Further investigation of the in vivo pharmacological properties of the putative 5-HT1A antagonist, BMY 7378

The present study examined the actions of the putative 5-HT1A antagonist BMY 7378 on central pre- and postsynaptic 5-HT1A function in the rat in vivo. Unlike the direct acting 5-HT1A agonist 8-hydroxy-2-(di-n-pro-pylamino)tetralin (8-OH-DPAT), BMY 7378 (0.25-5 mg/kg s.c.) did not induce the full postsynaptically mediated 5-HT behavioural syndrome (forepaw treading, head weaving, flat body posture hindlimb abduction). Indeed, the maximal 5-HT behavioural syndrome scores of BMY 7378 were about 10% of those for 8-OH-DPAT. Following pretreatment, however, BMY 7378 dose dependently (0.25-5 mg/kg s.c.) reduced to undetectable levels forepaw treading and head weaving induced by 8-OH-DPAT (0.75 mg/kg s.c.). BMY 7378 also inhibited stereotypy and locomotor activity induced by 0.5 mg/kg apomorphine although this effect was only statistically significant at the highest dose tested (5 mg/kg). In contrast to its apparent 5-HT1A antagonist properties in the behavioural experiments, BMY 7378 caused a marked and dose-dependent (0.01-1.0 mg/kg s.c.) decrease of 5-HT release in ventral hippocampus of the anaesthetized rat as detected by brain microdialysis. This effect of BMY 7378 had a similar onset and duration of action but with slightly reduced efficacy compared to that previously described for 8-OH-DPAT. As with 8-OH-DPAT, the inhibitory effect of BMY 7378 on 5-HT release was attenuated by pretreatment with the 5-HT1 receptor/beta-adrenoceptor antagonist pindolol (8 mg/kg s.c.) but not its counterpart propranolol (20 mg/kg s.c.). Pretreatment with a combination of the beta 1- and beta 2-adrenoceptor antagonists metoprolol (4 mg/kg s.c.) and ICI 118 551 (4 mg/kg s.c.), respectively, did not alter the 5-HT response to BMY 7378. From these data we conclude that BMY 7378 is a mixed agonist/antagonist at central 5-HT1A receptors.     

Repeated treatment with 8-OH-DPAT induces tolerance to its ability to produce the 5-HT1A behavioural syndrome, but not to its ability to attenuate haloperidol-induced catalepsy

When administered acutely, 5-hydroxytryptamine1A (5-HT1A) agonists attenuate the cataleptic side effects of antipsychotics. We investigated whether tolerance occurs to these effects after repeated administration of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). For comparison, we also assessed the ability of 8-OH-DPAT to produce elements of the 5-HT1A behavioural syndrome (i.e. forepaw treading, flat body posture and lower lip retraction), some of which readily demonstrate tolerance. Catalepsy was measured in rats using both the cross-legged position test and the bar test. Repeated treatment with 8-OH-DPAT (0.63-2.5 mg/kg subcutaneously), once daily for 4 days, did not significantly alter the ability of acute treatment with 8-OH-DPAT (0.01-2.5 mg/kg) to inhibit catalepsy induced by haloperidol (2.5 mg/kg) in either test. In contrast, the ability of 8-OH-DPAT to produce the 5-HT1A behavioural syndrome was significantly attenuated by the repeated treatment. The present data, showing an absence of tolerance to the anti-cataleptic effects of a 5-HT1A agonist, indicate that mixed dopamine antagonist/5-HT1A agonist compounds may continue to have a low propensity to induce extrapyramidal side effects during chronic treatment.     

