Drug Lever Research Articles

5-HT 2A/2C receptor agonists potentiate the discriminative cue of (+)-amphetamine in the rat

The possible effect of 5-HT 2A/2C receptor agonists on an amphetamine-induced behavioral response was examined using the two-lever drug discrimination paradigm. The experiments were designed to investigate an interaction of the hallucinogenic 5-HT 2A/2C agonists lysergic acid diethylamide (LSD) and 2,5-dimethoxy-4-iodoamphetamine (DOI), with the discriminative stimulus elicited by a relatively low dose of (+)-amphetamine (1.35 μmol/kg, 0.25 mg/kg, which produced approximately 50% selection of the drug lever). DOI and LSD did not produce amphetamine-like responding at any dose tested or time of administration. However, LSD alone was able to induce a drug-appropriate response in two of nine amphetamine-trained rats. Simultaneous administration of DOI or LSD with amphetamine was not significantly different from the response produced by amphetamine alone. Pre-administration of DOI (3 hr) or of LSD (2 hr) before amphetamine, however, evoked significant enhancement of the amphetamine cue. The results suggest that the enhanced behavioral response to amphetamine may be due either to an increased sensitivity of dopaminergic neurons in the mesolimbic area, or to an enhanced release of dopamine by amphetamine.

Dihydrobenzofuran analogues of hallucinogens. 4. Mescaline derivatives.

Dihydrobenzofuran and tetrahydrobenzodifuran functionalities were employed as conformationally restricted bioisosteres of the aromatic methoxy groups in the prototypical hallucinogen, mescaline (1). Thus, 4-(2-aminoethyl)-6,7-dimethoxy-2,3-dihydrobenzofuran hydrochloride (8) and 1-(8-methoxy-2,3,5,6-tetrahydrobenzo[1,2-b:5,4-b']difuran-4-yl)-2- aminoethane hydrochloride (9) were prepared and evaluated along with 1 for activity in the two-lever drug discrimination (DD) paradigm in rats trained to discriminate saline from LSD tartrate (0.08 mg/kg). Also, 1, 8, and 9 were assayed for their ability to displace [3H]ketanserin from rat cortical homogenate 5-HT2A receptors and [3H]8-OH-DPAT from rat hippocampal homogenate 5-HT1A receptors. In addition, these compounds were evaluated for their ability to compete for agonist and antagonist binding to cells expressing cloned human 5-HT2A, 5-HT2B, and 5-HT2C receptors. Finally, agonist efficacy was assessed by measurement of phosphoinositide hydrolysis in NIH 3T3 cells expressing the rat 5-HT2A or 5-HT2C receptors. Although 1 fully substituted for LSD in the DD assays (ED50 = 33.5 mumol/kg), neither 8 nor 9 substituted for LSD, with just 50% of the rats administered 8 selecting the drug lever, and only 29% of the rats administered 9 selecting the drug lever. All of the test compounds had micromolar affinity for the 5-HT1A and 5-HT2A receptors in rat brain homogenate. Curiously, the rank order of affinities of the compounds at 5-HT2A sites was opposite their order of potency in the behavioral assay. An evaluation for ability to stimulate phosphoinositide turnover as a measure of functional efficacy revealed that all the compounds were of approximately equal efficacy to serotonin in 5-HT2C receptors. At 5-HT2A receptors, however, 8 and 9 were significantly less efficacious, eliciting only 61 and 45%, respectively, of the maximal response. These results are consistent with the proposed mechanism of action for phenethylamine hallucinogens, that such compounds must be full agonists at the 5-HT2A receptor subtype. In contrast to the 2,5-dimethoxy-substituted phenethylamines, where rigidification of the methoxy groups had no deleterious effect on activity, the loss of activity in the 3,4,5-trioxygenated mescaline analogues may suggest that the 3 and 5 methoxy groups must remain conformationally mobile to enable receptor activation.

N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4- isoxazoleproprionate (AMPA) glutamate-receptor antagonists have different interactions with the discriminative stimuli of abused drugs.

