Douglas M. Wood

Mediation in the nucleus accumbens of the discriminative stimulus produced by cocaine.

Rats were trained to detect an intraperitoneal (IP) administration of cocaine, 10.0 mg/kg, using a two-lever choice discrimination procedure in which food reinforcement was only delivered following 10 responses on the correct lever (FR10): one lever was correct after cocaine injection, and the other lever was correct after saline injection. Following training, cocaine was generalized to the cocaine training stimulus in a dose-dependent manner. Subsequently, guide cannulae were implanted bilaterally in the prefrontal cortex (from bregma, A = 2.7, L = 1.0, V = 3.0 mm), nucleus accumbens (A = 2.2, L = 1.5, V = 6 mm) or caudate putamen (A = 0.2, L = 2.5, V = 4). Injections were made via cannulae that extended 1 mm past the tip of the guide cannulae. Injection in the nucleus accumbens substituted for the IP training dose of cocaine in a dose-dependent manner with maximum generalization occurring with 10 micrograms of cocaine per side (87% cocaine-lever responding); in contrast, injections of cocaine in the prefrontal cortex or caudate-putamen produced only partial cocaine-lever responding (a maximum of 48 and 37% cocaine-lever responding, respectively). These data support the hypothesis of central mediation of the cocaine stimulus and show that cocaine administered in the nucleus accumbens is sufficient to produce the stimulus. The partial substitution of cocaine in the prefrontal cortex and caudate-putamen may reflect partial mediation of the cocaine stimulus in these brain areas.

Anxiogenic properties of cocaine withdrawal

Rats were trained to discriminate an injection of pentylenetetrazol (PTZ), 20 mg/kg, from saline using a two-lever operant procedure with food as a reinforcer. In substitution tests, rats selected the PTZ-appropriate lever after PTZ, but not after cocaine (20 mg/kg). A higher dose of cocaine (40 mg/kg) was behaviorally disruptive which resulted in no lever selection during the test session. Subsequently, training and testing were halted, and cocaine, 20 mg/kg/8-hr, was administered for 7 days. Following this chronic drug regimen, substitution of PTZ for the PTZ stimulus was increased. Furthermore, cocaine (40 mg/kg) substituted for the PTZ stimulus. Following redetermination of the PTZ and cocaine dose-response curves, chronic cocaine injections were terminated and spontaneous withdrawal was assessed by determining its substitution for the PTZ stimulus. Cocaine withdrawal progressively substituted for the PTZ stimulus reaching a peak 120 hrs after the last cocaine injection. Diazepam, 5 mg/kg, blocked the PTZ-like stimulus. These data demonstrate that 1) chronic administration of cocaine produced sensitization for the PTZ stimulus, 2) tolerance developed to the behaviorally disruptive effects of cocaine, and 3) cocaine withdrawal produced a PTZ-like stimulus which was blocked by diazepam.

Substitution and cross-tolerance profiles of anorectic drugs in rats trained to detect the discriminative stimulus properties of cocaine

Rats were trained to discriminate cocaine, 10.0 mg/kg, using a two-lever operant procedure. Dose-effect data were determined for the substitution of cocaine, diethylpropion, methylphenidate, phenmetrazine, phentermine, and fenfluramine for the cocaine stimulus. All of these drugs, except fenfluramine, substituted fully for the cocaine stimulus. Subsequently, training was halted and cocaine, 20 mg/kg/8 h, was administered for 9 days, and dose-effect data were redetermined for all of these drugs on days 7–9 of chronic administration. Chronic administration of cocaine produced tolerance to the stimulus properties of cocaine, and cross-tolerance to the stimulus properties of methylphenidate, phenmetrazine, and phentermine, such that doses approximately two-fold higher than those used acutely were necessary to reproduce the original effect; the potency for the substitution of diethylpropion for the cocaine stimulus was decreased greater than four-fold; and fenfluramine still failed to substitute for the cocaine stimulus. These data suggest that 1) a common mechanism may mediate tolerance to the discriminative stimulus properties of cocaine, methylphenidate, phenmetrazine, and phentermine, and 2) tolerance in the drug discrimination procedure may have potential for establishing a comprehensive evaluation of dependence liability of CNS stimulants.

Acquisition and recovery of tolerance to the discriminative stimulus properties of cocaine

Rats were trained to discriminate the stimulus properties of cocaine using a two-lever choice paradigm, in which food reinforcement was delivered for responses on the correct lever: one lever was always correct after a 5 mg/kg injection of cocaine, and the other lever was always correct after an injection of saline. After training, administration of cocaine and methamphetamine were generalized to the cocaine lever in a dose-dependent fashion, but administration of phenylethylamine was only partially generalized. Training was then suspended, and cocaine (20 mg/kg) was injected every 8 hr. Tolerance developed progressively to the discriminative stimulus properties of cocaine. After six days of chronic administration, redetermination of dose-effect data showed the presence of tolerance and cross-tolerance to the stimulus properties of cocaine and methamphetamine, respectively, with no evidence for cross-tolerance to phenylethylamine. No tolerance or sensitization developed to the suppressant effects of cocaine on operant responding. After termination of the chronic administration of cocaine, the tolerance was lost at the same rate at which it was acquired. These data demonstrate that tolerance occurs to the stimulus properties of cocaine and suggests that a common mechanism mediates the stimulus properties of cocaine and methamphetamine.