Partial postsynaptic 5-HT1A agonist properties of the novel stereoselective 8-OH-DPAT analogue (+)cis-8-hydroxy-1-methyl-2-(di-n-propylamino)tetralin, (+)ALK-3

The present study assessed the pharmacological activity of the stereoisomers of the novel 8-OH-DPAT analogue cis-8-hydroxy-1-methyl-2-(di-n-propylamino)tetralin, ALK-3, at postsynaptic 5-HT_1A receptors involved in 5-HT-mediated behaviour. Reserpine-pretreated rats were injected with (+)8-OH-DPAT (0.03–1.0 mg/kg s.c), (+)ALK-3 (0.3–10.0 mg/kg s.c.) or (-)ALK-3 (3.0–10.0 mg/kg s.c.), and components of the ‘5-HT behavioural syndrome’ were scored. (+8-OH-DPAT dose dependently elicited forepaw treading, flattened body posture and hindlimb abduction. In this respect, (+)ALK-3 was significantly less efficacious although its beahvioural action was prevented by pindolol (8 mg/kg s.c.), indicating that it was 5-HT_1A receptor mediated. Following pretreatment, (+)ALK-3 dose dependently, but partially, attenuated the effect of (+)8-OH-DPAT. (-)ALK-3 did not elicit 5-HT behaviours per se, and only very weakly antagonized the behavioural actions of (+)8-OH-DPAT at the highest dose tried. Our data indicate that the (+) enantiomer of ALK-3 is a partial but stereoselective agonist at postsynaptic 5-HT_1A receptors.     

Lack of interaction between flibanserin and antidepressants in inducing serotonergic syndrome in rats

This study was aimed at evaluating the ability of flibanserin, a 5-HT1A receptor full agonist with antidepressant potential, to induce the 5-HT syndrome (flat body posture, hindlimb abduction and forepaw treading) in rats previously administered with clinically active antidepressants imipramine, fluoxetine or paroxetine. The 5-HT syndrome was observed for 50 min after intraperitoneal administration of flibanserin (0, 8 or 64 mg/kg) given 10 min after antidepressants (0 or 15 mg/kg). Flibanserin induced flat body posture and very slight hindlimb abduction only at 64 mg/kg. No dose of flibanserin elicited forepaw treading. Similar but milder symptoms were induced by antidepressants. No interaction between flibanserin and antidepressants was observed. A dose of 10 mg/kg flibanserin did not change the flat body posture induced by 8 mg/kg (+/-)-8-OH-DPAT but antagonized (+/-)-8-OH-DPAT-induced forepaw treading.     

Behaviors induced by 5-hydroxytryptophan in neonatal, preweaning, postweaning, and adult Sprague-Dawley rats.

The behaviors induced by the 5-hydroxytryptamine (5-HT) precursor 5-hydroxytryptophan (5-HTP) has been called the "5-HT (serotonin) syndrome." These behaviors and others identified in rat pups were observed following administration of 5-HTP (300 mg/kg, SC) on postnatal (PN) days 3, 14, and 28 and in adult rats. Certain 5-HT syndrome behaviors and other uniquely neonatal behaviors were present in PN3 pups treated with vehicle. 5-HTP-treated PN3 pups showed increased head-shakes, rollovers, vocalizations, and forepaw treading and decreased hindlimb abduction. No 5-HT syndrome or neonatal behaviors were present at PN14 or PN28 or in adults treated with vehicle. 5-HTP administered at PN14 stimulated circling, forepaw treading, and resting tremor; at PN28, stimulated head-shakes and resting tremor; and in adults produced only head-shakes. To determine if prior exposure to 5-HTP affected the sensitivity of 5-HT receptor subtypes, the 5-HT1A agonist (+/-)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT) and the 5-HT2/1C agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) were administered to all rats as adults. 8-OH-DPAT (1 mg/kg, SC) produced flattened body posture unaffected by prior exposure to 5-HTP. Head-shakes induced by DOI (5mg/kg, IP) were decreased by prior exposure to 5-HTP at PN3 and adult, but increased by preexposure at PN28. Thus, serotonergic neural systems are implicated in some behaviors of neonates. The developmental patterns suggest changes in the sensitivity to these systems. Further, lasting changes in 5-HT2/1C receptor sensitivity occur due to exposure to 5-HTP.     