The effects of the AMPA-receptor antagonists NBQX and GYKI 52466 were compared with those of the NMDA-receptor channel blocker dizocilpine in two drug discrimination tests. In the first, rats were trained to discriminate morphine (2 mg/kg) from saline and in the second, to discriminate ketamine (7 mg/kg) from saline, using a two-lever food reinforced method. NBQX (1-6 mg/kg) did not substitute for either morphine or ketamine, even at a dose which reduced response rates (6 mg/kg). Likewise, the noncompetitive antagonist GYKI 52466 (5 and 10 mg/kg) produced only saline lever responding in the ketamine trained rats. When tested in combination with the training drug, NBQX (4.5 mg/kg) did not alter the morphine generalisation gradient, and similarly, neither NBQX (3 mg/kg) nor GYKI 52466 (5 and 10 mg/kg) interacted with the ketamine cue. In contrast, dizocilpine (0.05 mg/kg) significantly disrupted discrimination of morphine and produced clear drug lever responding (0.0125-0.1 mg/kg) in ketamine trained rats. These results suggest that AMPA-receptor antagonists and non-competitive NMDA-antagonists have different stimulus properties.

Stimulus properties of the L-type calcium channel agonist BAY k 8644 in rats.

Calcium (Ca(2+)) channels appear to be involved in the regulation of ethanol (EtOH) intake, as indicated by the effectiveness of both L-type Ca(2+) channel antagonists and agonists in reducing EtOH intake in animals. The present study was aimed to investigate rewarding/aversive and discriminative stimulus effects of the Ca(2+) channel agonist BAY k 8644, a compound showing pronounced anti-alcohol effects in rats. Therefore, a series of conditioned taste aversion (CTA), conditioned place preference (CPP) and two-lever drug discrimination (DD) experiments were conducted in Wistar rats, with (+/-)-BAY k 8644 and its enantiomers. After i.p. application, (+/-)-BAY k 8644 (0.0625-1mg/kg), (-)-BAY k 8644 (0.125-1mg/kg) and (+)-BAY k 8644 (2.5-20mg/kg) all induced a dose-dependent CTA. The minimal effective doses (MED) for (+/-)-, (-)- and (+)-BAY k 8644 were 0.25, 0.25 and 10mg/kg, respectively. In a CPP study, however, (+/-)-BAY k 8644 (0.25-2mg/kg, i.p.) showed neither aversive nor rewarding stimulus properties. Rats were trained to discriminate (-)-BAY k 8644 (0.3mg/kg, i.p.), the enantiomer acting as a high potency Ca(2+) channel agonist, from vehicle, in a two-lever DD procedure (ED(50)) value: 0.05mg/kg); full generalisation: 0.1mg/kg). The (-)-BAY k 8644 cue dose-dependently generalized to (+/-)-BAY k 8644 and (+)-BAY k 8644, the enantiomer acting as a low potency Ca(2+) channel antagonist, with ED(50) values of 0.06 and 0.28mg/kg, respectively. Both (+/-)- and (+)-BAY k 8644 produced full generalization at 1mg/kg, the latter compound showing an inverted U-shaped curve (i.e., this was the only dose showing >80% drug lever selection). The stimulus patterns of BAY k 8644 and its enantiomers appear to resemble the anti-alcohol profiles of these compounds. Therefore, commonalities between the stimulus properties of the agonistic and antagonistic enantiomers might provide a clue for the mechanism underlying the anti-alcohol effects of L-type Ca(2+) channel antagonists and agonists.

