Drug-lever Responding Research Articles

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.

Influence of some drugs of abuse on the discriminative stimulus properties of amphetamine

The present study assessed the utility of a drug interaction paradigm for measuring the effects of various psychoactive drugs on the stimulus properties of d-amphetamine. In the first experiment, rats trained to discriminate 1.0mg/kg d-amphetamine from saline were tested for generalization to a range of d-amphetamine doses (0.25, 0.50 and 1.0mg/kg) injected alone or with cocaine, apomorphine or haloperidol. When given alone d-amphetamine yielded an orderly dose-response function and this was altered by the test drugs in a manner consistent with the dopamine agonist or antagonist actions of each compound. In the second experiment, the cueing effects of d-amphetamine were potentiated by nicotine and attenuated by morphine and midazolam. Ethanol enhanced the cueing effects of the lower d-amphetamine doses but produced no drug-lever responding when given alone. These findings confirm the results of previous studies which have assessed the effects of these classes of drugs on the stimulus properties of amphetamine. However, the results are inconsistent with the hypothesis that all drugs of abuse possess psychomotor stimulant properties.

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.

Monoamine reuptake inhibitors enhance the discriminative state induced by cocaine in the rat

Cocaine inhibits the reuptake of dopamine (DA), norepinephrine (NE), and serotonin (5-HT). To investigate the relative role of such reuptake processes in the discriminative stimulus properties of cocaine, male rats (N = 16) were trained to discriminate cocaine (10 mg/kg) from saline in a two-lever, water-reinforced drug discrimination task and were administered neuroactive compounds during substitution or combination tests. The DA reuptake inhibitor GBR 12909 (2-16 mg/kg) completely mimicked cocaine. The reuptake inhibitors for NE (desipramine; 2-8 mg/kg) and 5-HT (fluoxetine; 0.625-5 mg/kg) did not substitute for the training drug. A low dose of either desipramine (3 mg/kg), fluoxetine (1.25 mg/kg), or GBR 12909 (2 mg/kg) coadministered with low doses of cocaine (0.625-2.5 mg/kg) enhanced the discriminative stimulus properties of this psychostimulant. The dose predicted to elicit 50% drug-lever responding is reduced (ED50) in the presence of desipramine (0.38 mg/kg), fluoxetine (0.79 mg/kg) or GBR 12909 (0.84 mg/kg) compared to the ED50 for cocaine (1.57 mg/kg) in the absence of any reuptake inhibitor. The finding that GBR 12909 mimics the cocaine cue corroborates the hypothesis that the stimulus properties of cocaine are mediated predominantly by DA systems. The potentiation of the stimulus effects of cocaine by monoamine reuptake inhibitors in rats suggests that these drugs could also amplify the subjective effects of cocaine in humans, a possibility that should be considered given the current use of antidepressants in the treatment of cocaine abusers.

Discriminative and reinforcing effects of brotizolam in rhesus monkeys

The reinforcing and discriminative stimulus effects of brotizolam, a benzodiazepine-hypnotic, were evaluated in rhesus monkeys. In one experiment, separate groups of monkeys (N = 3 group) were trained to discriminate pentobarbital (10 mg/kg, IG) or d-amphetamine. (0.56-1.0 mg/kg, IG) from saline, in a discrete-trials avoidance/escape paradigm. Pentobarbital (5.6-10 mg/kg), diazepam (1.0-1.7 mg/kg), and brotizolam (0.3-1.7 mg/kg) resulted in 100% drug-lever responding in all three pentobarbital-trained monkeys. In d-amphetamine-trained monkeys brotizolam administration resulted only in saline-lever responding. In another experiment, monkeys were surgically prepared with indwelling intravenous catheters and lever pressing resulted in an injection of 0.1 mg/kg/injection sodium methohexital under a fixed-ratio 10 (FR 10) schedule. Pentobarbital (0.01-0.3 mg/kg/injection) and diazepam (0.003-0.10 mg/kg/injection) maintained responding above saline control levels when substituted for methohexital. Brotizolam (0.001-0.01 mg/kg/injection) resulted in more injections received compared to saline, but fewer injections compared to pentobarbital or diazepam. Thus, results from the present experiment suggest that brotizolam would have pentobarbital-like subjective effects. However, the abuse liability of brotizolam may be lower than that for diazepam.