Effects of cold stress on some 5-HT1A, 5-HT1C and 5-HT2 receptor-mediated responses.

The purpose of the present study was to analyze the influence of stress (24-h cold exposure) on presynaptic 5-HT1A receptors, and on postsynaptic 5-HT1A, 5-HT1C and 5-HT2 receptors. Cold exposure for 24 h affected neither pargyline-induced decreases in 5-hydroxyindoleacetic acid (5-HIAA) levels in midbrain and rest of brain, nor plasma glucose and corticosterone levels. Treatment with the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.5-1 mg/kg), 3-5 h after the end of cold exposure triggered less intense flat body posture and forepaw treading in cold-exposed rats than in controls. On the other hand, 15- and 30-min plasma glucose responses to 8-OH-DPAT (0.25-0.5 mg/kg, 3-5 h after cold) or to the alpha 2-adrenoceptor agonist, clonidine (0.025 mg/kg), were not affected by cold, while the 15-min, but not the 30 min, plasma corticosterone response to 8-OH-DPAT was slightly amplified in cold-exposed rats. Cold exposure affected neither the inhibitory effect of 8-OH-DPAT (0.25-0.5 mg/kg, 3-5 h after cold) on midbrain 5-HIAA levels, nor the hypothermic effect of 8-OH-DPAT (0.5-1 mg/kg, 3-5 h after cold). Lastly, the hypoactivity elicited by the 5-HT1C receptor agonist, m-chlorophenyl-piperazine (1.5-3 mg/kg, 3-5 h after cold), or head shakes elicited by the 5-HT2 receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (1-2 mg/kg, 3-5 h after cold), were of similar intensities in control and in cold-exposed rats.     

The behavioural, but not the hypothermic or corticosterone, response to 8-hydroxy-2-(DI-n-propylamino)-tetralin, is antagonized by NAN-190 in the rat

The 5-HT1A receptor antagonistic properties of 1-(2-methoxyphenyl)-4-[4-(2-phthalimmido)butyl] piperazine (NAN-190) were studied in rats: its effect on the 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)-induced behavioural syndrome (flat body posture and reciprocal forepaw treading), hypothermia and secretion of corticosterone, i.e. responses mediated by 5-HT1A receptors, were examined. The drug NAN-190 (1-8 mg/kg) antagonized dose-dependently behavioural effects of 8-OH-DPAT (in both non-reserpinized and reserpine-pretreated animals); however, when administered in doses of 0.5-4 mg/kg, it did not affect the hypothermic or the hormonal response to 8-OH-DPAT. However, NAN-190 (1-8 mg/kg) given alone, produced hypothermia and increased the concentration of corticosterone in serum. The latter effects of NAN-190 were not reduced by (-)pindolol or spiperone. Moreover, the NAN-190-induced secretion of corticosterone was not affected by ketanserin, prazosin or yohimbine. The above results indicate that NAN-190 acts as a 5-HT1A receptor antagonist, only in the model of the 8-OH-DPAT-induced behavioural syndrome. The lack of effect of NAN-190 on the hypothermic or corticosterone response to 8-OH-DPAT most probably results from its own action which mimics the effects of 8-OH-DPAT. The mechanisms responsible for the NAN-190-induced hypothermia and secretion of corticosterone are still unknown, though stimulation of 5-HT1A receptors (either effect), 5-HT2 receptors and alpha 1- and alpha 2-adrenoceptors (corticosterone response) seems to be excluded.     

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.     

Behavioural evidence for functional interactions between 5-HT-receptor subtypes in rats and mice.