S-8-3 - D2 receptor activation in distinct striatal neurons in comparison with D3 receptors

The putative D3 receptor agonist, (+)-PD 128907, is widely used to study the functional relevance of D3 receptors in vivo. Given that non-selective D2/3/4 receptor agonists serve as effective discriminative stimuli in rats we have trained animals to discriminate (+)-PD 128907 (30 μg kg−1, s.c.) from saline and examined the pharmacological specificity of the response. Consistent with a D3 receptor mediated response, the non-selective D2/3 receptor agonist apomorphine and the D3 preferring agonists 7-OH-DPAT and (−) quinpirole generalised to the cue whilst the D2/3 receptor antagonists haloperidol, raclopride, spiperone and (+)-butaclamol antagonised drug lever responding. In contrast, the D1 selective agonist (±)-SKF 81297 and D1/5 selective antagonist, R-(+)-SCH 23390 had no effect. Results also suggest that presynaptic dopamine receptors are involved. Thus the dopamine depleting agent α-methyl-p-tyrosine potentiated the effects of a submaximal dose of (+)-PD 128907 whereas amphetamine failed to generalise per se and blocked (+)-PD 128907 lever selection. However, studies using subtype selective antagonists argue against a role for the D3 receptor. Thus the 10-fold selective D2 receptor antagonist L-741,626 blocked the (+)-PD 128907 discriminative stimulus whereas L-745,829 and GR 103,691, antagonists >40 and >100-fold selective for D3 receptors, failed to modify the response. These results suggest that presynaptic D2 receptors mediate the discriminative stimulus properties of (+)-PD 128907 and highlight the lack of selectivity of (+)-PD 128907 for D3 receptors in vivo.

Rats self-inject a dopamine antagonist in the lateral hypothalamus where it acts to increase extracellular dopamine in the nucleus accumbens

Local injection of sulphide to block dopamine (primarily D 2type) receptors in the perifornical lateral hypothalamus (pf-LH) can induce locomotion, feeding, and drinking, and in the present study, local sulphide induced reward and dopamine (DA) release in the nucleus accumbens. Sulpiride injected bilaterally (4, 8, and 16 μg/0.3 μl), ipsilaterally, or contralaterally (8 μg) in the pf-LH increased extracellular levels of DA and its metabolites in the accumbens. Bilateral sulpiride injected posterior and medial to the pf-LH controlled for diffusion to the ventricle or ventral midbrain. Rats self-injected sulpiride (210 ng/21 nl/2 s) in the pf-LH (111 resp/2 h on drug lever vs. 20 resp on a blank lever). Thus, cells in the pf-LH establish connections with mesolimbic DA neurons involved in the behavior reinforcement process. Evidently hypothalamic cells with DA receptors normally inhibit aspects of behavior reinforcement. Disinhibition with hypothalamic sulpiride is reward for self-injection and cause of overeating that can lead to obesity.

Effects of the NMDA antagonist, dizocilpine, in various drug discriminations

In each of different groups of rats trained to discriminate either 8-OH-DPAT, DOI, d-amphetamine, cocaine, chlordiazepoide or ethanol from saline, dizocilpine produced maximum percentages of drug lever (DL) selection that were intermediate between those produced by the training conditions. Dizocilpine also decreased DL selection produced by the training dose in each of the discriminations, except in ethanol-trained rats. In all discriminations, with the exception of ethanol-trained rats, the intermediate levels of DL, selection produced by dizocilpine were associated with increased FRF values (sum of the responses made on either lever before the first reinforcement occurred), increased lever selection latencies, and increased responding on the nonselected lever. At doses that, in general, had effects on response rate similar to those of dizocilpine, intermediate levels of DL selection were produced by BMY 7378 in 8-OH-DPAT-trained rats, by WY 50,324 in DOI-trained rats, by (-)-3-PPP in d-amphetamine- and in cocaine-trained rats, by alpidem in chlordiazepoxide-trained rats, and by PCP in ethanol-trained rats. The intermediate levels of DL selection produced by these latter drugs were not associated with simultaneous increases of FRF values, selection latencies, and responding on the nonselected lever. The results suggest that dizocilpine produces intermediate levels of drug-appropriate responding through the behavioral mechanism of partial generalization only in ethanol-trained rats; in all other discriminations examined here, the effects of dizocilpine appear to involve (1) pharmacological effects that differ from those of the training drug, and (2) behavioral mechanisms that are unrelated to stimulus generalization. The differentiation of partial generalization and other mechanisms whereby intermediate responding can occur in the drug discrimination paradigm requires analyses that are more detailed than those commonly used in drug discrimination research.