The discriminative stimulus properties of cocaine: effects of BAY K 8644 and nimodipine

Calcium channel blockers appear to reduce the cardiac toxicity of cocaine and some stimulant-induced behaviors. The present experiment was designed to test whether the internal state induced by cocaine is altered by the calcium antagonist nimodipine. Substitution tests with the calcium agonist BAY K 8644 were also conducted in rats (N = 8) trained to discriminate cocaine (10 mg/kg) from saline in a two-lever, water-reinforced drug discrimination paradigm. Cocaine (0.625–10 mg/kg) produced a dose-related increase in drug-lever responding while BAY K 8644 (0.25–2 mg/kg) and nimodipine (0.2–0.8 mg/kg) engendered primarily saline responding. In combination with cocaine (2.5–10 mg/kg), nimodipine shifted the cocaine dose-response curve to the right at doses of 0.2 and 0.4 mg/kg; this attenuation did not increase with higher doses of nimodipine (0.8 and 1.6 mg/kg). The present results suggest that nimodipine may partially block the discriminative stimulus properties of cocaine, however, this reduction is neither robust nor dose-related. Thus, nimodipine might be expected to only marginally alter the subjective cocaine state in humans.

Amphetamine-like stimulus properties produced by electrical stimulation of reward sites in the ventral tegmental area

The present study examined whether the stimulus properties of d-amphetamine could be mimicked by electrical stimulation of the ventral tegmental area (VTA). Rats trained to discriminate 1.0 mg/kg d-amphetamine from saline were given generalization tests with a range of d-amphetamine doses administered either alone or in combination with VTA stimulation. The results suggested that the VTA stimulation could enhance the cueing effects of d-amphetamine, as levels of responding on the d-amphetamine-appropriate lever during stimulation trials were increased relative to tests without stimulation. Individual differences were observed in the amount of drug-lever responding elicited by the VTA stimulation during drug-free substitution tests, and the different levels of drug-lever responding correlated positively with the response rates obtained from these rats during subsequent intracranial self-stimulation tests. These findings suggest that VTA stimulation can have d-amphetamine-like stimulus properties and such stimulus properties may be related to the rewarding effects of the brain stimulation.

Drug discrimination in rats successively trained to discriminate diazepam and pentobarbital

In Phase 1, rats were trained to discriminate either diazepam or pentobarbital from the no-drug condition. Diazepam, pentobarbital, triazolam, meprobamate, and zopiclone occasioned 100% drug-lever responding in tests under both training conditions; but the generalization gradients determined under the pentobarbital training condition were shifted to the right of those determined under the diazepam training condition. In Phase 2, the training drugs were reversed for the two groups, as well as which lever was paired with drug or no drug, in an effort to produce greater specificity of the Phase 2 discrimination. In Phase 2 tests, the Phase 1 training drug occasioned responding on the Phase 2 drug lever in all rats, suggesting that retraining overrode the Phase 1 discrimination. There were indications, however, that Phase 1 training influenced Phase 2 responding: 1) Rats ceased responding partway through no-drug training sessions using the former drug lever, and criterion performance was somewhat more difficult to maintain in Phase 2. 2) In Phase 2, dose-effect curves determined under pentobarbital training were shifted even further to the right of those determined under diazepam training than in Phase 1.

Asymmetrical cross‐generalization in drug discrimination with lorazepam and pentobarbital training conditions

AbstractDepressants have been characterized as showing lower specificity as training drugs than drugs from other pharmacological groups, because drug–lever responding has been occasioned by drugs that are very diverse. In contrast, recent work with lorazepam as a training drug under a food‐maintained drug vs. no‐drug discrimination procedure found unreliable pentobarbital generalization, although pentobarbital‐trained animals showed generalization to lorazepam. Exploration of the limits of this asymmetrical cross‐generalization has included manipulation of species and training doses and studies with a variety of classic and novel sedative‐anxiolytic drugs. To date, comparison of lorazepam to other benzodiazepines used as training drugs suggests that the lorazepam training condition appears to result in a lower probability of generalization to other sedative/anxiolytic drugs than other benzodiazepine training conditions. Review of drug discrimination studies with sedative/anxiolytic drugs suggests that there may be more specificity among the depressants as training drugs than initially appeared to be the case.