1. Different 5-hydroxytryptamine (5-HT) receptor subtypes mediate different behavioural responses. Compounds acting at more than one 5-HT receptor exert behavioural effects which may be the result of response competition or a specific interaction between pathways within the CNS. Therefore the mutual interaction between different 5-HT receptor subtypes was studied. 2. Hypothermia and hypoactivity in mice induced by the 5-HT1A-agonist 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) could be attenuated by the preferential 5-HT1C-agonists MK 212, 1-(meta-chlorophenyl)-piperazine (mCPP) and m-trifluoromethyl phenyl piperazine (TFMPP), and by the mixed 5-HT2/1C-agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). The mixed 5-HT1A/1B-agonist CGS 12066B at 10 mg kg-1 potentiated hypothermia and had no effect on hypoactivity. 3. Forepaw treading in rats induced by the 5-HT1A-agonist 8-OH-DPAT was attenuated by the 5-HT1C-agonists MK 212 and mCPP. The 5-HT1C-agonist TFMPP had a bimodal effect: at low doses (less than 1 mg kg-1) it potentiated, and at higher doses (greater than 2.2 mg kg-1) it attenuated forepaw treading, the mixed 5-HT2/1C-agonist DOI produced 5-HT2-related behaviours and potentiated 8-OH-DPAT-induced forepaw treading. This indicates an attenuating effect of 5-HT1C-receptor activation and a potentiating effect of 5-HT2-receptor activation. CGS 12066B had no effect in this respect. 4. Head shakes in rats induced by DOI could be attenuated by 8-OH-DPAT, TFMPP, mCPP and MK 212. The ID50S were 0.03, 0.7, 0.1 and .2 mg kg-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Different effects on the responses of functional pre- and postsynaptic 5-HT1A receptors by repeated treatment of rats with the 5-HT1A receptor agonist 8-OH-DPAT.

The effects of repeated treatment of rats with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 1.0 mg/kg, subcutaneously, twice daily for 7 days, on the stimulation of post- and presynaptic 5-HT1A receptors were examined. The postsynaptic responses, hypothermia and inhibition of the cage-leaving response, evoked by 0.05 mg/kg 8-OH-DPAT, were measured 48 hr after the final injection. Another postsynaptic response, the 5-HT syndrome (flat body posture and forepaw treading) was observed after the third injection of 8-OH-DPAT (1.0 mg/kg s.c.). One presynaptic response examined was the 8-OH-DPAT-induced decrease in the concentration of 5-hydroxyindoleacetic acid (5-HIAA), that indicates a decrease in turnover of 5-HT, due to stimulation of 5-HT receptors on the cell bodies and measured as the ratio of 5-HIAA to 5-HT in the hippocampus, hypothalamus and medulla oblongata. Another presynaptic response was the 8-OH-DPAT-induced decrease in the accumulation of 5-hydroxytryptophan (5-HTP) in the hippocampus and hypothalamus, after inhibition of L-aromatic amino acid decarboxylase by 3-hydroxybenzylhydrazine (NSD 1015), that is due to stimulation of autoreceptors on the 5-HT cell bodies. The kinetic properties of 5-HT1A receptors in the cerebral cortex and hippocampus, hippocampus alone, hypothalamus and medulla oblongata were determined with [3H]8-OH-DPAT. It was found that the postsynaptic effects were markedly attenuated after the treatment, the hypothermic effect already after a single dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

The behavioural effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in mice

The effects of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on the behaviour of mice were studied. 8-OH-DPAT given i.v. in doses greater than 1 mg/kg induced the distinct 5-HT syndrome, including head weaving, hindlimb abduction, forepaw treading and tremor. The 8-OH-DPAT-induced behaviour was not affected by the 5-HT depleter, p-chlorophenylalanine. Reserpine, which depletes monoamines, significantly decreased the head weaving elicited by 8-OH-DPAT, although it did not reduce the other components of the behavioural syndrome. The non-specific 5-HT receptor antagonist, metergoline, attenuated the 8-OH-DPAT-induced behaviour, while the 5-HT2 receptor antagonist, ketanserin, was without effect. In addition, the 5-HT1A receptor antagonist, spiperone, inhibited the 5-HT syndrome elicited by 8-OH-DPAT, while the dopamine receptor antagonist, haloperidol, affected only the head weaving. These results suggest that 8-OH-DPAT-induced behaviour in mice is mediated by the postsynaptic 5-HT1A receptor.     

