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)     

Naloxone alters the effects of LSD, DOM and quipazine on operant behavior of rats

Administration of the indolealkylamine hallucinogen d-lysergic acid diethylamide (LSD), the phenethylamine hallucinogen 2,5-dimethoxy-4-methylamphetamine (DOM) and the putative 5-hydroxytryptamine (5-HT) agonist quipazine all produced a dose-dependent decrease in fixed ratio (FR-40) response rates and a concomitant increase in the number of 10-second pause intervals. Although naloxone (4.0 mg/kg) had no effect on FR-40 responding per se, the pause-producing effects of LSD and, to a lesser extent, DOM were potentiated by pretreatment with naloxone. The action of quipazine on reinforcers was unaffected by combination with naloxone, while the effect on pause intervals was slightly attenuated by naloxone pretreatment. These data and previous studies suggest that the pause-producing effects of indolealkylamine and phenethylamine hallucinogens reflect their activation of a selective portion of brain 5-HT receptors. The potentiation of these effects by naloxone may relate to a modulation of central 5-HT systems by endogenous opioid mechanisms tending to restore an imbalance in various 5-HT pathways caused by the hallucinogenic 5-HT agonists. The more generalized disruptive effects of quipazine on brain 5-HT systems may be less susceptible to the endogenous opioid modulation or may actually combine with it to induce a greater disruption.     

Cross generalization with LSD and yohimbine in the rat

Rats trained to discriminate intraperitoneal injections of 0.16 mg/kg LSD from saline injections were found to show stimulus generalization with 0.31-5 mg/kg of yohimbine. Partial generalization also occurred with clonidine and xylazine. Rats discriminating intraperitoneal injections of 5 mg/kg of yohimbine from saline generalized LSD at doses of 0.08-0.63 mg/kg. The data establish an equivalence between LSD and yohimbine as to discriminative effects in rats. This equivalence is consistent with LSD and yohimbine producing at least partly similar subjective effects in humans.     

Interactions between serotonergic agonists and antagonists in rats trained with LSD as a discriminative stimulus

Drugs purported to have selective affinities for 5-HT1A, 5-HT1B, and 5-HT2 receptors were tested in rats trained with 0.1 mg LSD versus saline. Included were 5-methoxy-dimethyltryptamine (MDMT), 2,5-dimethoxy-4-methyl-amphetamine (DOM), 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), m-trifluoromethylphenyl-piperazine (TFMPP), and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU-24969). Tests were then repeated in the presence of either pizotyline or pirenperone. DOM substituted for LSD and both were blocked by pizotyline and pirenperone. MDMT, 8-OH-DPAT, TFMPP, and RU-24969 substituted less completely and were variably affected by the antagonists. An unexpected result was potentiation of the stimulus or disruptive effects of certain doses of 8-OH-DPAT and TFMPP by pizotyline and pirenperone. The present findings suggest more complex interactions between these drugs than has previously been assumed.     

Comparative neurobiological effects of ibogaine and MK-801 in rats

Ibogaine is a plant-derived alkaloid with putative 'anti-addictive' properties. Although ibogaine binds to multiple targets in the brain, recent evidence suggests the drug acts as an N-methyl-D-aspartate (NMDA) antagonist similar to MK-801. The purpose of the present study was to compare neurochemical and neuroendocrine effects of ibogaine and MK-801 in vivo. Male rats received either i.p. saline, ibogaine (10 and 100 mg/kg), or MK-801 (0.1 and 1 mg/kg). Groups of rats (N=6-8/group) were decapitated 30 or 60 min after injection. Brains were harvested for analysis of dopamine (DA) and its metabolites, while trunk blood was collected for analysis of plasma corticosterone and prolactin. Ibogaine produced marked dose-dependent reductions in tissue DA with concurrent increases in the metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This profile of ibogaine-induced effects on DA metabolism was consistently observed in the cortex, striatum, olfactory tubercle, and hypothalamus. MK-801, on the other hand, did not reduce DA levels in any brain region but did cause modest region-specific elevations in DA metabolites. Ibogaine and MK-801 caused comparable elevations in circulating corticosterone, but only ibogaine increased prolactin. The present findings show that the effects of ibogaine on DA neurotransmission and neuroendocrine secretion are not fully mimicked by MK-801. Thus, the wide spectrum of in vivo actions of ibogaine can probably not be explained simply on the basis of antagonism at NMDA receptors.     