Isolation rearing enhances the locomotor response to cocaine and a novel environment, but impairs the intravenous self-administration of cocaine

Male Lister hooded rats were raised from weaning either alone (isolation reared) or in groups of five (socially reared controls). At 5 months of age, experiments began. Experiment 1 examined the effect of isolation rearing upon the locomotor response to a novel environment, and the locomotor stimulant effect of an injection of cocaine (10 mg/kg). Isolation reared animals were more active in a novel environment, and were more responsive to the locomotor stimulant action of cocaine. In succeeding experiments, the effects of isolation rearing on the reinforcing efficacy of intravenous cocaine were assessed. Animals were never "primed" with noncontingent infusions of cocaine at any time during these experiments. In experiment 2, the effect of isolation rearing upon the acquisition of the intravenous self-administration of cocaine was examined. Two levers were present in the operant chambers. Depression of one lever resulted in the intravenous delivery of a 1.5 mg/kg infusion of cocaine, responses on the second, control lever were recorded but had no programmed consequences. Isolation reared animals acquired a selective response on the drug lever at a slower rate than socially reared controls. In experiment 3, a full cocaine dose-response function was examined. Isolation rearing shifted the cocaine dose-response function to the right. In addition, isolation rearing impaired the selectivity of the response on the drug lever at lower doses of cocaine. In experiment 4, the effect of isolation rearing upon the response to a conditioned reinforcer associated previously with cocaine delivery was observed. In the absence of cocaine, the contingent presentation of the conditioned reinforcer enhanced selectively the rate of response by socially reared controls. However, isolation reared animals were unresponsive to this manipulation. These data are discussed with reference to dysfunctional cortico-limbic-striatal systems, and their interactions with the mesoaccumbens dopamine projection.

Isolation rearing impairs the reinforcing efficacy of intravenous cocaine or intra-accumbensd-amphetamine: impaired response to intra-accumbens D1 and D2/D3 dopamine receptor antagonists

Male Lister hooded rats were raised from weaning either alone (isolation reared) or in groups of five (socially reared controls). At 5 months of age, bilateral guide cannulae were implanted within the nucleus accumbens, and experiments began. The effect of isolation rearing upon the reinforcing efficacy of the intravenous self-administration of cocaine (experiment 1), or the bilateral intra-accumbens self-administration of d-amphetamine (experiment 2) was assessed. Self-administration was made contingent upon the acquisition of a novel lever-pressing response. Two identical levers were available within each operant chamber. Responding on one lever resulted in the delivery of drug (experiment 1: cocaine, 1.5 mg/kg per infusion; experiment 2: d-amphetamine, 0.25 micrograms/side), responding on the second, control lever was recorded but had no programmed consequences. Animals were not "primed" with noncontingent infusions at any time. For experiment 1, animals received intra-accumbens infusions of the D1 dopamine receptor antagonist SCH-23390, or the D2 dopamine receptor antagonist sulpiride over two test sessions. Within each session, animals received a cumulative series of doses of each dopamine receptor antagonist. A validation group received doses of each antagonist according to more conventional methods (one dose per session). In either case, intra-accumbens infusions of SCH-23390 or sulpiride enhanced the rate of the self-administration of cocaine in socially reared controls. However, isolation rearing impaired this response to intra-accumbens infusions of the dopamine receptor antagonists. Experiment 2a examined the acquisition of the intra-accumbens self-administration of d-amphetamine. Socially reared controls acquired readily a selective response upon the drug lever. However, isolation reared animals acquired a selective response at a greatly retarded rate. In experiment 2b, a full d-amphetamine dose-response function was examined. Isolation rearing impaired the response to a range of doses of d-amphetamine. In experiment 2c, the infusate (1 microgram d-amphetamine per infusion) was adulterated with either SCH-23390 or sulpiride. Adulteration with either dopamine receptor antagonist enhanced the rate of response by socially reared controls. Isolation rearing impaired this response to SCH-23390, and blocked the response to sulpiride. These data are discussed in relation to the functioning of cortico-limbic-striatal systems, with particular reference to the mesoaccumbens dopamine projection.

