A) receptors appear to play a direct role in mediating the effects of LSD on rodent locomotion.     

Behavioral characterization of alpha-ethyltryptamine,a tryptamine derivative with MDMA-like properties in rats

Several reports have speculated that the tryptamine-derived drug alpha-ethyltryptamine (AET) may have effects similar to those of the amphetamine-derived drug 3,4-methylenedioxymethamphetamine (MDMA). Indeed, the US Drug Enforcement Administration has recently placed AET on the Schedule I list because of its putative similarity to MDMA. The Behavioral Pattern Monitor, which quantifies locomotor and investigatory responses of rats, was used to characterize the effects of AET in a paradigm that distinguishes between the effects of traditional hallucinogens, amphetamine-like stimulants, and MDMA-like drugs. First, a dose-response study revealed that all doses of AET tested (5, 10, 20 mg/kg) significantly increased locomotor activity. Locomotor hyperactivity is produced by MDMA or amphetamine-like stimulants, but not by classical hallucinogens, such as LSD or mescaline. Additionally, AET significantly decreased measures of investigatory behavior. Similar decreases occur with MDMA or hallucinogen administration, but not with amphetamine-like stimulant administration. Second, as with MDMA, the locomotor hyperactivity induced by AET was attenuated by pretreatment (10 mg/kg) with the serotonin reuptake inhibitor fluoxetine. Thus, AET, a tryptamine-derived drug, appears to produce an MDMA-like profile of behavioral changes by virtue of releasing presynaptic serotonin.     

Effects of Hallucinogens on Locomotor and Investigatory Activity and Patterns: Influence of 5-HT2A and 5-HT2C Receptors

The 5-HT_2A and 5-HT_2C antagonists MDL 100,907 and SER-082 were tested with the 5-HT_2A/C agonist DOI and the 5-HT_1A/2A/2C agonist LSD in the Behavioral Pattern Monitor, which provides multiple measures of locomotor and investigatory activity. Previous investigations have shown that these measures load onto three independent behavioral factors: amount of activity, exploratory behavior, and behavioral organization. Rats pretreated with saline, MDL 100,907 (0.25-2.0 mg/kg), or SER-082 (0.5-1.0 mg/kg) were treated with saline, 0.25 mg/kg DOI, or 60 μg/kg LSD. All effects of DOI were blocked by all doses of MDL 100,907, but only by the highest dose of SER-082. While the effects of LSD on activity and exploratory behavior were largely unaffected, either pretreatment antagonized the effects of LSD on behavioral organization. Thus, all of these effects of DOI were attributable to 5-HT_2A receptors, whereas the effect of LSD on behavioral organization was influenced by both 5-HT_2A and 5-HT_2C receptors.     

The 5-HT1A receptor and the stimulus effects of LSD in the rat

Rationale It has been suggested that the 5-HT_1A receptor plays a significant modulatory role in the stimulus effects of the indoleamine hallucinogen lysergic acid diethylamide (LSD). Objective The present study sought to characterize the effects of several compounds with known affinity for the 5-HT_1A receptor on the discriminative stimulus effects of LSD. Methods Twelve male Fischer 344 rats were trained in a two-lever, fixed-ratio (FR) 10, and food-reinforced task with LSD (0.1 mg/kg, i.p.; 15-min pretreatment) as a discriminative stimulus. Combination and substitution tests with the 5-HT_1A agonists, 8-OH-DPAT, buspirone, gepirone, and ipsapirone, with LSD-induced stimulus control were then performed. The effects of these 5-HT_1A ligands were also tested in the presence of the selective 5-HT_1A receptor antagonist, WAY-100,635 (0.3 mg/kg, s.c.; 30-min pretreatment). Results In combination tests, stimulus control by LSD was increased by all 5-HT_1A receptor ligands with agonist properties. Similarly, in tests of antagonism, the increase in drug-appropriate responding caused by stimulation of the 5-HT_1A receptor was abolished by administration of WAY-100,635. Conclusion These data, obtained using a drug discrimination model of the hallucinogenic effects of LSD, provide support for the hypothesis that the 5-HT_1A receptor has a significant modulatory role in the stimulus effects of LSD.     