Effects of the phenethylamine derivatives,BL-3912, fenfluramine,and Sch-12679, in rats trained with LSD as a discriminative stimulus

Six rats were trained to discriminate the effects of LSD (100 g/kg) and saline in a two-lever choice task. They were then tested with each of three phenethylamine derivatives, BL-3912 (2,5-dimethoxy-4-methyl--ethyl-phenethylamine), fenfluramine (N-ethyl--methyl-m-(trifluoro-methyl)phenethylamine), and Sch-12679 (N-methyl-1-phenyl-7,8-dimethoxy-2,3,4,5-tetra-hydro-3-benzazepine maleate). Fenfluramine and Sch-12679 yielded intermediate results, i.e., responding was not fully appropriate for either training condition while BL-3912 substituted completely for LSD. The LSD-like effects of each of the drugs were antagonized by pretreatment with BC-105, a serotonergic antagonist known to block the stimulus effects of indole and phenethylamine hallucinogens. The present data together with consideration of the known clinical effects of BL-3912, fenfluramine, and Sch-12679 are consistent with the following conclusions: (1) a variety of drugs may substitute in whole or in part for LSD in LSD-trained rats, and (2) even complete substitution of a drug for LSD in the rat is not necessarily associated with the production by that drug of hallucinations in man.     

Serotonergic/glutamatergic interactions: the effects of mGlu2/3 receptor ligands in rats trained with LSD and PCP as discriminative stimuli

Rationale On the basis of electrophysiological evidence, it has been proposed that both antagonism of NMDA receptors by drugs such as PCP and stimulation of 5- HT_2A receptors by drugs such as LSD result in the release of glutamate. Furthermore, it has been observed that antagonists and agonists at mGlu_2/3 receptors increase and decrease, respectively, the release of glutamate. Taken together, these observations predict behaviorally significant interactions between ligands at mGlu_2/3 receptors and hallucinogens such as LSD and PCP.Objective The present study sought to test in rats the glutamate hypothesis of hallucinogenesis using drug-induced stimulus control as the dependent variable and selected glutamatergic and serotonergic receptor ligands as independent variables.Methods Male F-344 rats were trained in a two-lever, fixed ratio 10, food-reinforced task with either phencyclidine (PCP; 3.0 mg/kg; IP; 30 min pretreatment) or lysergic acid diethylamide (LSD; 0.1 mg/kg; IP; 15 min pretreatment) as discriminative stimuli. The interactions of PCP and the mGlu_2/3 selective ligands, LY341495 and LY379268, with stimulus control by LSD were determined. The effects of these drugs were compared with those of serotonergic antagonists known to antagonize the stimulus effects of LSD, specifically, pirenperone and M100907.Results Stimulus control by LSD was potentiated by both PCP and the mGlu_2/3 antagonist, LY341495. In tests of antagonism, stimulus control by LSD was significantly but incompletely diminished by the mGlu_2/3 agonist, LY379268; this result was in contrast with the complete antagonism of LSD by both pirenperone and M100907. In PCP-trained rats, LY341495 was without effect on stimulus control by an intermediate dose of PCP. In contrast, the training dose of PCP was significantly but incompletely antagonized by LY379268.Conclusions These data, obtained using a stimulus control model of the hallucinogenic effects of PCP and LSD, provide support for the hypothesis that glutamate release is a factor in hallucinogenesis by both 5-HT₂ agonists and non-competitive NMDA antagonists.     

Discriminative stimulus effects of tizanidine hydrochloride: Studies with rats trained to discriminate either tizanidine,clonidine, diazepam,fentanyl, or cocaine

Male Sprague Dawley rats were trained in a two-lever food-reinforced procedure to discriminate between the effects of saline and either tizanidine hydrochloride, clonidine hydrochloride, diazepam, fentanyl, or cocaine hydrochloride. Tizanidine-trained rats dose-dependently generalized the effects of tizanidine and clonidine but not pentobarbital, diazepam, morphine, or cocaine. Clonidine-trained rats dose-dependently generalized the effects of clonidine and tizanidine but not pentobarbital, diazepam, or morphine. Diazepam-trained rats dose-dependently generalized the effects of diazepam but did not generalize tizanidine. Fentanyl-trained rats dose-dependently generalized the effects of fentanyl but did not generalize tizanidine. Cocaine-trained rats did not generalize the effects of tizanidine to the cocaine discriminative stimulus. Yohimbine hydrochloride but not naloxone hydrochloride dose-dependently antagonized the discriminative stimuli produced by both tizanidine and clonidine. These data demonstrate that tizanidine shares discriminative stimulus properties with clonidine but not with pentobarbital, diazepam, fentanyl, morphine, or cocaine. The discriminative stimuli produced by tizanidine and clonidine are mediated via an agonistic interaction with alpha₂-adrenergic receptors and not via an agonistic interaction with opioid receptors.     