An investigation into the discriminative stimulus and reinforcing properties of the CCK B-receptor antagonist, L-365,260 in rats

The discriminative stimulus properties of the selective CCK B-receptor antagonist, L-365,260 were evaluated in rats trained to discriminate diazepam (2 mg/kg) or morphine (5 mg/kg) from vehicle, using a two-lever food reinforced technique. In the diazepam drug discrimination, the benzodiazepine-receptor agonist FG8205 (0.063–2 mg/kg) produced dose-related drug associated responding, whereas L-365,260 (0.125–4 mg/kg) treated animals showed vehicle appropriate behaviour. In rats trained to discriminate morphine from saline, L-365,260 (0.063–4 mg/kg) produced saline lever responding. When a dose of 1 mg/kg L-365,260 was administered in combination with morphine, the dose response curve for drug lever responding was not significantly affected. This was in contrast to the effect produced by the opiate antagonist naloxone (0.3 mg/kg) which shifted the dose-response curve to the right. Another group of rats underwent training to discriminate a dose of 6 mg/kg L-365,260 from vehicle. None of the animals learned the discrimination within 50 daily training sessions. In addition, unlike morphine (3 mg/kg), or changing the training dose of cocaine, intravenous administration of L-365,260 (0.3–10 mg/kg) did not modify lever pressing or the number of injections received by rats trained to self administer cocaine (0.25 mg/injection). L-365,260 (0.1–3 mg/kg) produced a dose-related inhibition of pentagastrin-stimulated gastric acid secretion in vivo. When administered dissolved in a mixture of ethanol/propylene glycol/saline, the ID 50 was 0.83 mg/kg, and when suspended in an ethanol/carboxymethylcellulose vehicle, it was 0.7 mg/kg. It was concluded: 1) that L-365,260 does not produce discriminative stimuli similar to either diazepam or morphine; 2) that the potentiation of morphine-induced behaviour by L-365,260 1,2 does not extend to the discriminative stimulus properties of morphine; 3) that L-365,260 itself does not produce readily discriminable interoceptive stimuli in rats; and 4) that L-365,260 does not substitute for the reinforcing drug cocaine.

Bilateral intra-accumbens self-administration of d-amphetamine: antagonism with intra-accumbens SCH-23390 and sulpiride.

The efficacy of d-amphetamine to support a selective bilateral intra-accumbens self-administration response was examined. Bilateral intra-accumbens infusions of d-amphetamine were made contingent upon the acquisition of a lever-pressing response. Two identical levers were available within the operant chamber. Depression of the drug lever resulted in the intra-accumbens delivery of 1 microgram d-amphetamine; responses upon the second, control lever were recorded but had no programmed consequences. Animals were not 'primed' with non-contingent infusions of d-amphetamine at any time during these experiments. Nonetheless, animals readily acquired a selective response upon the drug lever. Removal of the d-amphetamine moiety from the infusate resulted in a large decline in responding, and the abolition of the selectivity of the response for the drug lever. Adulteration of the infusate with either the D1 dopamine receptor antagonist SCH-23390 or the D2 dopamine receptor antagonist sulpiride enhanced the rate of response selectively upon the drug lever. Reductions in the dose of d-amphetamine also increased the rate of response. The effect of co-adulteration of the infusate with both SCH-23390 and sulpiride together was purely additive. The implications of these data for the methodology of intracranial drug self-administration, and the relationship between D1 and D2 dopamine receptors within the nucleus accumbens are discussed.

