Differentiating the discriminative stimulus effects of gamma-hydroxybutyrate and ethanol in a three-choice drug discrimination procedure in rats

Anecdotal reports indicate that GHB produces subjective effects similar to those of ethanol. However, recent investigations comparing the discriminative stimulus effects of GHB to those of ethanol suggest that the subjective effects of these substances may differ considerably. To explore further potential differences between GHB and ethanol, 16 male Sprague–Dawley rats were trained in a three-lever drug discrimination procedure to discriminate ethanol (1.0 g/kg, experiment 1; 1.5 g/kg, experiment 2) and GHB (300 mg/kg) from vehicle. Dose–response functions determined with both training compounds revealed a clear dissociation between the discriminative stimulus effects of these drugs. As expected, the GHB precursors gamma-butyrolactone and 1,4-butanediol produced full substitution for GHB. In addition, the GABA_B receptor agonist baclofen substituted for GHB, whereas the benzodiazepine flunitrazepam and the NMDA receptor antagonist ketamine engendered greater responding on the ethanol-lever. GHB's discriminative stimulus effects were blocked by the GABA_B receptor antagonist CGP-35348 but only partially blocked by the putative GHB receptor antagonist NCS 382. These findings are consistent with previous reports of GHB's discriminative stimulus effects in two-choice drug discrimination procedures and provide additional evidence that these effects are distinct from those of ethanol.     

Training dose as a factor in LSD-saline discrimination

To assess the effects of training dose on the discriminative stimulus properties of LSD, groups of rats (eight/group) were trained to discriminate each of three doses of LSD (0.02, 0.08 or 0.32 mg/kg) from saline. This was accomplished by using a method of progressively altering dose (fading). Dose-response tests revealed that the three LSD cues were specific to the dose used during training and that, as the training dose declined, the slope of the LSD dose-response curve became less steep. Substitution tests with direct serotonin (5-HT) agonists (quipazine, MK-212, 5-methoxy-N,N-dimethyltryptamine) and antagonism tests with central 5-HT antagonists (methiothepin and cyproheptadine) indicated that 5-HT is involved in mediating the in vivo effects of LSD and that training dose co-determines (along with the dose of the test compound) the extent of substitution or antagonism. In addition, substitution tests with the peripherally-active 5-HT agonist 5-methoxytryptamine and 5-HT antagonist xylamidine suggested that the peripheral serotonergic actions of LSD may be involved (in part) in the low dose (0.02 mg/kg) LSD cue. In contrast to 5-HT, dopamine (DA) did not appear to be involved in the discriminative stimulus properties of LSD, because no significant dose or group effects were seen during tests with the DA agonists apomorphine and d-amphetamine or the DA antagonist haloperidol.     

Patterns of exploration in rats distinguish lisuride from lysergic acid diethylamide

In order to further validate a previously proposed animal model of the effects of LSD in humans, doses of 5, 15, 30 and 60 micrograms/kg lisuride (a non-hallucinogenic congener of LSD) were studied using a behavioral pattern monitor (BPM). The BPM provided both quantitative measures of crossovers, rearings, and holepokes and qualitative measures of spatial patterns of locomotion. A holeboard chamber connected to a homecage provided two test situations. Rats were tested either with (free exploration) or without access to the homecage (forced exploration). In both situations, lisuride exhibited a biphasic dose-response curve for horizontal locomotion (low dose suppression and high dose enhancement), while rearing was significantly reduced at all doses. Lisuride also produced a dose-dependent increase in the perseverative quality of locomotor patterns. A comparison of these results with our previous studies with lysergic acid diethalmide (LSD) indicate that, with the exception of rearings, lisuride fails to mimic LSD's characteristic effects on exploratory activity. Rather, lisuride exhibited many similarities to the dopamine angonist apomorphine.     