Reinforcement schedule effects in rats trained to discriminate 3,4-methylenedioxymethamphetamine (MDMA) or cocaine

Rationale Relatively few studies have compared the discriminative stimulus effects of 3,4-methylenedioxymethamphetamine (MDMA) and cocaine, and findings from different laboratories are somewhat inconsistent. One possible reason for discrepant results may be the use of different reinforcement schedules during discrimination training.Objective The present study compared fixed ratio (FR) 20 and variable interval (VI) 15-s reinforcement schedules to determine their influence on discrimination acquisition, response rates, frequency of reinforcements, and stimulus generalization in rats trained to discriminate cocaine or MDMA.Materials and methods Thirty-two male Sprague–Dawley rats were trained to discriminate cocaine (10 mg/kg; n=16) or MDMA (1.5 mg/kg; n=16) from saline under either a FR 20 or a VI 15-s schedule of food reinforcement. Stimulus generalization tests were conducted with a range of doses of cocaine, MDMA, d-amphetamine, and lysergic acid diethylamide in all four training groups.Results The FR 20 schedule facilitated more rapid discrimination acquisition compared to the VI 15-s schedule and established differential response rates and frequency of reinforcement under drug and vehicle conditions. However, reinforcement schedule had little influence on stimulus generalization between MDMA and cocaine. Cocaine produced partial substitution for MDMA in both training groups (FR 20, 51%; VI 15-s, 58%). Likewise, MDMA produced only partial substitution for cocaine in both training groups (FR 20, 40%; VI 15-s, 72%).Conclusions The present findings suggest that the number of sessions required to establish discriminative stimulus control varies with different reinforcement schedules. Nevertheless, training schedules alone do not appear to have significant effects on stimulus generalization between MDMA and cocaine.     

Salvinorin A fails to substitute for the discriminative stimulus effects of LSD or ketamine in Sprague-Dawley rats

Salvia divinorum is a small perennial shrub that has gained recent popularity among the drug-using subculture as a legal alternative to hallucinogens. Salvinorin A, the main active compound found in the S.divinorum plant, is an atypical hallucinogen with pharmacological selectivity at kappa opioid (KOP) receptor sites and is a unique non-nitrogenous neoclerodane diterpene which is structurally distinct from other opioid compounds. The novel structure of salvinorin A and its specific binding affinity to KOP receptors provide a unique opportunity to investigate neurochemical mechanisms of hallucination and hallucinogenic compounds. The current investigation assessed the substitution of salvinorin A in 16 male Sprague-Dawley rats trained to discriminate either the prototypical serotonergic hallucinogen, LSD (0.08 mg/kg, S.C., n = 8) or the dissociative anesthetic and glutamatergic hallucinogen, ketamine (8.0 mg/kg, I.P., n = 8) from vehicle under a FR 20 schedule of food-reinforced responding. Results indicated that neither LSD nor ketamine discrimination generalized to salvinorin A. These findings are consistent with the growing body of evidence that salvinorin A is pharmacologically distinct from other traditional hallucinogenic compounds.     

Interactions of partial LSD analogs with behavioral disrupting effects of LSD and DMT in the rat.

Adult male Holtzman rats were trained to barpress on a schedule whereby every fourth press earned a reward of 0.01 ml of sugar-sweetened milk (FR4). After an i.p. injection of LSD (0.1 mg/kg) or DMT (3.2 or 10 mg/kg) such barpressing is abolished completely and resumed, usually within an hour, at a rate near the preinjection control rate of pressing. It continues at a steady, uninterrupted pace until the animals are removed from the operant chamber one-half hour later. A series of N,N-diethylnipecotamide derivatives were synthesized and tested for their ability to modify the disruptive effect of these hallucinogens. N,N-diethylbutyramide (DBA) and 1-methyl-1,2,5,6-tetrahydropyridine-3-(N,N-diethylcarboxamide) (THPC) were also tested. Pretreatment with a single i.p. injection of any of these compounds (5--40 mg/kg) either had no effect on or else prolonged the duration of hallucinogen-induced cessation of barpressing.     

