D.E. McMillan

Effects of access to a running wheel on food, water and ethanol intake in rats bred to accept ethanol

Rats from the University of Indiana lines bred to accept ethanol (P rats) and not to accept ethanol (NP rats) were divided into two groups of 3 rats per group. The first group of P and NP rats was given free access to food, water and 5% (w/v) ethanol 24 h a day. After food, water and ethanol intake stabilized, a running wheel was introduced into the cage. Access to the running wheel decreased ethanol intake and increased water intake in P rats. When the running wheel was locked in place, ethanol intake by P rats increased, but when the wheel was unlocked again, no decrease in ethanol intake occurred. Access to the running wheel did not affect food, water or ethanol intake in NP rats. The decrease in ethanol intake when the running wheel was introduced was replicated in the second group of P rats exposed to 5% ethanol and later to 10% ethanol. The decreases in ethanol consumption produced by the introduction of a running wheel for this genetic model of alcohol consumption are similar to those previously reported using schedule-induced polydipsia to induce ethanol intake.

Differences between alcohol-preferring and alcohol-nonpreferring rats in ethanol generalization.

Alcohol-preferring (P rats) and alcohol-nonpreferring rats (NP rats) were trained to discriminate intraperitoneal injections of 0.5 g/kg ethanol, or subcutaneous injections of 0.6 mg/kg nicotine from saline. P rats learned the ethanol discrimination more rapidly and made a higher percentage (88%) of their responses on the ethanol lever after ethanol and a lower percentage (7%) after saline than NP rats (78 and 15%, respectively). In substitution tests, increasing doses of ethanol produced increases in the percentage of responses on the ethanol lever with similar ED50s (0.43 and 0.44 g/kg) in P and NP rats. P rats trained to discriminate ethanol from saline made more responses on the ethanol lever after nicotine (80%) and d-amphetamine (63%) than NP rats (33 and 40%). The ethanol stimulus did not generalize to morphine in either P or NP rats. NP rats trained to discriminate ethanol from saline responded more on the ethanol lever after bupropion (77%) than P rats (49%). In rats trained to discriminate nicotine from saline, the nicotine discriminative stimulus did not generalize to ethanol in either P or NP rats, suggesting that the genetic difference in the stimulus generalization of ethanol was not symmetrical.

Schedule control of quantal and graded dose–effect curves in a drug–drug-saline discrimination

Pigeons were trained to discriminate among 5 mg/kg pentobarbital, 5 mg/kg morphine, and saline when responding was maintained under fixed-interval (FI) or fixed-ratio (FR) reinforcement schedules. After the discrimination was established, other drugs were substituted for the training drugs. After low doses of pentobarbital and chlordiazepoxide, responding shifted from the saline key to the pentobarbital key under both FR and FI schedules. After low doses of morphine and methadone, responding shifted from the saline key to the morphine key under both reinforcement schedules. After all doses of d-amphetamine, responding occurred largely on the saline key under both schedules. Responding also was confined largely to the saline key after phencyclidine administration under the FR schedule, but under the FI schedule, responding shifted from the saline key to the pentobarbital key at high doses of phencyclidine. When responding was maintained under the FR schedule, the dose-response curves for drugs that generalized to the training drugs were quantal in shape, while under the FI schedule, the dose-response curves for drugs that generalized to the training drugs were graded. These data extend observations that FR schedules generate quantal dose-response curves, and FI schedules generate graded dose-response curves to complex three-key drug discriminations.

Stability of opioid craving over time as measured by visual analog scales

Sixteen methadone maintenance patients reported their 24-h peak opioid craving on a visual analog scale and the time of day at which the peak craving occurred on weekdays over a 4-week period. Both intersubject and intrasubject craving scores were highly variable. Craving scores did not correlate highly with time since the previous dose, mean methadone dose, requests for changes in maintenance dose, or occurrence of positive urine-drug screens. These data suggest that 24-h craving recall (as measured by visual analog scales) varies over time and is not closely correlated with changes in methadone blood levels.

Effects of food deprivation and satiation on sensitivity to the discriminative-stimulus effects of pentobarbital in pigeons and morphine in rats.

Food deprivation can produce a substantial increase in the self-administration of drugs of abuse, suggesting that food deprivation increases their reinforcing properties. This finding has been replicated with a wide variety of reinforcing drugs. The present experiments examined the effects of food deprivation and satiation on the discriminative stimulus properties of drugs, to determine whether food deprivation affects the discriminative-stimulus effects of drugs in a similar manner. Using pigeons that were trained to discriminate 5 mg/kg i.m. pentobarbital from saline, dose-effect curves were determined under both food-deprivation conditions (80% free-feeding body weight) and partial food-satiation conditions (25% and 50% of the amount of full satiation). It was found that generalization curves for both pentobarbital and saline were similar at all levels of food deprivation. In a second set of experiments, rats were trained to discriminate 10 mg/kg i.p. morphine from saline, and the discriminative properties of morphine were then tested when the animals were either food-deprived or after a 15 min supplemental feeding. The ED50 value for the food-deprived condition was comparable to that the food-satiated condition (3.6 vs. 4.8 mg/kg, respectively). Thus, in both pigeons and rats, there was little evidence that food deprivation increased sensitivity to the discriminative stimulus properties of drugs. Thus, food deprivation must increase drug self-administration by a mechanism other than by increasing the discriminative stimulus properties of self-administered drugs.