Pharmacological analysis of the heterogeneous discriminative stimulus effects of ethanol in rats using a three-choice ethanol-dizocilpine-water discrimination

The present study used a three-choice operant drug discrimination procedure to determine if NMDA-mediated discriminative stimulus effects could be separated from other stimulus effects of 2.0 g/kg ethanol. Adult male Long-Evans rats (n = 7) were trained to discriminate dizocilpine (0.17 mg/kg; IG) from ethanol (2.0 g/kg; IG) from water (4.7 ml; IG) using food reinforcement. Substitution tests were conducted following administration of the GABA_A positive modulators allopregnanolone (5.6–30.0 mg/kg; IP), diazepam (0.3–10.0 mg/kg; IP) and pentobarbital (1.0–21.0 mg/kg; IP), the non-competitive NMDA antagonist phencyclidine (0.3–10.0 mg/kg; IP), the 5-HT₁ agonists TFMPP (0.3–5.6 mg/kg; IP) and RU 24969 (0.3–3.0 mg/kg; IP), and isopropanol (0.10–1.25 g/kg; IP). Allopregnanolone, diazepam and pentobarbital substituted completely (>80%) for ethanol. Isopropanol partially (77%) substituted for ethanol. Phencyclidine substituted completely for dizocilpine. RU 24969 and TFMPP did not completely substitute for either training drug, although RU 24969 partially (62%) substituted for ethanol. Successful training of this three-choice discrimination indicates that the discriminative stimulus effects of 0.17 mg/kg dizocilpine were separable from those of 2.0 g/kg ethanol. The finding that attenuation of NMDA-mediated effects of ethanol occurred without altering significantly GABA_A- and 5-HT₁-mediated effects suggests that the NMDA component may be independent of other discriminative stimulus effects of 2.0 g/kg ethanol. Received: 18 November 1997 / Final version: 10 February 1998     

Effects of repeated administration of the monoamine oxidase inhibitor phenelzine on the discriminability of d-lysergic acid diethylamide (LSD) and 1-(m-trifluoromethylphenyl) piperazine (TFMPP)

Rats trained to discriminate d-lysergic acid diethylamide (LSD; 0.08 mg/kg) or 1-(m-trifluoromethylphenyl) piperazine (TFMPP; 0.8 mg/kg) were treated with the monoamine oxidase inhibitor (MAOI) phenelzine (10 mg/kg/day) for 7 days. After a 24 h washout period, they were challenged with the training drug (and dose) or saline, during extinction test sessions. Following 0.08 mg/kg LSD, LSD-trained rats responded primarily on the saline lever (29% drug-appropriate responding) while, after TFMPP (0.8 mg/kg), TFMPP-trained animals responded on the drug lever (75% drug-appropriate responding). These preliminary data suggest that, if serotonin receptors are involved in the behavioral effects of TFMPP, these receptors differ from those involved in the effects of LSD.     

Discriminative stimulus properties of the atypical antipsychotic clozapine and the typical antipsychotic chlorpromazine in a three-choice drug discrimination procedure in rats

Rationale The atypical antipsychotic drug (APD) clozapine elicits a robust discriminative cue that is generally selective for other atypical APDS in two-choice drug discrimination (DD) procedures.Objectives The present study determined whether a three-choice DD procedure with the atypical APD clozapine (CLZ) versus the typical APD chlorpromazine (CPZ) versus vehicle (VEH) could provide greater selectivity between atypical and typical APDs.Methods Sprague-Dawley rats were trained to discriminate 5.0 mg/kg CLZ from 1.0 mg/kg CPZ from VEH in a three-lever DD task with an FR30 food reinforcement schedule.Results Generalization testing with CLZ produced CPZ-appropriate responding at lower doses (ED₅₀=0.103 mg/kg) and CLZ-appropriate responding at higher doses (ED₅₀=1.69 mg/kg). Generalization testing with the atypical APD olanzapine produced similar results. In contrast, the atypical APD risperidone and the typical APDs CPZ and haloperidol produced only CPZ-appropriate responding. The muscarinic antagonist scopolamine produced CPZ-appropriate responding at lower doses and CLZ-appropriate responding at higher doses in a manner similar to CLZ and olanzapine. The co-administration of haloperidol (0.00625 mg/kg) with scopolamine shifted the dose–response curve for CLZ-appropriate responding to the left. The 5-HT_2A/2C antagonist ritanserin and the H₁ histamine antagonist pyrilamine did not substitute for either CLZ or CPZ. The ₁ adrenergic antagonist prazosin did not substitute for CLZ, but produced full substitution for CPZ.Conclusions The three-choice DD procedure clearly distinguished the atypical APDs CLZ and olanzapine from the typical APDs CPZ and haloperidol; however, the stimulus properties of the atypical APD risperidone were similar to CPZ, but not to CLZ. These findings further suggest that CLZ, as well as CPZ, elicits a compound cue.     