Evidence of a central mechanism mediating tolerance to the discriminative stimulus properties of cocaine

Rats were trained to detect intraperitoneal (IP) administration of cocaine, 10.0 mg/kg, using a two-lever choice discrimination procedure. Following training, cocaine was generalized to the cocaine training stimulus in a dose-dependent manner. Subsequently, bilateral cannulae were implanted in the lateral ventricles in ten animals, and intracerebroventricular (ICV) administration of cocaine was also generalized to the IP training dose in a dose-dependent manner with maximum generalization occurring with 80 micrograms cocaine. After baseline testing, training was halted and cocaine, 20 mg/kg/8-hr, was injected chronically in all rats for 6 days, and then the dose-effect curve for generalization of cocaine was redetermined. Chronic administration of cocaine significantly shifted the dose-effect curve three-fold to the right for both IP and ICV routes of administration. These data suggest that the stimulus properties of cocaine administered centrally are generalized in rats trained by peripheral administration and supports the hypothesis of central mediation of the cocaine stimulus. Also, the comparable shift of the cocaine dose-effect curve following chronic cocaine administration suggests that a central pharmacodynamic mechanism mediates tolerance to the discriminative stimulus properties of cocaine.

One-way generalization of clonidine to the discriminative stimulus produced by cocaine.

Rats were trained to discriminate the stimulus properties of either cocaine or clonidine using a food reinforced two-lever choice paradigm. After training, cocaine was generalized to the cocaine lever in a dose-dependent manner, and clonidine was generalized to the clonidine lever in a dose-dependent manner. Yohimbine, an alpha-2 antagonist, blocked the clonidine stimulus but not the cocaine stimulus. Cocaine was not generalized to the clonidine stimulus; however, clonidine was generalized to the cocaine stimulus, and this generalization was blocked by yohimbine. The one-way generalization of clonidine to cocaine suggests that clonidine has at least two discrete stimulus components: a major component that is not cocaine-like, and a minor component that can be detected by cocaine-trained subjects. In addition, the yohimbine blockade data suggest that both components of the clonidine stimulus are mediated via alpha-2 receptors.

Evidence for dopaminergic involvement in tolerance to the discriminative stimulus properties of cocaine

Rats were trained to discriminate cocaine, 10.0 mg/kg, in a two-lever operant procedure. Dose-effect data for generalization to cocaine and substitution of apomorphine for the cocaine stimulus were determined. Subsequently, training was halted and either apomorphine, 2.5 mg/kg per 8 h, or cocaine, 20 mg/kg per 8 h, was administered for 7-9 days. During chronic administration, the efficacy of cocaine and apomorphine as discriminative stimuli was decreased. These data suggest that dopaminergic mechanisms may mediate tolerance to the discriminative stimulus properties of cocaine.

Task-specific tolerance to d-amphetamine.

Rats were trained concurrently on sweetened-milk drinking and bar-press-responding behavior, which alternated on a daily basis. Dose-response functions for d-amphetamine were determined before and after conditions of chronic treatment. When given before chronic treatment, d-amphetamine decreased both milk consumption and reinforcement received for lever-pressing in a dose-dependent manner. Subsequently, three conditions of chronic injection were established in which one group received saline, prior to both tasks, another group received d-amphetamine prior to drinking milk and saline prior to lever-pressing and the third group received d-amphetamine prior to lever-pressing and saline before drinking milk. The rats became tolerant to d-amphetamine in the task in which the drug had been administered chronically; however, the same rats showed no tolerance in the other task in which saline had been administered chronically. Tolerance to d-amphetamine was thus shown to be behaviorally specific.

A method to shorten the training phase of drug discrimination.

Rats were trained to discriminate “drug” from “no drug” in a two-lever, food-reinforced task. One group was trained with cocaine (10 mg/kg) and a second group was trained with pentylenetetrazol (20 mg/kg). A method designed to shorten the time required for the training phase of drug discrimination experiments was assessed in subgroups for each drug. In one subgroup, single training sessions were conducted daily. In the other subgroup, a second session (either drug or saline) was conducted on days for which the first condition was saline. The training conditions were presented in an irregular sequence, with the same condition occurring in no more than two consecutive sessions. Rats trained by the accelerated method learned the discrimination in fewer days, with no decrement in acquisition per session, suggesting that drug discrimination training can be accomplished more rapidly by reducing inter-session interval.