Discriminative stimulus properties of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT): implications for understanding the actions of novel anxiolytics

8-Hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) has effects both characteristic of a serotonin (5-hydroxytryptamine; 5-HT) agonist and antagonist. To investigate the mechanism(s) of action of 8-OHDPAT in vivo, rats were trained to discriminate 8-OHDPAT (0.4 mg/kg) from saline and given various neuroactive compounds during substitution test sessions. Of the 5-HT agonists tested, d-lysergic acid diethylamide, 5-methoxy-n,n-dimethyltryptamine, quipazine, Ru 24969 and 1-(m-trifluoromethylphenyl) piperazine did not mimic the training drug; the dopamine agonists apomorphine and SKF 38393 as well as the alpha 2-adrenoceptor agonist clonidine engendered predominantly saline-lever responding. However, the novel anxiolytics buspirone and ipsapirone as well as the ergot derivative lisuride substituted completely for 8-OHDPAT. In combination tests, 5-HT (ketanserin, metergoline, methysergide, pirenperone), dopamine (haloperidol) and norepinephrine antagonists (prazosin, propranolol) failed to attenuate the 8-OHDPAT cue. The similar stimulus properties of 8-OHDPAT and the novel anxiolytics (buspirone, ipsapirone) are mirrored by the common abilities of these agents to selectively inhibit 5-HT1A binding and release punished responding. Thus, the subpopulation of 5-HT1A receptors may mediate the behavioral effects of these compounds in animals and, in turn, the anxiolytic effects of buspirone and ipsapirone in humans. Although not primarily selective for 5-HT, lisuride may also mimic 8-OHDPAT by direct or indirect stimulation of 5-HT1A receptors.     

Effects of 5-HT-1A receptor agonists on CRF-induced behavior

Buspirone (2.0 or 4.0 mg/kg) and 8-hydroxy-2-(di-N-propylamino)-tetralin (8-OH-DPAT) (0.25 or 0.5 mg/kg) were used to examine the effects of serotonin 1A receptor agonists on the behavioral response of rats to centrally administered corticotropin-releasing factor (CRF). Behavioral observations were done with animals in their home cages. Parameters measured included locomotor activity, grooming and food consumption. CRF alone increased locomotor activity. 8-OH-DPAT also increased locomotion in both saline control and CRF-treated rats. Buspirone had no effect on basal locomotion or on CRF-induced hyperactivity. Both buspirone and 8-OH-DPAT antagonized CRF-induced grooming. Food consumption by fasted rats was suppressed by ICV CRF. 8-OH-DPAT suppressed eating by both ICV CRF and ICV saline-treated animals, while buspirone was without effect. These results demonstrate differences between the two putative 5-HT-1A agonists in their effects on CRF-induced behavior but also demonstrate that both suppress CRF-induced grooming.     

Effects of the novel anxiolytics gepirone,buspirone and ipsapirone on free feeding and on feeding induced by 8-OH-DPAT

The effects of the novel anxiolytics gepirone, buspirone and ipsapirone on free feeding and on feeding induced by the 5-HT_1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), were examined. Gepirone dose-dependently increased feeding 2 and 4 h after injection, the magnitude of the response being larger than previously observed with any other 5-HT_1A receptor ligand. Previous studies have suggested that buspirone and ipsapirone can block some of the behavioural effects of 8-OH-DPAT. However, gepirone, buspirone and ipsapirone did not inhibit feeding induced by 8-OH-DPAT. These results indicate that gepirone is a very efficacious appetite stimulant in rats and suggest that gepirone, buspirone and ipsapirone act as 5-HT autoreceptor agonists in the feeding model.     