5-HT1A and 5-HT2 receptors mediate discrete behaviors in the Mongolian gerbil.

Although the ability of agonists at specific serotonin (5-HT) receptor subtypes to induce distinct behaviors has been well documented in the rat, similar studies have not been reported in the Mongolian gerbil. We have found that the 5-HT1A/5-HT2 agonist 5-methoxy,N-N dimethyltryptamine (5-MeODMT) (0.5-8 mg/kg, SC), the specific 5-HT1A agonist 8-hydroxy(di-n-propylamino)tetralin (8-OH-DPAT) (0.125-16 mg/kg, SC), and the 5-HT precursor L-5-hydroxytryptophan (L-5-HTP) (100-250 mg/kg, SC) all elicit a 5-HT syndrome in the gerbil. This syndrome, analogous to the 5-HT syndrome in the rat, consists of reciprocal forepaw treading (RFT), hindleg abduction (HA), body tremors (BT), and Straub tail (ST). The putative 5-HT1A antagonist NAN-190 (0.25-8 mg/kg, SC) when dosed 15 min prior to either 5-MeODMT (4 mg/kg, SC) or 8-OH-DPAT (16 mg/kg, SC) blocked both RFT and HA in a dose-dependent manner, suggesting these 5-HT syndrome behaviors are mediated via 5-HT1A receptor activation. We also identified a unique, dose-responsive behavior in the gerbil, induced selectively by 5-HT1A agonists such as quipazine (2-16 mg/kg, SC) and (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.125-8 mg/kg, SC). This reciprocal hindleg body scratch (RHBS) behavior is dose dependently inhibited by pretreatment with the selective 5-HT2 antagonist ritanserin (0.0125-0.2 mg/kg, SC). RHBS behavior is also potently inhibited by pretreatment with the selective 5-HT1A agonist 8-OH-DPAT (0.005-0.04 mg/kg, SC), demonstrating a 5-HT1A/5-HT2 receptor subtype interaction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effects of 5-hydroxytryptamine1a selective drugs on the 5-HT behavioral syndrome

The effects of 8-hydroxy-2-(di-n-propyl-amino) tetralin (8-OH-DPAT), 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), buspirone and isapirone were examined at 5-hydroxytryptamine1A (5-HT1A) binding sites and on the 5-HT behavioral syndrome in the rat. 8-OH-DPAT, 5-MeODMT, buspirone and isapirone are all potent inhibitors of 3H-8-OH-DPAT binding to rat brain membranes (Ki values = 1.9-13 nM). However, these drugs have differential effects on the 5-HT behavioral syndrome. 8-OH-DPAT, 5-MeODMT and buspirone induce hindlimb abduction, flattened body posture and Straub tail. Isapirone induces only a slight flattening of body posture. By contrast, 8-OH-DPAT and 5-MeODMT, but not buspirone and isapirone, and isapirone, also induce forepaw treading, head-weaving and tremor. However, both buspirone and isapirone antagonize the induction of these three behaviors by 8-OH-DPAT or 5-MeODMT. These data show that 8-OH-DPAT and 5-MeODMT are "full agonists" in relation to six components of the 5-HT behavioral syndrome. Buspirone and isapirone, on the other hand, act as "antagonists" in relation to forepaw treading, head-weaving and tremor. Therefore, these data suggest that specific components of the 5-HT behavioral syndrome are mediated by 5-HT1A receptors.     