Dopaminergic and serotonergic mediation of the discriminable effects of Ergot alkaloids

The involvement of dopamine (DA) and serotonin (5-HT) neuronal systems in the discriminative stimulus effects of various ergot derivatives was assessed by administering four ergots to 36 rats which had been trained to discriminate either apomorphine (APO) or d-lysergic acid diethylamide (LSD) from saline. Lergotrile, lisuride and LSD substituted for APO (0.25 mg/kg) while bromocriptine and ergonovine (ergometrine) did not; only lisuride mimicked LSD (0.08 mg/kg). Antagonism tests showed that the DA antagonist haloperidol but not the 5-HT antagonist BC-105 (pizotifen) blocked the APO cue; both the LSD cue and the substitution of LSD for APO were blocked by BC-105 but not by haloperidol. It was concluded that DA receptor activation plays a prominent role in the discriminative stimulus effects of lergotrile and lisuride as well as APO and a secondary role in the LSD cue; 5-HT seems to be of major importance in the mediation of the effects of LSD and, to a lesser extent, lisuride. The functions of the two monoamines in the discriminable effects of bromocriptine and, particularly, ergonovine are less clear.     

Effects of training dose and two- versus three-choice testing procedure on nicotine discrimination responding in humans

Rationale: Discrimination of a drug’s interoceptive stimulus effects often depends substantially on training and testing conditions. Objectives: We examined changes in nicotine discrimination behavior in humans as a function of lowering the training dose and of varying the discrimination testing procedure. Methods: Smokers and never-smokers (n=10 each) were initially trained to discriminate 20 μg/kg nicotine by nasal spray from placebo (0) and tested on generalization of discrimination responding across a range of doses from 0 to 20 μg/kg. Each subsequently learned to reliably discriminate progressively smaller doses of nicotine from placebo until his or her threshold dose for discrimination was identified (mean=2.7 μg/kg). A repeat testing of generalization responding across 0–20 μg/kg was then conducted, using placebo and the subject’s threshold dose as training doses. Generalization testing involved both two-choice and three-choice (novel response option) quantitative procedures. Results: A significant shift to the left was seen in nicotine-appropriate responding in the two-choice procedure when the nicotine training dose was lowered (i.e. from the first to the second test of generalization). In the three-choice procedure, however, there was no such leftward shift. Instead, in never-smokers, a flattening of nicotine-appropriate responding occurred with a lowering of the training dose, while novel-appropriate responding significantly increased. The subjective effects of ”head rush” and, in never-smokers only, ”jittery” also showed a shift to the left in their relationship with nicotine generalization dose when the training dose was lowered. Conclusions: These results confirm the importance of training and testing conditions on discrimination behavior and subjective drug responses within subjects and demonstrate the utility of the novel-response, three-choice procedure for assessing qualitatively different stimulus effects of novel drug doses. Received: 21 December 1998 / Final version: 11 March 1999     

Locomotor effects of lisuride: A consequence of dopaminergic and serotonergic actions