Behavioral pharmacological and electroencephalographic effects of the 5-HT1A partial agonist ipsapirone]

The behavioral and EEG effects of the 5-HT1A partial agonist ipsapirone were investigated to determine its pharmacological characteristics as an anxiolytic drug in rats, mice and rabbits, as compared with those of buspirone and diazepam. 1) The anticonflict effect of ipsapirone was almost equipotent as that of buspirone and less potent than that of diazepam in rats. Ro15-1788 antagonized the anticonflict effect of diazepam, but did not that of ipsapirone. 2) Muricide in midbrain raphe-lesioned and olfactory bulbectomized rats was inhibited by ipsapirone. However, the inhibition of muricide by ipsapirone was attenuated by its repeated administration. 3) The muscle relaxant effects of ipsapirone and buspirone on rotarod performance were less potent than that of diazepam. Ethanol-induced muscle relaxation was markedly potentiated by diazepam, but less potently by ipsapirone and buspirone. 4) The pentetrazol-induced convulsion was dose-dependently antagonized by diazepam, while it was weakly potentiated by ipsapirone and buspirone. 5) The limbic afterdischarges induced by either hippocampal or amygdaloid stimulation in rabbits were markedly inhibited by diazepam. Conversely, ipsapirone and buspirone slightly potentiated afterdischarges. In conclusion, it is suggested that ipsapirone has anxiolytic activities similar to that of buspirone and moderate antimuricidal action. In addition, ipsapirone, like buspirone, is also characterized by its less potent muscle relaxant, alcohol-potentiating and anticonvulsant actions.     

Antidepressant-like activity of 5-HT1A agonists measured with the forced swim test

This study examined the abilities of 5-hydroxytryptamine (5-HT) agonists with varying selectivity for different subtypes of 5-HT receptors to produce antidepressant-like behavioral effects in the forced swim test in rats. The 5-HT_1A agonists 8-OH-DPAT (0.125–1.0 mg/kg, SC) and tandospirone (SM-3997) (5–20 mg/kg, SC) both produced dose-related decreases in immobility time following subchronic treatment in rats. These effects were similar to those of the tricyclic antidepressants imipramine (5–15 mg/kg) and desipramine (5–15 mg/kg). In addition, the 5-HT_1A agonists, buspirone (20 mg/kg), gepirone (20 mg/kg) and ipsapirone (10 and 20 mg/kg) demonstrated antidepressant-like effects. Other groups of rats treated subchronically with each of the 5-HT_1A agonists or antidepressants showed no increase in locomotor activity, so that general changes in activity could not account for the reduction of immobility time in the forced swim test. 5-HT agonists selective for other receptor subtypes, such as the 5-HT_1B/1C agonistm-CPP (5 mg/kg) and the 5-HT_2/1C agonist DOB (1 mg/kg), were not effective in this behavioral test. The benzodiazepine diazepam (5 mg/kg) also failed to reduce immobility time, suggesting that anxiolytic properties of 5-HT_1A agonists did not mediate this behavioral effect. A common metabolite of some of the 5-HT_1A agonists, 1-PP, was ineffective in reducing immobility time. The stimulantd-amphetamine (2 mg/kg) significantly reduced immobility time but also significantly increased locomotor activity. Pretreatment with the 5-HT synthesis inhibitor PCPA alone did not alter immobility time, and did not alter the antidepressant-like effects of 8-OH-DPAT or tandospirone, suggesting that the 5-HT_1A agonists are producing their antidepressant-like effects through postsynaptic 5-HT_1A receptors. These results suggest that 5-HT_1A agonists may have antidepressant efficacy and act as a novel class of antidepressant drug.     