The effects of 2,5-dimethoxy-4-methylamphetamine (DOM), 2,5-dimethoxy-4-ethylamphetamine (DOET), d-amphetamine,and cocaine in rats trained with mescaline as a discriminative stimulus

The effects of mescaline (3,4,5-trimethoxyphenylethylamine), a hallucinogen, can function as a discriminative stimulus in appropriately trained rats. As a test of the hypothesis that those pharmacologic properties which distinguish hallucinogens and non-hallucinogens in man are reflected in distinctive stimuli in rats, the present experiments examined the effects of 2,5-dimethoxy-4-methylamphetamine (DOM), 2,5-dimethoxy-4-ethylamphetamine (DOET), d-amphetamine, and cocaine in rats trained with mescaline as a discriminative stimulus. Administration of a range of doses of DOM and DOET to subjects in which saline functioned as S^D and mescaline as S revealed that a dose of 0.3 mg of either DOM or DOET was equivalent to the training dose of mescaline. When tested in rats in which mescaline served as S^D, DOM and DOET were likewise found to mimic mescaline. In contrast, doses of d-amphetamine and cocaine (1 and 30 mg/kg, respectively) which were equivalent to the training dose of mescaline as S , did not result in responding appropriate for the mescaline condition when mescaline was trained as S^D. When DOET (0.3 mg/kg) was substituted for saline as S , no evidence of discriminated responding was obtained in the course of 50 sessions. The present data, in conjunction with previous observations, suggest that those effects of mescaline in the rat which function as a discriminative stimulus are better correlated with pre-hallucinogenic LSD-like activity in man then with hallucinogenic activity per se. Thus, these effects in rats represent a necessary but not a sufficient condition for prediction of hallucinogenic activity in man.This investigation was supported in part by Grant 15406 from the National Institute of Mental Health.     

Differential effects of prazosin and yohimbine on fentanyl-induced muscular rigidity in rats

Whereas muscular rigidity is a well-known phenomenon that is related to anesthesia induced by large doses of narcotic drugs, the precise underlying mechanism(s) remain to be fully elucidated. This study investigated the possible role of noradrenergic neurotransmission and the participation of alpha-adrenoceptors in this phenomenon. Male Sprague-Dawley rats, under ketamine-induced anesthesia (120 mg/kg, i.p.) and with proper control of respiration, body temperature and end-tidal CO2 were used. Intravenous administration of fentanyl (100 micrograms/kg) consistently caused a significant increase in the electromyographic (EMG) activity, recorded from both gastrocnemius and abdominal rectus muscles. This implied muscular rigidity was markedly antagonized by pretreatment with the specific alpha 1-adrenoceptor blocker, prazosin (50 or 250 micrograms/kg, i.v.). This antagonism occurred in spite of a high level of fentanyl in the plasma, as determined by radioimmunoassay. The specific alpha 2-adrenoceptor blocker, yohimbine (1.15 or 2.3 mg/kg, i.v.), on the other hand, not only failed to prevent fentanyl-induced activation of the EMG, but actually potentiated the response. It is concluded that noradrenergic neurotransmission, possibly originating from the locus coeruleus, may participate in the elicitation of muscular rigidity by fentanyl. Furthermore, this process may involve an excitatory action through alpha 1-, and an inhibitory action through alpha 2-adrenoceptors, in the spinal cord.     

Behavioral effects of 2,5-dimethoxy-4-methylamphetamine (DOM) in rats and mice.

The characteristics of the behavioral effects of 2,5-dimethoxy-4-methylamphetamine (DOM or STP) were compared with those of mescaline and methamphetamine in rats and mice. DOM significantly increased locomotor activity in an open-field situation at 0.5-1.0 mg/kg i.p., but at doses above 5 mg/kg i.p. caused biphasic changes, i.e. an initial decrease followed by an increase in motility and exploratory behavior. This hyperactivity was not accompanied by simultaneous increase in rearing. Besides, DOM induced head twitches in rats as well as in mice at doses above 0.1 mg/kg i.p., and marked backward locomotion only in rats at doses larger than 5 mg/kg i.p. The occurrence of backward locomotion might be attributable to the initial decrease in general activity. Behavioral effects of DOM were different from those of either mescaline or methamphetamine although they resembled those of mescaline in some respects.     

The effects of yohimbine and amphetamine on fear expression and extinction in rats

Rationale

Psychostimulants, such as yohimbine and amphetamine, can enhance learning and memory. Extinction of conditioned fear involves new learning, so we asked whether psychostimulants could enhance this learning. Previous work suggests that yohimbine facilitates extinction, using freezing as a fear measure. However, psychostimulant-induced alterations in locomotion can confound freezing measurements. Furthermore, the effects of amphetamine on fear extinction have never been examined.

Objective

We evaluated the effectiveness of yohimbine and amphetamine in enhancing fear extinction. In addition to freezing, we measured bar-press suppression, which is less sensitive to changes in locomotion. We asked: Do psychostimulants reduce fear during extinction training when drug is present? Does learning extinction with psychostimulants result in better extinction retention?