The open-field test was used to study the involvement of serotonergic and dopaminergic mechanisms in the action of lisuride on locomotor activity in the rat. Lisuride produced a biphasic locomotor effect. The maximum locomotor stimulatory response of lisuride was stronger than that of apomorphine and comparable with that of apomorphine and LSD combined. Hypermotility induced by high doses of lisuride was partially suppressed by the serotonin antagonist cyproheptadine and not further enhanced by LSD. A moderate dose of lisuride potentiated apomorphine-induced hypermotility in the same manner as has been shown for LSD. Lesion of dopaminergic structures within the median raphe nucleus by 6-OHDA produced a potentiation of lisuride-induced hypermotility. This effect was suppressed by cyproheptadine. The locomotor inhibitory effect of low doses of lisuride may be related to a stimulation of presynaptic mesolimbic dopamine receptors. It is concluded that the locomotor stimulant effect of higher doses of lisuride may depend on stimulation of postsynaptic dopamine receptors and a scrotonergic action and that the locomotor effects of lisuride reflect a complex interaction at dopaminergic and serotonergic transmission systems.     

Re-evaluation of lisuride pharmacology: 5-hydroxytryptamine1A receptor-mediated behavioral effects overlap its other properties in rats

Abstract Rationale. There is substantial evidence that lisuride can produce effects linked to 5-HT_1A receptor occupancy. Nevertheless, this action has generally been ignored in the mechanism of action of lisuride, in favor of an exclusive role for dopamine receptors in considering its antiparkinsonian effects, or an exclusive role of 5-HT_2A/2C receptor activation in hallucinogenesis. These conclusions are surprising when one considers that the potent interaction of lisuride with 5-HT_1A receptors has been demonstrated in several different laboratories and that activation of 5-HT_1A and 5-HT_1B receptors can modulate dopaminergically mediated responses. Objective. The lack of full substitution of lisuride for lysergic acid diethylamide (LSD) in drug discrimination experiments and induction of a pronounced 5-HT syndrome by this compound at relatively low doses convinced us to execute two series of experiments that might explain the primary mechanism responsible for lisuride-mediated biological effects and its paradoxical classification as a dopamine agonist in the literature. Results. In drug discrimination studies, lisuride fully mimicked the 5-HT_1A agonist LY 293284, only partially substituted for LSD and DOI, and failed to substitute for (+)-amphetamine. Lisuride produced a significant dose-related increase in flat body posture, forepaw treading, and lower-lip retraction which reflect a modulation of behavior by action at central 5-HT_1A receptors. Only pMPPI [4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridynyl-benzamide hydrochloride], a selective 5-HT_1A antagonist, was effective in inhibiting all 5-HT syndrome behaviors produced by lisuride, whereas pMPPI was without effect on any behavior induced by LSD. Lisuride dose dependently decreased body temperature in rats with a potency similar to that of the selective 5-HT_1A agonist LY 293284. The hypothermic effect of lisuride was prevented by pre-injection of pMPPI, but not by ketanserin or haloperidol. Conclusion. We have demonstrated that the behavioral effects of low doses of lisuride are clearly mediated by stimulation of 5-HT_1A receptors. Electronic Publication     

The discrimination of drug mixtures using a four-choice procedure in pigeons

Abstract Rationale. The purpose of these experiments was to study drug combinations as discriminative stimuli using a new four-choice procedure. Objectives. To determine whether pigeons could discriminate among a mixture of two drugs, each of the component drugs and saline, and to study other drug combinations in these birds. Methods. Pigeons were trained to discriminate among saline, 5 mg/kg morphine, 5 mg/kg pentobarbital, and a mixture of these two doses using a four-choice procedure. Results. When responding stabilized, the birds responded on the correct key more than 90% of the time. Low doses of all drugs given alone produced responding on the saline key. Higher doses of pentobarbital and chlordiazepoxide produced responding on the pentobarbital key, and higher doses of morphine produced responses on the morphine key. Methamphetamine produced responding on the saline key. None of the drugs given alone produced responding on the mixture key. When pentobarbital was combined with morphine, doses both below and above the combined training doses of these drugs usually produced responding on the mixture key. The combination of chlordiazepoxide with morphine produced similar results. Combinations of methamphetamine with pentobarbital or with morphine produced effects similar to those of pentobarbital or morphine given alone. Conclusions. A wide range of combinations of pentobarbital and morphine, or chlordiazepoxide and morphine produce responding on the mixture key, even though the pigeons were not exposed to these dose combinations during training. The four-choice procedure provides the opportunity to study drug mixtures in a detail not possible with more limited response choices. Electronic Publication     