8-OH-DPAT and buspirone analogs inhibit the ketanserin-sensitive quipazine-induced head shake response in rats

Behavioral syndromes mediated by serotonergic mechanisms may reflect interactions between distinct effects initiated by specific 5-HT receptors, such as the 5-HT1A and the 5-HT2 receptor. This hypothesis was tested by examining the effect of various 5-HT1A agonists on the 5-HT2 receptor-mediated quipazine-induced head shake response in rats. Subcutaneous administration of 8-OH-DPAT, buspirone, gepirone, and ipsapirone produced a dose-dependent inhibition of the ketanserin-sensitive quipazine-induced head shake response. These effects were produced by doses of agonists which did not induce reciprocal forepaw treading. Furthermore, pretreatment with a partial 5-HT1A agonist (+/-)pindolol blocked the inhibitory effects of 8-OH-DPAT to the level of inhibition produced by (+/-)pindolol itself. These results suggest that stimulation of central 5-HT1A receptors can modulate the expression of a central 5-HT2 receptor-mediated behavior.     

A comparison of feeding and locomotion responses to serotonin agonists in three rat strains

The hyperphagic effects of two selective 5-HT1A agonists (8-OHDPAT and buspirone) in a free feeding paradigm and the locomotor suppressant effect of the serotonin agonist, m-chlorophenylpiperazine (m-CPP) were compared in three different rat strains: Wistar, Sprague-Dawley (SD), and Fawn-Hooded (FH) rats. Administration of various doses of 8-OHDPAT and buspirone produced significant increases in two-hour food intake only in Wistar and SD strains and not in the FH strain. Similarly, various doses of m-CPP produced significant decreases in locomotor activity only in Wistar and SD strains and not in the FH strain. Isolated FH animals gained significantly less body weight relative to both Wistar and SD animals. These findings demonstrate attenuated feeding and behavioral responses to serotonergic agonists in the FH strain relative to both Wistar and SD strains.     

The stimulus effects of 8-OH-DPAT: evidence for a 5-HT2A receptor-mediated component

A previous investigation in our laboratory found that the stimulus effects of the 5-HT2A agonist, LSD, are potentiated by 5-HT1A receptor agonists including the prototypic agonist, 8-OH-DPAT. Also suggestive of behaviorally relevant interactions between 5-HT1A and 5-HT2A receptors are behavioral analyses of locomotor activity, head-twitch response, forepaw treading and production of the serotonin syndrome; in some instances effects are augmented, in other, diminished. These observations led us in the present investigation to test the hypothesis that stimulus control by 8-OH-DPAT [0.2 mg/kg; 15 min pretreatment time] is modulated by 5-HT2A ligands. Stimulus control was established with 8-OH-DPAT in a group of 10 rats. A two-lever, fixed ratio 10, positively reinforced task with saline controls was employed. As shown previously, stimulus control by 8-OH-DPAT and the generalization of 8-OH-DPAT to the 5-HT1A partial agonist, buspirone, was completely blocked by the selective 5-HT1A antagonist, WAY-100635. In contrast, antagonism by the selective 5-HT2A antagonist, M100907 [0.1 mg/kg; 30 min pretreatment time], of 8-OH-DPAT and of the generalization of 8-OH-DPAT to buspirone was statistically significant but less than complete. In light of our previous conclusions regarding the interactions of 5-HT1A agonists with LSD-induced stimulus control, the present data suggest that the interaction between 5-HT1A and 5-HT2A receptors is bidirectional in drug discrimination studies.     

Antidepressant-like action of 5-HT1A agonists and conventional antidepressants in an animal model of depression