Effects of drugs on response duration differentiation III. Acute variation of reinforced duration

Rats trained to hold a lever down for at least 1.0 s but less than 1.3 s could differentiate the reinforced response duration on about 50% of the trials. The response duration frequency distribution was a normal distribution with a peak near the minimum reinforced response duration. Dose-effect curves were determined for the effects of phencyclidine (PCP) and methamphetamine. Subsequently, rats continued to be trained for 3 days a week with responses between 1.0 and 1.3 s reinforced, but on days when injections were given either the maximum reinforced duration was increased to 2.3 s, or the minimum reinforced duration was lowered to 0.5. When the maximum duration was increased to 2.3 s, the percentage of reinforced responses increased to 60% and when the minimum reinforced duration was decreased to 0.5 s, the percentage of reinforced responses increased to 89%. Despite the increased percentage of reinforced responses when the time window was widened, the effects of PCP and methamphetamine were not changed. These data suggest that the effects of drugs on response duration differentiation are not greatly influenced by transient changes in reinforcement frequency.

Effects of cocaine and ethylcocaine on schedule-controlled responding in rats.

The effects of cocaine and benzoylecognine ethyl ester (ethylcocaine), its metabolite found only in simultaneous users of cocaine and ethanol, were studied in rats responding for food under a multiple fixed-ratio fixed-interval schedule of food presentation. Both cocaine and ethylcocaine increased rates of responding under the fixed-interval component and decreased the quarter life. Both drugs only decreased rates of responding under the fixed-ratio component. Cocaine was approximately equipotent to ethylcocaine. Ethylcocaine may contribute to interactions between cocaine and ethanol by exerting cocaine-like effects not seen with other cocaine metabolites.

A comparison of interoceptive and exteroceptive discrimination in the pigeon

In pigeons performing a conditional discrimination under a second-order, color-tracking procedure, stimulus control of responding was established using a blinking versus a nonblinking light as exteroceptive stimuli (light-discrimination group). Another group performing under the same second-order schedule of reinforcement was trained to discriminate the interoceptive stimuli produced by an IM injection of 1.5 mg/kg phencyclidine (PCP) versus saline (drug-discrimination group). In the drug-discrimination group, administration of PCP or pentobarbital resulted in dose-dependent increases in PCP-appropriate responding, while, in general, d-amphetamine did not result in appreciable drug-appropriate responding. In the light-discrimination group, all three drugs over the same dose ranges resulted in decreased discriminative control over responding. In both groups, doses of PCP and pentobarbital which resulted in intermediate (30 to 70%) levels of stimulus-appropriate responding were associated with responding at a single key position rather than tracking a key color. In contrast, intermediate responding after d-amphetamine administration was not associated with position responding in either group. These results emphasize the similarity between discriminative control maintained by interoceptive drug stimuli and exteroceptive visual stimuli.

Quantitative analysis of naloxone antagonism of the discriminative stimulus properties of morphine in the pigeon

Pigeons were trained to discriminate morphine (5.0 mg/kg) from saline under a second-order fixed ratio 10 (fixed-ratio 5) color-tracking schedule for food reinforcement. After reliable stimulus control was established, cumulative graded doses of morphine (0.3-30.0 mg/kg) were tested and resulted in dose-dependent increases in morphine-appropriate key pecking and decreases in response rate. Cumulative doses of naloxone (0.1-10.0 mg/kg) or consecutive injections of saline did not elicit morphine-appropriate responding or affect response rate. Pre-treatment with naloxone (0.1-1.0 mg/kg) before determination of cumulative dose-effect curves for morphine caused the morphine generalization curves to be shifted, in a parallel manner, rightward. Dose-ratio analysis of naloxone antagonism of morphine generalization, using a Schild plot with the slope constrained to -1, gave an apparent pA2 value (95% confidence limits) of 6.53 (6.18-6.89).

Interaction of the discriminative stimulus effects of phencyclidine with those of (+)-N-allynormetazocine, pentobarbital and d-amphetamine☆

Pigeons trained to discriminate 1.0 mg/kg phencyclidine from saline were used to study the interaction between the stimulus effects of phencyclidine and those of (+)-N-allylnormetazocine [(+) NANM], pentobarbital and d-amphetamine using a cumulative-dosing procedure. Both (+) NANM and pentobarbital enhanced the discriminative stimulus effects of phencyclidine. The enhancement of the phencyclidine stimulus by pentobarbital was predicted by adding the effects of the individual drugs, but the enhancement of the phencyclidine stimulus by (+) NANM was sometimes more than would have been expected from adding the effects of the individual drugs. d-Amphetamine did not enhance the discriminative stimulus effects of phencyclidine, but neither did it interfere with these effects. Combinations of (+) NANM or pentobarbital with phencyclidine also enhanced the rate-decreasing effects of phencyclidine, but to a lesser extent than they enhanced the discriminative stimulus effects of phencyclidine. d-Amphetamine only slightly enhanced the rate-decreasing effects of phencyclidine.