Lorazepam and pentobarbital discrimination: Interactions with CGS 8216 and caffeine

Baboons and rats were trained under a two-lever, food-reinforced drug discrimination procedure. The training drug was either lorazepam (1.0 mg/kg) or pentobarbital (5.6 mg/kg in baboons, 10.0 mg/kg in rats). Under test conditions, a range of training drug doses occasioned 100% drug lever responding. CGS 8216 (3.2–10.0 mg/kg) combined with lorazepam produced a complete shift to the no-drug lever in both species; this shift was surmountable with higher doses of lorazepam. CGS 8216 (32.0 mg/kg) combined with pentobarbital produced a statistically significant decrease in drug-lever responding in rats, and in baboons CGS 8216 initially, but not subsequently, produced a complete shift to the no-drug lever. Caffeine (0.32–10.0 mg/kg) combined with lorazepam inconsistently decreased drug-lever responding across multiple determinations in baboons and significantly decreased drug lever responding in rats. Caffeine combined with pentobarbital also yielded an inconsistent decrease in drug lever responding in baboons but there was no effect in rats. Thus the most reliable and complete antagonism across species was obtained with the CGS 8216/lorazepam combinations.

Differentiation between the stimulus effects of 1-5-hydroxytryptophan and LSD

The stimulus properties of the serotonin precursor 1-5-hydroxytrptophan (5-HTP) and the hallucinogen d-lysergic acid diethylamide (LSD) were compared in a two-lever, water-reinforced drug discrimination task. 5-HTP (in combination with the peripheral decarboxylase inhibitor Ro 4-4602) elicited no more than 50% drug-lever responding in rats trained to discriminate LSD (0.08 mg/kg) from saline while LSD substituted completely in animals trained to discriminate 5-HTP (50 mg/kg) from saline. Combination tests indicated that, while the 5-HTP cue was unaffected by pretreatment with various serotonin antagonists, the substitution of LSD for 5-HTP was abolished by the putative serotonin-2 antagonist ketanserin. It was concluded that LSD mimics 5-HTP by stimulating a subset of serotonin receptors activated by 5-HTP which are sensitive to ketanserin (serotonin-2?).

A procedure for rapid evaluation of the discriminative stimulus effects of drugs

Rhesus monkeys were trained in a two-lever drug-discrimination procedure with several discrete trials per session. During training sessions, either a sham injection or a subcutaneous injection of the training drug was administered ten minutes prior to each trial. During each trial, completion of 100 consecutive responses on the lever appropriate for the animal's pharmacological condition (e.g., left for sham, right for drug) resulted in the delivery of three grams of food. Training sessions consisted of from zero to four sham trials that preceded two consecutive drug trials. The number of sham trials varied unsystematically to preclude discrimination of the drug trials on the basis of the number of preceding trials. Discriminations were established with each of the training drugs employed (codeine, methohexital, and ketamine). During dose-effect evaluations of the training drug or other drugs (test sessions), a progressively larger dose of drug was injected prior to each trial and 100 consecutive responses on either the sham- or drug-appropriate lever resulted in the delivery of food. Test sessions continued until either drug-lever responding or a marked suppression in the rate of responding occurred. Thus, a cumulative dose-effect curve for each drug was generated within a single session. Preliminary findings suggest that the pattern of cross-drug generalization generated by this cumulative-dosing procedure is similar to that obtained with procedures that evaluate only a single dose of drug per session.

Tolerance to the discriminative stimulus properties of d-amphetamine

Male rats (F-344) responding for milk on a VI 20 sec schedule of reinforcement were trained to discriminate which of two levers to press on the basis of whether they had been injected with d-amphetamine (0.50, 1.00 or 1.50 mg/kg) or saline 15 min prior to daily training sessions. Dose-response functions determined for each of the three ( n = 6) training-dose groups indicated that ED 50 values were directly correlated with training dose. Two days following chronic amphetamine injections (a total of 78 mg/kg over 4 days) rats were tested for tolerance at a dose which normally produced about 80% drug-lever responding. Rats in all three groups showed tolerance to the cue properties of amphetamine. In the 0.50 and 1.00 mg/kg groups, complete tolerance was shown as evidenced by the fact that the drug lever responding did not differ from that which was appropriate following saline injections.