Pharmacological characterization of the discriminative stimulus properties of the dopamine D1 agonist, SKF 81297

A range of selective dopamine D1 and D2 receptor agonists and antagonists was used to characterize to the discriminative stimuli produced by d-amphetamine (0.5mg/kg) and the D1 agonists SKF 81297 (0.1mg/kg). In rats trained to discriminate d-amphetamine (0.5mg/kg) from saline, d-amphetamine produced a dose-related increase in per cent drug lever responding, and SKF 81297 did not show any d-amphetamine-like discriminative stimulus effects; neither did SKF 81297 potentiate nor antagonize the d-amphetamine discriminative stimulus. In rats trained to discriminate SKF 81297 (0.1mg/kg) from saline, SKF 81297 produced a dose-related increase in per cent drug lever responding, and SKF 38393 and SKF 83565 elicited full SKF 81297-like effects despite the fact that these compounds have widely differing efficacies for stimulating adenylate cyclase. SKF 81297 had a 25-fold greater potency than SKF 38393 in this assay. The D2 agonists, PHNO and ropinirole, did not display any SKF 81297-like discriminative stimulus effects. The SKF 81297 discriminative stimulus was completely blocked by the D1 antagonist SCH 23390 but was not blocked by the D2 antagonist BRL 34778.

Postnatal lead exposure induces supersensitivity to the stimulus properties of a D 2-D 3 agonist

To examine the impact of lead (Pb) exposure during the ontogeny of dopaminergic (DA) systems on resultant DA function, rats were exposed postnatally (0–21 days of age) via the lactating dam to 0, 100 or 350 ppm Pb acetate in drinking water. At 2 months of age, the postnatally Pb-exposed rats were trained to discriminate the stimulus properties of either the D 1 receptor agonist SKF38393 (6.0 mg/kg) or the D 2-D 3 receptor family subtype agonist quinpirole (0.05 mg/kg) from saline using a standard two-lever operant food-reinforced drug discrimination paradigm. In each training group, dose-effect curves describing drug lever responding to lower doses of the training drug and to preadministration of selective DA antagonists were obtained to examine Pb-induced changes in DA sensitivity. Doses of other DA agonists were substituted for the training drug to determine the generality of any changes in DA sensitivity, and doses of non-DA compounds were substituted to determine the specificity of any changes in DA sensitivity. In the D 1/saline training condition, Pb exposure was not associated with any specific or consistent changes in DA sensitivity. In contrast, exposure to Pb was associated with D 2-D 3 receptor subtype supersensitivity as was indicated by significantly elevated levels of drug lever responding in the presence of quinpirole and haloperidol and to at least one dose of apomorphine. No differences in the dose-effect curves for either (+)-amphetamine or NMDA were observed in the D 2-D 3-trained control and Pb-exposed groups, but an increase in drug lever responding in the presence of pentobarbital was noted in the Pb-exposed group relative to control. Taken together, these findings are consistent with a Pb-induced functional D 2-D 3 supersensitivity possibly mediated via autoreceptors. Moreover, this functional D 2-D 3 supersensitivity necessarily represents a permanent effect of postnatal Pb exposure since both blood and brain Pb levels were negligible at the time drug discrimination training began.

Discriminative stimulus effects of the optical isomers of 3,4-methylenedioxyamphetamine (MDA)