Serotonergic and dopaminergic effects on yawning in the cat

The serotonergic agents LSD (0.01–0.05 mg/kg) and lisuride (0.025 and 0.05 mg/kg) elicited a high frequency of limb flicking in the cat after IP doses; LSD, but not lisuride, elicited a significantly increased frequency of yawning as well. In combination, LSD plus lisuride (0.25 mg/kg each) gave additive frequencies of limb flicking, but the frequency of yawning was half that after LSD alone. The dopamine agonist apomorphine had no significant effect on either yawning or limb flicking over the dose range 0.006 to 3.2 mg/kg. Pretreatment of cats with 1.0 mg/kg of apomorphine (but not with 0.05 mg/kg) significantly reduced the frequency of yawning elicited by 0.01 or 0.025 mg/kg of LSD, but had no effect of limb flicking. The dopamine antagonist haloperidol had no effect on limb flicking at doses from 0.008 to 0.512 mg/kg, but produced a significantly increased frequency of yawning at 0.256 mg/kg, an effect antagonized by lisuride administration. Given that lisuride has more potent dopamine agonist properties than LSD, these results are consistent with serotonergic elicitation of yawning, dopaminergic inhibition of yawning, and with their concomitant interaction in the expression of drug-induced yawning in the cat. The behavioral pharmacologies of limb flicking and yawning are different in this species.     

Behavioral effects of intracerebroventricular administration of LSD, DOM, mescaline or lisuride

The effects on a fixed ratio-40 (FR-40) operant behavior of intracerebroventricular (ICV) administration of the hallucinogens lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-methylamphetamine (DOM), mescaline or the non-hallucinogenic LSD-analogue lisuride were compared with intraperitoneal (IP) administration. Infusion of LSD (8.5 to 34 micrograms) into the left lateral ventricle produced a dose-dependent decrease in reinforcers and an increase in 10-sec periods of non-responding (pause intervals). The time-course of LSD showed a shorter latency to onset after ICV than IP administration. The ED50 for doses increasing pause intervals by ICV administration was 15 micrograms. This disruption was greater than that produced by IP administration of equivalent doses of LSD (IP ED50: 19 micrograms). DOM (40 to 120 micrograms) infused into the lateral ventricle also produced a dose-dependent disruption of FR-40 behavior. ICV DOM also showed a rapid onset to peak effects, but a slower offset than LSD, and was 3 times more potent than systemic administration (ED50s: 58 micrograms ICV vs. 153 micrograms IP). Mescaline was much more potent in disrupting FR-40 behavior by the ICV route than by IP administration. The ICV ED50 for doses of mescaline increasing pause intervals was 74 micrograms, in contrast to an ED50 following systemic administration of 2251 micrograms, demonstrating a 30-fold difference in potency. Lisuride administered via the ICV route was no more potent than by IP administration with ED50s of 4 micrograms ICV and 4 micrograms IP. Lower doses of lisuride administered by both routes had a similar effect over time on pause intervals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Complex discriminative stimulus properties of (+)lysergic acid diethylamide (LSD) in C57Bl/6J mice

