Seymore Herling

IV. DISCRIMINATIVE STIMULUS EFFECTS OF NARCOTICS: EVIDENCE FOR MULTIPLE RECEPTOR-MEDIATED ACTIONS

Abstract Results of studies on the discriminative stimulus effects of narcotics are consistent with the hypothesis that multiple receptors mediate the effects of these compounds. In the rat, at least three subsets of discriminative effects exist, although some drugs appear to have effects that transcend more than one subset. The discriminative effects of morphine-like narcotics (μ agonists), for example, are often clearly distinguishable from the discriminative effects produced by κ agonists, such as ketazocine, and from those produced by phencyclidine-like agonists, such as SKF-10,047 and cyclazocine. Cyclazocine, however, has been reported to have discriminative effects in common with morphine (45) and fentanyl (17) and appears to have κ-like, in addition to phencyclidine-like, discriminative effects. The relative ability of pure narcotic antagonists to block the discriminative effects of these compounds also provides evidence for distinct pharmacologic actions of these drugs. In the rat, the discriminative effects of morphine are blocked by doses of naloxone that are considerably smaller than those that are needed to block the discriminative effects of cyclazocine (44). The discriminative effects of phencyclidine are not altered at all by naltrexone (63).

Evidence for a behavioral deficit during withdrawal from chronic nicotine treatment

Rats that had been trained to respond for food on a fixed-interval 3-minute schedule were treated once daily with nicotine (2 mg/kg) for 50 days. Animals developed marked tolerance to the depressant effect of nicotine as measured by the decreased effect of the treatment dose on response rates over days. Substitution of saline for nicotine during chronic treatment resulted in response rates which were significantly less than pretreatment values. In addition, following cessation of chronic treatment, response rates were initially suppressed below pretreatment rates; by the third day of withdrawal, response rates had returned to baseline levels. It is proposed that the response deficit observed during nicotine absence represents one behavioral component of a nicotine withdrawal syndrome.

Evidence for opioid mechanisms in the behavioral effects of nicotine

The effects of nicotine, heroin, mecamylamine, and naltrexone were studied in rats trained to respond under a fixed-interval 3-min schedule of food presentation. Nicotine (0.1–3.0 mg/kg) first increased, then decreased response rates; heroin (0.03–0.6 mg/kg) produced only dose-related response rate decreases. Mecamylamine (0.1–3.0 mg/kg) and naltrexone (0.3–10.0 mg/kg), administered alone, each had little effect on response rates. However, when administered in combination with increasing doses of nicotine, mecamylamine (1.0 mg/kg) blocked the increases in response rate caused by 0.3 and 1.0 mg/kg nicotine and partially reversed the decreases in rate caused by 3.0 mg/kg nicotine. In contrast, the combination of naltrexone and nicotine, at doses of each that alone either had no effect or increased response rates, markedly decreased responding. This phenomenon was not evident during the first pairing of naltrexone and nicotine, but appeared in the second and subsequent pairings. After drug combinations had been tested, the nicotine dose-response curve was unchanged from its previous values, and naltrexone alone produced no tendency to decrease response rate. These observations may be related to previous results that have suggested a role for endogenous opioids in mediating certain of the behavioral effects of nicotine.

Similarity of the discriminative stimulus effects of ketamine, cyclazocine, and dextrorphan in the pigeon.

Separate groups of pigeons were trained to discriminate the IM injection of ketamine, cyclazocine, or dextrorphan from saline. Each of the training drugs and phencyclidine produced dose-related, drug-appropriate responding in each group of birds. In contrast, ethylketazocine and nalorphine generally produced responding appropriate for saline. These results indicate that common elements of discriminable effects exist among ketamine, cyclazocine, and dextrorphan, structurally dissimilar compounds that are generally considered to belong to distinct pharmacological classes.

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 animals 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 large 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.

Discriminative stimulus effects of pentobarbital in pigeons

Pigeons were trained to discriminate the IM injection of pentobarbital (5 or 10 mg/kg) from saline in a task in which 20 consecutive pecks on one of two response keys produced access to mixed grain. Pentobarbital (1.0–17.8 mg/kg) produced a dose-related increase in the percentage of the total session responses that occurred on the pentobarbital-appropriate key. The concomitant administration of bemegride (5.6–17.8 mg/kg) antagonized the discriminative control of behavior exerted by the training dose of pentobarbital. Benzodiazepines, diazepam (1.0 mg/kg) and clobazam (3.2 mg/kg), and barbiturates, methohexital (10 mg/kg), phenobarbital (56 mg/kg), and barbital (56 mg/kg), produced responding on the pentobarbital-appropriate key similar to that produced by pentobarbital. In contrast, narcotics such as morphine, ethylketazocine, cyclazocine, and SKF-10,047, at doses up to and including those that markedly suppressed response rates, produced responding predominantly on the saline-appropriate key. Similarly, the anticonvulsants, valproate, phenytoin, and ethosuximide occasioned only saline-appropriate behavior, indicating that not all anticonvulsants share discriminative stimulus effects with pentobarbital. Muscimol, a direct GABA agonist, and baclofen, a structural analogue of GABA, also failed to produce pentobarbital-appropriate responding. Ketamine, dextrorphan, and ethanol (0.3–3.2 g/kg, orally) produced intermediate levels of pentobarbital-appropriate responding, suggesting that the discriminative effects of these drugs may be somewhat like those of pentobarbital.