The isomers of 3,4-methylenedioxyamphetamine (MDA) functioned as discriminative stimuli in rats trained to discriminate either (-) MDA (1.25mg/kg) or (+) MDA (1.25mg/kg) from saline. Dose- and time-response curves indicated that drug lever selection occurred at doses of at least 1.00mg/kg of (-) MDA and 0.75mg/kg of (+) MDA and that drug-appropriate responding for both isomers was maintained for at least 90min. Cross-substitution was observed between the MDA isomers; both (+) and (-) 3,4-methylenedioxymethamphetamine (MDMA) also substituted completely for (+) and (-) MDA. The hallucinogens (+)-lysergic acid diethylamide (LSD) and (+/-)-2,5-dimethoxy-4-methylamphetamine (DOM), substituted for (-) MDA; neither mescaline nor (+) amphetamine or cocaine had (-) MDA-like effects. LSD also substituted for (+) MDA; DOM, mescaline, (+) amphetamine and cocaine failed to have (+) MDA-like effects. The (-) but not the (+) MDA cue was blocked by the 5-HT(2) antagonist pirenpirone; the dopamine (DA) antagonists SCH-23390 and (-) sulpiride had no effect on either the (-) or (+) MDA cues. When animals were trained to discriminate LSD (0.16mg/kg) or (+) amphetamine (1.0mg/kg) from saline, neither (-) MDA nor (+) MDA substituted completely. These results indicate that: (1) the stimulus effects of the isomers of MDA and MDMA are similar; (2) (-) MDA may be more hallucinogenic (or more accurately, LSD- or DOM-like) than (+) MDA; (3) neither (+) nor (-) MDA has potent amphetamine-like effects; and (4) the effects of (-) MDA may be more serotonergic than those of (+) MDA.

Behavioral pharmacology of abecarnil in baboons

The behavioral effects of abecarnil, a beta-carboline which has been suggested to function as a partial and/or selective agonist at the benzodiazepine receptor, were assessed in baboons. In a chronic administration study, 100mg/kg/day abecarnil for 6-8 weeks produced few signs of sedation: lip droop and intention tremor were observed in two of the four baboons. Flumazenil administration (5mg/kg, i.m.) on day 8 of chronic abecarnil produced only a mild precipitated benzodiazepine withdrawal syndrome. Vehicle substitution after 6-8 weeks of chronic abecarnil produced transient signs of a mild withdrawal syndrome, including decreased food intake, but did not produce vomiting, twitches/jerks or seizures. In a self-injection study, abecarnil (0.032-1.0mg/kg/injection) did not maintain rates of self-injection above vehicle control levels; higher rates of self-injection were maintained in the same animals by cocaine (0.32mg/kg/injection) and triazolam (0.01mg/kg/injection). The highest i.v. abecarnil dose (1.0mg/kg/injection) produced sedation and ataxia in two of the three baboons. In a drug discrimination study, generalization from lorazepam training conditions (1.8mg/kg, p.o.) to abecarnil was an increasing function of dose, and maximal drug lever responding occurred reliably in all baboons 5h after 10-32mg/kg, p.o. abecarnil administration. Flumazenil (0.32mg/kg, i.m.), given 4h after abecarnil, completely antagonized the abecarnil stimulus in test sessions 1h later. The present experiments show that the behavioral profile of abecarnil is clearly distinguisable from that of benzodiazepines.

Zacopride and its optical isomers produce stereoselective antagonism of a 2-methylserotonin discriminative stimulus

The serotonin 5-HT 3 receptor antagonist effects of zacopride and its optical isomers were evaluated in rats trained to discriminate 5.0 mg/kg of 2-methylserotonin (2-Me 5-HT) from saline in a 2-lever operant task. Zacopride and its enantiomers potently antagonized the 2-Me 5-HT stimulus; on the basis of 50% inhibition (ID 50) of drug lever responding the order of potency is S(−)-zacopride (ID 50 = 0.05 μg/kg) > (±)-zacropride (ID 50 = 0.60 μg/kg) > R(+-zacopride (ID 50 = 1.6 μg/kg). The stereoselectivity and potency ratio of zacopride's isomers for antagonizing the 2-Me 5-HT stimulus parallels their previously reported results in binding studies. It is concluded that zacopride's isomers produce antagonism of a 2-Me 5-HT stimulus by stereoselective interaction at 5-HT 3 receptors and that stereochemical factors are important in evaluating the stimulus properties of 5-HT 3 agents.