Rationale The drug discrimination procedure is the most frequently used in vivo model of hallucinogen activity. Historically, most drug discrimination studies have been conducted in the rat. With the development of genetically modified mice, a powerful new tool has become available for investigating the mechanisms of drug-induced behavior. The current paper is part of an ongoing effort to determine the utility of the drug discrimination technique for evaluating hallucinogenic drugs in mice.Objective To establish the training procedures and characterize the stimulus properties of (+)lysergic acid diethylamide (LSD) in mice.Methods Using a two-lever drug discrimination procedure, C57Bl/6J mice were trained to discriminate 0.45 mg/kg LSD vs saline on a VI30 sec schedule of reinforcement, with vanilla-flavored Ensure serving as the reinforcer.Results As in rats, acquisition was orderly, but the training dose was nearly five-fold higher for mice than rats. LSD lever selection was dose-dependent. Time-course studies revealed a rapid loss of the LSD stimulus effects. The 5-HT_2A/2C receptor agonist, 2,5-dimethoxy-4-bromoamphetamine [(–)DOB] (1.0 mg/kg), substituted fully for LSD and the 5-HT_1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) (1.6 mg/kg), substituted partially for LSD. Pretreatment with the 5-HT_2A receptor-selective antagonist, MDL 100907, or the 5-HT_1A-selective antagonist WAY 100635, showed that each antagonist only partially blocked LSD discrimination. Substitution of 1.0 mg/kg (–)DOB for LSD was fully blocked by pretreatment with MDL 100907 but unaltered by WAY 100635 pretreatment.Conclusions These data suggest that in mice the stimulus effects of LSD have both a 5-HT_2A receptor and a 5-HT_1A receptor component.     

Lisuride and LSD: Dopaminergic and serotonergic interactions in the “serotonin syndrome”

A characteristic behavioral syndrome has been associated with stimulation of central serotonin receptors in rats. This behavior can be produced by inhibition of monoamine oxidase and administration of 5-hydroxytryptophan as well as by direct acting serotonergic agonists. LSD and the novel ergot derivative lisuirde produced this syndrome in rats. These drugs possess both serotonergic and dopaminergic properties. Since changes in dopaminergic function have also been reported to affect the so-called serotonin syndrome, it was not clear how the two ergot drugs acted to produce this syndrome. The syndrome produced by pargyline and 5-hydroxytryptophan methyl ester was blocked by haloperidol, methysergide, parachlorophenylalanine, and alpha-methylparatyrosine; these treatments failed to block the effects of lisuride. Metoclopramide did not block the syndrome produced by either lisuride or pargyline plus 5-hydroxytryptophan methyl ester. Methysergide partially blocked the behavioral effects of LSD; pretreatment with either haloperidol or metoclopramide potentiated and prolonged the behavioral effects of LSD. The results suggest that dopaminergic modulation of the serotonin syndrome occurs before the serotonin receptor involved in this behavior. Also, the differences between LSD and lisuride may be relevant to their different psychopharmacological properties.     

The discriminative stimulus effects of methamphetamine in pigeons

This experiment was designed to elucidate the neurotransmitter systems that mediate the discriminative stimulus effects of methamphetamine. Four pigeons were trained to peck one key following saline injections and a second key following methamphetamine injections (1.0 or 1.7 mg/kg, IM). Substitution tests revealed drug-appropriate responding following administration of the psychomotor stimulants methamphetamine, amphetamine and cocaine, the dopamine (DA) reuptake inhibitor bupropion, norepinephrine (NE) reuptake inhibitors imipramine and tomoxetine, and the serotonin (5-HT) releaser fenfluramine. Salinekey responding occurred following administration of the D₁ agonist SKF-38393, the D₁ antagonist SCH-23390, the α₂ receptor agonist clonidine, the α₁ antagonist prazosin, a nonselective β-antagonist propranolol and the selective 5-HT reuptake inhibitor fluoxetine. The D₂/D₃ agonist quinpirole produced drug-appropriate responding in two pigeons and partial substitution in the remaining two pigeons. The 5HT_1A agonist 8-OH-DPAT produced drug-appropriate responding at higher doses (0.3–1.0 mg/kg), whereas much lower doses (0.003–0.1 mg/kg) antagonized the methamphetamine stimulus. The stimulus effects of methamphetamine were attenuated by pretreatment with prazosin, SCH-23390 and eticlopride, whereas pretreatment with propranolol and the 5-HT₃ antagonist, MDL 72222, failed reliably to attenuate drug key responding. These results suggest that NE and DA reuptake inhibition and 5-HT release mediate the discriminative stimulus effects of methamphetamine as do the 5-HT_1A and DA D₁ and D₂ receptors.     