Cocaine, d-Amphetamine, and Pentobarbital Effects on Responding Maintained by Food or Cocaine in Rhesus Monkeys

The effects of IM injections of cocaine, d-amphetamine, and pentobarbital were studied in rhesus monkeys whose lever-press responding was maintained under a second-order fixed-interval, fixed ratio schedule of reinforcement. Within each session, fixed-interval components, ending with the IV injection of 30 μg/kg cocaine (one group of monkeys) or the delivery of a 300 mg food pellet (second group of monkeys), alternated with fixed-interval components ending without an injection of cocaine or the delivery of food (extinction). Drug pretreatments generally caused comparable dose-related decreases in the overall rates of responding reinforced either by cocaine or by food. Response rates during extinction usually increased and then decreased as the dose of each drug increased. An analysis of the drug effects on response rates in different temporal segments of the fixed intervals showed that in both the reinforcement and extinction components, the normally low control rates of responding which occurred earlier in the intervals were usually increased, while higher control rates which occurred later in the intervals were increased less or decreased. Thus, the effects of these drugs were relatively independent of the reinforcing event (food or cocaine) and tended to depend more on the ongoing rate of responding under these conditions.

Discriminative stimulus effects of pentobarbital in rhesus monkeys: Tests of stimulus generalization and duration of action

Rhesus monkeys were trained to emit 20 or 30 consecutive responses on one lever following an IM injection of pentobarbital (10 or 18 mg/kg) and the same number of consecutive responses on another lever following an injection of saline. The required number of correct consecutive responses in both cases resulted in food delivery. When responding was reliably under the control of the presession injection, the ability of a variety of other compounds to produce pentobarbital-appropriate responding was examined. Diazepam, clobazam, methohexital, pentobarbital, and phenobarbital, given 10 or 20 min before the session, produced dose-related pentobarbital-appropriate responding in each monkey. Ethylketazocine and dextromethorphan produced responding primarily on the saline-appropriate lever, whereas codeine, cyclazocine, dextrorphan and ketamine resulted in responding that was, on the average, intermediate between that appropriate for pentobarbital and that appropriate for saline. When tested at various times after their injection, methohexital (3.2 mg/kg) and pentobarbital (10 mg/kg) produced pentobarbital-appropriate responding within 10 min. Barbital (56 mg/kg) resulted in pentobarbital-appropriate responding only if at least 1 h intervened between the injection and the experimental session. The discriminative effects of methohexital, pentobarbital, and barbital lasted approximately 20–60, 120–240, and 480–720 min, respectively. The time-course of the discriminative stimulus effects of barbiturates in the rhesus monkey appears to parallel closely other pharmacological actions of these compounds.

Discriminative stimulus effects of etorphine in rhesus monkeys

Two rhesus monkeys were trained to discriminate the IM injection of etorphine (0.001 mg/kg) from saline in a task in which 20 consecutive responses on one of two levers resulted in food delivery. In both monkeys, etorphine (0.0001–0.0018), meperidine (0.1–1.0 mg/kg), morphine (0.1–3.2 mg/kg), and codeine (0.3–3.2) produced dose-related increases in the percentage of total session responses that occurred on the etorphine-appropriate lever. In contrast, ethylketazocine, SKF-10047, and pentazocine, at doses up to and including those that suppressed response rates, produced responses primarily on the saline-appropriate lever. Thus, etorphine-like narcotics, including morphine, have discriminative stimulus effects in rhesus monkeys which can be distinguished from those produced by narcotics with nonmorphine-like actions such as ethylketazocine, SKF-10047, and pentazocine.

CHLORPROMAZINE-AND HALOPERIDOL-INDUCED CHANGES IN SOME BEHAVIORAL EFFECTS OF COCAINE AND AMPHETAMINE*

Abstract Schedule-controlled performances of rhesus monkeys provided endpoints for the evaluation of the effects of chlorpromazine and haloperidol on behavior maintained either by intravenous injections of cocaine or amphetamine, or by food delivery. The dose-related rate-reducing effects of chlorpromazine on food- and cocaine-reinforced responding were indistinguishable when the dose of cocaine was small. When the reinforcing dose of cocaine was increased, the rate-decreasing effects of chlorpromazine and haloperidol were correspondingly attenuated, suggesting a dose-related antagonism by cocaine of the rate-decreasing effects of chlorpromazine and haloperidol. When self-injections of high doses of cocaine or amphetamine induced relatively low rates of behavior, chlorpromazine and haloperidol increased stimulant-reinforced responding. Thus, while neuroleptic-stimulant interactions involved a mutual antagonism of rate-decreasing effects, no evidence was obtained suggesting an antagonism by neuroleptics of stimulant reinforcement.