Discriminative stimulus properties of triadimefon: Comparison with methylphenidate

Two groups of rats (N = 4 each) were trained to discriminate either triadimefon (40 mg/kg) or methylphenidate (4 mg/kg) from saline in a two-lever, milk-reinforced drug discrimination paradigm. Dose-response functions were determined during 5-min extinction sessions. Both agents produced a dose-related increase in the percentage of responses that occurred on the drug lever. In the substitution phase of the study, rats trained to discriminate triadimefon were tested with methylphenidate and rats trained to discriminate methylphenidate were tested with triadimefon. Triadimefon substituted completely for methylphenidate and methylphenidate substituted completely for triadimefon. These results indicate that triadimefon can function as a discriminative stimulus and that it shares discriminative stimulus properties with methylphenidate.

EFFECTS OF SCHEDULE OF REINFORCEMENT ON A PENTOBARBITAL DISCRIMINATION IN RATS

The purpose of this study was to determine the effects of the schedule of reinforcement on a pentobarbital discrimination in rats. Five rats were trained to discriminate 10 mg/kg pentobarbital from saline under a multiple fixed-interval 180-s fixed-ratio 20 schedule of reinforcement. During both saline and pentobarbital training sessions, subjects emitted a higher percentage of correct responses under the fixed-ratio component as compared to the fixed-interval component of the multiple schedule. Determination of the pentobarbital dose-response curve under the fixed-ratio component resulted in a steep curve characterized by responding on the saline lever at low doses and on the drug lever at higher doses. Under the fixed-interval component, a graded dose-effect curve was produced, with considerable responding on both levers after intermediate doses of pentobarbital. The administration of phencyclidine and MK-801 resulted in an intermediate level of drug-lever responding for some subjects. Administration of d-amphetamine resulted in saline (nondrug) appropriate responding. The results of this study demonstrate that the schedule of reinforcement is a determinant of drug stimulus control, just as it is a determinant of other drug effects.

Low level lead exposure increases sensitivity to the stimulus properties of dopamine D 1 and D 2 agonists

To examine the impact of Pb exposure on dopaminergic (DA) function, weanling rats were chronically exposed to 0, 50 or 250 ppm Pb acetate in drinking water. At 3 months of age, the rats were trained to discriminate the stimulus properties of either the D 1 agonist SKF38393 (3.0 mg/kg i.p.; D 1/sal) or the D 2 agonist quinpirole (0.05 mg/kg i.p., D 2/sal) from saline using a standard two-lever operant food-reinforced drug discrimination paradigm. Lead-exposed rats learned the discriminations faster than respective controls. Moreover, they exhibited greater levels of drug lever responding to lower doses of the training drugs (D 1/sal and D 2/sal), and to selected doses of other direct and indirect DA agonists (D 2/sal only), including apomorphine, cocaine and (+)-amphetamine, and less blockade of drug lever responding by haloperidol (D 2/sal). Taken together, these findings are consistent with a generalized DA supersensitivity. There were no differential Pb effects when non-DA compounds including morphine, pentobarbital and MK-801 were substituted for the training drugs, indicating the selectivity of the DA effects in the context of these experiments, and the improbability of a non-specific behavioral causation. Pb-exposed rats in the D 2/sal group also showed a pronounced enhancement of drug lever responding when NMDA was substituted for quinpirole, suggesting the possibility of a Pb-induced NMDA supersensitivity as well.

Discriminative stimulus properties of 8-OH-DPAT in rats are not altered by pretreatment with para-chlorophenylalanine

The role of 5-HT1A autoreceptors in the discriminative stimulus properties of 8-OH-DPAT (0.1 mg/kg, SC) in rats, was investigated. Drug lever appropriate responding to 8-OH-DPAT (0.1 mg/kg, SC) and ipsapirone (3 mg/kg, SC) was measured before and after treatment with para-chlorophenylalanine (pCPA) at a dose (150 mg/kg IP, -3 and -2 days) which causes severe depletion of brain 5-HT stores. The recognition of the drug stimulus was not significantly altered by pCPA. These results indicate that activation of 5-HT1A autoreceptors is of minimal importance to the 8-OH-DPAT cue.