Discriminative stimulus effects of a low dose of apomorphine in the rat

The discriminative stimulus (DS) effect of apomorphine was investigated in rats trained in a two-lever, food-reinforcement procedure. Rats were given subcutaneous injections of saline or 0.1 mg/kg apomorphine HCl, 15 min before training sessions. The training dose of apomorphine was chosen to activate dopamine autoreceptors selectively. Stimulus generalization studies demonstrated that the DS effects generalized completely to other directacting dopaminergic agonists such as N-n-propylnorapomorphine (NPNA), pergolide, lergotrile, and bromocriptine. The indirect-acting dopamine agonists, (+)amphetamine, cocaine, and methylphenidate produced predominantly saline-appropriate lever responses. The DS effect of apomorphine at the training dose was incompletely antagonized by haloperidol or metoclopramide. The dopaminergic antagonists tested, however, also partially generalized to apomorphine. Both enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) produced apomorphine-appropriate lever choice with the (-) enantiomer being slightly more potent. The discriminative property of this (0.1 mg/kg) dose of apomorphine has characteristics consistent with selective dopamine autoreceptor activation.     

Effects of the delta opioid agonist BW373U86 in pigeons trained to discriminate fentanyl,bremazocine and water in a three-choice drug discrimination procedure

The delta opioid agonist BW373U86 was examined alone and in combination with mu agonists in pigeons trained to discriminate the mu agonist fentanyl (0.056 mg/kg), the kappa agonist bremazocine (0.017 mg/kg), and distilled water in a three-choice drug discrimination procedure. BW373U86 (0.01–10 mg/kg) produced a dose-dependent increase in fentanyl-appropriate responding and complete generalization to fentanyl in four of five subjects. BW373U86 did not elicit bremazocine-appropriate responding in any of the subjects. Fentanyl-appropriate responding elicited by BW373U86 was antagonized by the delta selective antagonist naltrindole (0.1–10 mg/kg) but not by the mu selective antagonist naloxone (0.1–30.0 mg/kg). When BW373U86 was administered in combination with the mu agonists fentanyl, morphine and nalbuphine, a low dose of BW373U86 (0.01 mg/kg) that elicited primarily water-appropriate responding when administered alone did not produce a significant change in the ED₅₀ values for fentanyl, morphine or nalbuphine. Higher doses of BW373U86 (0.1–1.0 mg/kg) increased levels of fentanyl-appropriate responding elicited by low doses of fentanyl, morphine and nalbuphine to levels similar to those produced by BW373U86 alone. These results indicate that BW373U86 shares discriminative stimulus properties with the mu agonist fentanyl in pigeons, possibly by acting at delta opioid receptors. However, BW373U86 does not potentiate the discriminative stimulus effects of mu agonists or share discriminative stimulus effects with the kappa agonist bremazocine.     

Differential effects of a new serotoninomimetic drug, 8-OH-DPAT, on copulatory behavior and pelvic thrusting pattern in the male rat

Treatment of sexually experienced male rats with 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a new drug having central serotoninomimetic activity, caused a dose-dependent decrease in the number of mounts and intromissions to ejaculation and shortened the ejaculation latency. These changes in the coital pattern were not accompanied by any marked changes in the organization of the thrusting pattern. It was concluded that treatment with 8-OH-DPAT may influence the excitability of the central neural circuits determining the elicitation of ejaculation without affecting those involved in the pelvic thrusting pattern, despite evidence of general motor disturbances.     

Clozapine blocks disruptive and discriminative stimulus effects of quipazine

Clozapine was tested in two serotonin-dependent behavioral measures. One group of rats was trained to discriminate the serotonin agonist, quipazine, from saline in a two-lever operant choice task. Pretreatment with clozapine completely blocked the discrimination of quipazine. Another group of rats was trained to bar press for milk on a variable interval schedule of reinforcement. Quipazine decreased the response rate in these animals and pretreatment with clozapine completely reversed this effect. Thus, clozapine acted as a serotonin antagonist in both measures of serotonin function.