Materials and methods

Rats received fear conditioning on day 1 followed by partial extinction training on days 2 and 3. Yohimbine (1.0, 2.0, or 5.0 mg/kg, i.p.), amphetamine (1.0 mg/kg, i.p.), or vehicle were injected prior to extinction on day 2.

Results

Yohimbine dose-dependently reduced freezing during extinction training on day 2, whereas bar-press suppression was reduced at the highest dose only. When tested drug-free, yohimbine-treated rats showed equivalent levels of freezing and suppression to controls. Amphetamine also decreased freezing during extinction, but did not decrease suppression. During the drug-free test, there was no difference between amphetamine-treated rats and controls in either measure.

Conclusions

Although yohimbine and amphetamine are capable of decreasing freezing, neither drug strengthened retention of fear extinction. Based on these rodent findings, psychostimulants may not be suitable adjuncts to extinction-based therapies for the treatment of anxiety disorders.

     

Pharmacokinetic characterization of the indole alkaloid ibogaine in rats

To investigate the pharmacokinetic properties of ibogaine, a putatively anti-addictive alkaloid, levels of this drug were quantified in plasma and tissues for up to 3 h following i.v. infusion in rats. Immediately following a 31-35 min infusion (20 mg/kg), mean plasma ibogaine levels were 373 ng/ml; these values declined rapidly thereafter in a biexponential manner. The plasma time course in 5 of 7 animals demonstrated an excellent fit to a two-compartment pharmacokinetic model, with alpha and beta half-lives of 7.3 min and 3.3 h, respectively. Drug clearance was estimated to be 5.9 l/h (n = 7). Ibogaine levels in brain, liver and kidney 3 h after the end of drug infusion were 143-170 ng/g, close to simulated values for the peripheral pharmacokinetic compartment. However, 3-h drug levels in adipose tissue were much higher (3,328 ng/g), implying the need for a more complex pharmacokinetic model. Mechanisms for the initial, rapid disappearance of plasma ibogaine are thought to include metabolic demethylation as well as redistribution to body stores. The sequestration of ibogaine by adipose tissue probably contributes to a protracted persistence of drug in the body. This persistence may be underestimated by the beta half-life reported in the present study.     

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.     

Ethanol effects in pigeons trained to discriminate MK-801, PCP or CGS-19755

The non-competitive N-methyl-D-aspartate (NMDA) antagonists MK-801, PCP and ketamine have recently been found to produce full drug-appropriate responding in pigeons trained to ethanol (1.5g/kg) in a two-key operant drug discrimination procedure. In the present study, ethanol (0.56-3.2g/kg i.g.) was administered to pigeons trained to discriminate MK-801 (0.18mg/kg, n = 5), PCP (1.0mg/kg, n = 4) or the competitive NMDA antagonist CGS-19755 (1.8mg/kg, n = 4) from vehicle. Up to doses that caused large reductions in response rates, ethanol produced only vehicle-appropriate responding in the pigeons trained to PCP and only low levels of drug-appropriate responding in pigeons trained to MK-801 and CGS-19755. The present results suggest there could be asymmetric generalization between the discriminative stimulus effects of i.g. ethanol and NMDA antagonists.     

Differential generalization to pentobarbital in rats trained to discriminate lorazepam,chlordiazepoxide, diazepam,or triazolam

In drug discrimination studies benzodiazepinetrained animals have typically responded on the drug lever when tested with barbiturates. In a recent study, greater specificity appeared to be shown when lorazepam was used as a training drug. The generality and limits of this finding were explored in the present set of experiments. The asymmetrical cross-generalization found in lorazepam-and pentobarbital-trained baboons was replicated in rats and was shown not to be a function of either lorazepam (0.1., 0.32, or 1.0 mg/kg) or pentobarbital (10 or 25 mg/kg) training dose (i.e., pentobarbital-trained rats responded on the drug lever in tests with lorazepam, but lorazepam-trained rats did not show comparable pentobarbital generalization). In the next experiment, groups of rats were trained to discriminate chlordiazepoxide (10 mg/kg), triazolam (0.1 mg/kg), or diazepam (1.0 mg/kg). Generalization to both lorazepam and pentobarbital was shown by these rats. Finally after daily pentobarbital administration, lorazepam-trained rats made a sufficient number of responses after high pentobarbital doses to permit extension of the range of pentobarbital doses tested. Pentobarbital generalization increased, but still did not occur in all rats and was unreliable in successive tests in the same rats. These results suggest less homogeneity in the discriminative stimulus effects of depressant drugs than generally has been recognized.Portions of these data were presented at the meetings of the Federation of American Societies of Experimental Biology, Anaheim, 1985 (Ator and Griffiths 1985) and Behavioral Pharmacology Society, Rockville MD (1987)