The involvement of subtypes of the 5-HT1 receptor and of catecholaminergic systems in the behavioural response to 8-hydroxy-2-(di-n-propylamino)tetralin in the rat

The centrally active 5-HT receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) has a high affinity for the 5-HT1A subtype of the 5-HT1 recognition site in cerebral membranes and, in the rat, induces most aspects of the '5-HT behavioural syndrome' including hyperlocomotion, head weaving, a flat body posture and reciprocal forepaw treading. The mechanism of action of 8-OH-DPAT in producing these effects has been investigated. Consistent with an involvement of catecholaminergic neurons, reserpine dose-dependently reduced hyperlocomotion and head weaving, and most components of the syndrome were reduced by prazosin, haloperidol and sulpiride. However, reserpine did not block forepaw treading or the flat body posture, allowing pharmacological analysis of these behaviours in the absence of intact monoaminergic systems. Under these circumstances blockade by the selective 5-HT2 receptor antagonist, ketanserin, and by haloperidol was not seen, and only the flat body posture was significantly reduced by prazosin, rendering a key role for 5-HT2 receptors, alpha 1-adrenoceptors and dopamine receptors unlikely. In contrast, both behaviours in the reserpinised rat were inhibited stereospecifically by pindolol and by spiperone, which interact with 5-HT1 and 5-HT1A recognition sites. The residual behavioural effects of 8-OH-DPAT in reserpinised rats may, therefore, reflect the consequences of stimulation of the putative 5-HT1A receptor.     

Effects of the putative 5-HT1A receptor agonist 8-OH-2-(di-n-propylamino)tetralin on nociceptive sensitivity in mice

The ability of 8-OH-2-(di-n-propylamino)tetralin (8-OH-DPAT) to alter nociceptive sensitivity in mice was studied using the tail-flick, hot-plate and formalin tests. Subcutaneous (SC) administration of 8-OH-DPAT (0.63-1.0 mg/kg) dose-dependently increased the temperature at which hindpaw lick occurred in a hot-plate test using slowly rising temperature and increased the latencies to hindpaw lick, but reduced the latencies to jump in a conventional hot-plate test. Intracerebroventricular (ICV) injections (0.25-1.0 microgram) produced similar results in the conventional hot plate test. Following intrathecal (ITH) injections (0.25-1.0 microgram), however, the latencies to hindpaw lick were elevated without any change in jump latencies. In the formalin test a low systemic dose of 8-OH-DPAT (0.063 mg/kg) elicited hyperalgesia, while hypoalgesia was found after a high dose (1.0 mg/kg). ICV injection of 1.0 microgram produced hypoalgesia in the formalin test while the same dose injected ITH was without effect. 8-OH-DPAT did not alter tail-flick latencies, either by SC, ICV or ITH administration. Previous studies have shown that 8-OH-DPAT stimulates central serotonergic receptors, and shows selectivity for the 5-HT1A recognition site. The present findings indicate an involvement of 5-HT1A receptors in the processing of nociceptive information both at spinal and supraspinal sites. However, stimulation of 5-HT1A receptors does not seem to affect spinal, nociceptive reflexes.     

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.     

Characterization of a novel and potent 5-hydroxytryptamine1A receptor antagonist.

A series of pindolol derivatives (n = 7) was analyzed in radioligand binding, biochemical and behavioral studies. Three of these drugs (Compounds A, B, and C) are extremely potent (i.e., Ki values less than 1.0 nM) at 5-hydroxytryptamine1A (5-HT1A) sites labeled by [3H] 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT). Moreover, these drugs are selective in that they are approximately an order of magnitude less potent at beta-adrenergic receptors labeled by 3H-dihydroalprenolol (DHA). Compound A (N1-(bromoacetyl)-N8-[3-(4-indolyloxy)-2-hydroxypropyl]-(Z)-1,8-di amino-p- methane) is also significantly less potent at 10 other neurotransmitter receptor sites analyzed. In addition, Compound A (10(-10) M to 10(-3) M) has no effect on baseline forskolin-stimulated adenylate cycalse activity in rat hippocampus. By contrast, nanomolar concentrations of the drug significantly (p less than 0.01) reverse 8-OH-DPAT-induced inhibition of forskolin-stimulated activity. In behavioral studies. Compound A (0.5 mg/kg) alone has no effect on baseline measures of reciprocal forepaw treading in the rat. Pretreatment with Compound A, however, significantly (p less than 0.05) inhibits the reciprocal forepaw treading induced by 8-OH-DPAT. These data suggest that Compound A is a potent and selective antagonist of 5-HT1A receptors in the CNS.     