Previous results have suggested that behavioural adaptation to restraint might be promoted by post-restraint stimulation of 5-HT1A receptors. Therefore, rats were restrained for 2 h and injected with vehicle or 60-1,000 micrograms/kg of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) s.c. Vehicle-treated restrained rats showed reduced locomotor activity and increased defaecation in an open field test the day after the end of restraint. A single injection of 250 or 1,000 micrograms/kg 8-OH-DPAT attenuated these effects. The above locomotor deficits were also attenuated by chronic pretreatment with the antidepressants desipramine and sertraline but not by a single treatment with desipramine or the benzodiazepine anxiolytic drugs chlordiazepoxide and diazepam; none of these treatments unambiguously reversed stress-induced increases in defaecation. Evidence suggests that the above action of 8-OH-DPAT is mediated by 5-HT1A receptors since it was antagonised by the 5-HT1A antagonist spiperone but not by the 5-HT2 antagonist ketanserin and was not mimicked by the 5-HT1B agonist RU 24969. However, the 5-HT1A agonists buspirone and TVXQ 7821 (ipsapirone) and the non-specific 5-HT agonist quipazine all possess similar properties to 8-OH-DPAT in this test. The results suggest that 5-HT1A agonists may have rapid antidepressant properties.     

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.     

Behavioral effects of xylamine-induced depletions of brain norepinephrine: interaction with LSD

Male rats were treated with a combination of systemic fluoxetine and intraventricular xylamine (under ether anesthesia) to deplete brain norepinephrine (NE) in the projection areas of the locus coeruleus. Four days later, control and lesioned rats were tested following injections of either saline or 80 micrograms/kg LSD in a Behavioral Pattern Monitor which recorded the sequential patterns of their locomotor and investigatory (holepokes) responses. Liquid chromatographic measures of brain monoamines confirmed that xylamine reduced hippocampal NE by 80.8% and hypothalamic NE by 26% without affecting levels of serotonin or dopamine. Relative to controls, NE-depleted rats exhibited repetitive spatial patterns of locomotion with no alteration in the amount or rate of habituation of locomotor activity. Lesioned animals made fewer rearings and holepokes, particularly early in the hour test session. When given 80 micrograms/kg LSD, sham-lesioned rats exhibited the expected decreases in entries into and time spent in the center of the chamber, an increase in time spent in the corners, and fewer holepokes and rearings early in the session. With the exception of the effect on rearings and holepokes, the effects of LSD were diminished in rats depleted of brain NE. These results indicate that this profile of behavioral effects of LSD, which has been interpreted as a potentiation of neophobia, may be dependent upon the noradrenergic projections of the locus coeruleus.     

Neuroendocrine responses to the serotonin2 agonist DOI are differentially modified by three 5-HT1A agonists.

Evidence suggests that activation of 5-HT1A receptors leads to inhibition of 5-HT2-mediated behavior. The purpose of this study was to investigate the interaction between 5-HT1A and 5-HT2 receptor-mediated hormone secretion. Rats were pretreated with the 5-HT1A agonists buspirone (0, 0.5, 2.0 mg/kg, i.p.), 8-OH-DPAT (0, 0.05, 0.2 mg/kg, s.c.) or ipsapirone (0, 1.0, 2.5 mg/kg, i.p.), 45 min before decapitation. The 5-HT2 agonist DOI was administered (0-10 mg/kg, i.p.) 15 min after injection of the 5-HT1A agonists. The three 5-HT1A agonists differentially altered the DOI-induced increase of concentrations of hormone in plasma. None of the three 5-HT1A agonists influenced the basal levels of renin, ACTH and prolactin but 8-OH-DPAT and buspirone increased the basal level of corticosterone in plasma. Also, 8-OH-DPAT increased the effects of DOI on the concentration of ACTH in plasma but ipsapirone and buspirone did not. None of the 5-HT1A agonists significantly affected DOI-induced increase of concentration of corticosterone in plasma. Buspirone and 8-OH-DPAT potentiated the effect of DOI on prolactin in plasma, but ipsapirone did not. Ipsapirone potentiated the effect of DOI on the concentration of renin in plasma but this effect was not observed in 8-OH-DPAT- and buspirone-pretreated rats. The results do not support the hypothesis for a functional interaction between 5-HT1A and 5-HT2 receptors, since the three 5-HT1A agonists did not have the same influence on the hormonal effects of DOI.