The effects of 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) on food intake in non-deprived C57BL6 mice

The effects of the 5HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) were investigated on food intake in non-deprived mice. 8-OH-DPAT (50-200 mg/kg) administered subcutaneously (s.c.) 5 min prior to presentation of food, produced a dose-related increase in cumulative food intake in C57BC6 mice. The hyperphagic effect of 8-OH-DPAT (100 mg/kg, s.c.) was abolished by concurrent treatment with the 5HT1A receptor antagonist N-[2-(4-2-methoxyphenyl)-1-piperazinyl]-N-(2-pyridyl) cyclohexanecarboxamide (WAY100635; 0.3 mg/kg, s.c.). These data show that 8-OH-DPAT produces an increase in food consumption in non-deprived mice by a 5-HT1A receptor-mediated mechanism of action.     

Median raphe, but not dorsal raphe, application of the 5-HT1A agonist 8-OH-DPAT stimulates rat motor activity

Local application of the selective 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in the median raphe of rats caused locomotor stimulation. In contrast, dorsal raphe application of the compound induced flat body posture, which was discontinuous and not dose-dependent, and therefore distinct from that characteristic for postsynaptic 5-HT receptor-mediated behaviour. Injection of 8-OH-DPAT into the dorsal raphe or median raphe caused neither forepaw treading nor head-weaving; stiff tail and sniffing occurred inconsistently. By activating somatodendritic 5-HT1A autoreceptors in the median raphe, 8-OH-DPAT may disinhibit locomotor-enforcing neural pathways that receive 5-HT afferents from this nucleus. The data suggest that median raphe and dorsal raphe 5-HT neurons have different roles in motor control.     

A pharmacological validation of radiotelemetry in conscious, freely moving rats

Two reference substances were used in the present study. d-Amphetamine is a direct catecholamine-releasing agent which has a marked stimulant effect upon locomotor activity at low to moderate doses and induces stereotypy at higher doses. (+/-)8-Hydroxy-2-(di-n-propylamino)-tetraline [(+/-)8-OH-DPAT] is a selective 5-HT1A receptor agonist which produces a well-defined behavioral syndrome and a dose-dependent hypothermia. The first aim of this study was to validate that the d-amphetamine-induced activity monitored by telemetry correlated to that concomitantly measured in automated cages and complement these measures with an ethologically based direct observational technique. d-Amphetamine (2.5 and 5.0 micromol/kg s.c.) stimulated locomotion as assessed with radiotelemetry, in automatic cages and by observation. Accompanying these behavioral effects was a concurrent increase (assessed by radiotelemetry) in heart rate but not in blood pressure. The second part of this study examined the pharmacological effects of (+/-)8-OH-DPAT (0.09-6.1 micromol/kg s.c.) on behavior (observation and activity) and temperature and on the cardiovascular system. (+/-)8-OH-DPAT induced the classical serotonergic syndrome of lower lip retraction, forepaw treading, and flattened body posture (observation), and this was accompanied by a concomitant hypothermia (radiotelemetry). (+/-)8-OH-DPAT also induced a dose-dependent and significant decrease in heart rate for 50 min of the 1-h long observation period. This was not accompanied by an increase in blood pressure in spite of the increased activity as seen with all three methods. These results show that radiotelemetry can be used as a tool to measure activity, core temperature, and the cardiovascular parameters in animals that are less stressed than those that are restrained for similar more invasive measurements, and that this technique can be used in combination with others to produce a more complete ethogram of the animal's responses to pharmacological challenges.