Chlordiazepoxide impairs the performance of a learned discrimination

Chlordiazepoxide (CDP) (5 mg/kg) administered on four of eight sessions significantly impaired the performance of a previously learned, reinforcement-cued discrimination in male Sprague-Dawley rats. On four interspersed vehicle-injection sessions, the performance of subjects demonstrated immediate recovery and was indistinguishable from that of controls (0 mg/kg). An analysis of response components indicated that the impairment in discrimination performance was due to a "disinhibitory" effect of the drug on responding during "no-go" phases of the task. The results are discussed in the context of similarities and differences in the effect of CDP on performance and acquisition.     

Diazepam-induced impairment of a go-no go successive discrimination

Diazepam (2.0 and 4.0 mg/kg, but not 1.0 mg/kg) administered in eight acquisition sessions significantly impaired the light-cued successive discrimination of male Sprague-Dawley rats. In two postdrug (vehicle) sessions, groups previously treated with the drug demonstrated good recovery in discrimination. An analysis of response components indicated that the impairment was due to the failure of drugged subjects to inhibit or withhold responses during the no go periods of the task. These findings are consistent with a "disinhibitory hypothesis" of drug impairment. The similarity of the present findings to those previously reported with chlordiazepoxide suggests that such effects are a generalized characteristic of the benzodiazepine class of drugs.     

Development of behavioral compensation to the effects of scopolamine during fixed-interval reinforcement

Rats were injected with scopolamine before every daily session of water reinforcement on a fixed-interval (FI) schedule. Initially the drug decreased the rate of responding. Control injections of scopolamine following each session did not. Over 119 sessions, the typical FI performance developed more slowly in the animals drugged before the sessions. Their rates of responding increased from session to session, to a level slightly greater than that of the animals drugged after the sessions. Their rates did not increase. The effects of injections before the session were not duplicated by increasing the deprivation of animals drugged after the session.     

Using drugs to modify the effect of response prevention on avoidance extinction

Amobarbital and chlordiazepoxide were administered during avoidance response prevention and the effect evaluated in the nondrugged state in a subsequent test for avoidance extinction. It was found that Ss administered 15 mg/kg and 30 mg/kg amobarbital, and 30 mg/kg chlordiazepoxide during response prevention differed significantly from the control Ss in extinction performance. Rather than showing either reduced avoidance performance or no difference with the nondrugged Ss, the Ss drugged during response prevention showed increased avoidance performance in the subsequent test of avoidance extinction. That is, preventing avoidance responding under a drugged (versus nondrugged) state produced increased resistance to extinction of the avoidance response.     

Drug discrimination using a conditioned taste-aversion paradigm in rhesus monkeys.

The development of drug discrimination was assessed in rhesus monkeys using the conditioned taste-aversion paradigm. Monkeys were initially trained to respond under a fixed-ratio 30-response schedule of food-pellet delivery to assess the rate-decreasing effects of alprazolam (0.03 to 3 mg/kg, i.m., 60 min presession). Alprazolam decreased responding at doses greater than 0.1 mg/kg. Discriminative stimulus effects of alprazolam were then assessed by giving 0.03 mg/kg before sessions in which 1.8 mEq/kg lithium chloride was given immediately after the session (alprazolam/lithium session). On intervening days, saline was given before and after the session (saline/saline session). Rates of responding decreased over successive alprazolam/lithium sessions and also during the saline/saline session that immediately followed an alprazolam/lithium session. During subsequent saline/saline sessions, rates of responding returned to levels near baseline rates within two to four sessions. The discriminative stimulus effects of alprazolam were then assessed by giving 0.1 mg/kg before sessions in which 1 mg/kg d-amphetamine was given immediately after the session (alprazolam/d-amphetamine session). Rates of responding decreased during subsequent alprazolam/d-amphetamine sessions in drug-experienced monkeys, but did not decrease during intervening saline/saline sessions. These findings demonstrate that drug stimuli associated with postsession drug injections can rapidly develop control over behavior and suggest that similar methods be explored in the assessment of drug discrimination.     

Nicotine vs. Ethanol Discrimination: Extinction and Spontaneous Recovery of Responding

Studies regarding extinction and spontaneous recovery of the discriminative stimulus effects of drugs are limited. Eight rats were initially trained to discriminate nicotine (0.4 mg/kg) vs. ethanol (800 mg/kg). For four rats, itraperitaneal (IP) administrations of nicotine fifteen minutes prior to fifteen-minute training sessions served as a discriminative stimulus (SD) for predicting food-reinforced lever pressing (VI-1 min). On other sessions ethanol functioned in predicting nonreinforcement (SA). The stimulus roles of the drugs were counterbalanced for the remaining four rats. SA and SD sessions alternated quasi-randomly with two daily sessions at 1000 and 1400 hours. Discriminative control was not disrupted following ten extinction sessions under a non-drug/saline condition, but was disrupted following extinction sessions under the original training drugs. Instances of spontaneous recovery (SR) occurred throughout extinction under the drug condtions. There was no evidence for SR two weeks following extinction, but partial recovery four weeks following the final extinction phase. Contextual status (context renewal) had neither a restorative or disruptive impact on extinguished or discriminated responding, respectively. These results support and extend the limited number of other studies by demonstrating extinction and spontaneous recovery of responding discriminated by two distinct drugs. Some theoretical interpretations regarding history effects and training in the context of drug discrimination are entertained.     

Nicotine vs. ethanol discrimination: Extinction and spontaneous recovery of responding

Studies regarding extinction and spontaneous recovery of the discriminative stimulus effects of drugs are limited. Eight rats were initially trained to discriminate nicotine (0.4 mg/kg) vs. ethanol (800 mg/kg). For four rats, itraperitaneal (IP) administrations of nicotine fifteen minutes prior to fifteen-minute training sessions served as a discriminative stimulus (S^D) for predicting food-reinforced lever pressing (VI-1 min). On other sessions ethanol functioned in predicting nonreinforcement (S^Δ). The stimulus roles of the drugs were counterbalanced for the remaining four rats. S^Δ and S^D sessions alternated quasi-randomly with two daily sessions at 1000 and 1400 hours. Discriminative control was not disrupted following ten extinction sessions under a non-drug/saline condition, but was disrupted following extinction sessions under the original training drugs. Instances of spontaneous recovery (SR) occurred throughout extinction under the drug condtions. There was no evidence for SR two weeks following extinction, but partial recovery four weeks following the final extinction phase. Contextual status (context renewal) had neither a restorative or disruptive impact on extiguished or discriminated responding, respectively. Theser results support and extend the limited number of other studies by demonstrating extinction and spontaneous recovery of responding discriminated bytwo distinct drugs. Some theoretical interpretations regarding history effects and training in the context of drug discrimination are entertained.     

Effects of gonadectomy and androgen supplementation on attention in male rats

Androgens are hypothesized to enhance aspects of mnemonic processing. However, it is unclear whether the memory improvement is associated with changes in earlier aspects of information processing, such as attention. The present experiments examined the effects of gonadectomy or supplementation with testosterone or dihydrotestosterone on performance of male rats in a two-lever attention task that required discrimination of visual signals and non-signals. In Experiment 1, Long-Evans rats were trained in the attention task and then underwent gonadectomy or sham-surgery. Postsurgically, animals were tested for 20 sessions in the attention task and then received manipulations designed to increase attentional demands. Gonadectomized and sham-treated animals performed similarly during immediate postsurgical testing and across all manipulations. Finally, the effects of administering the muscarinic receptor antagonist scopolamine (0, 0.1, and 0.2 mg/kg) on attentional performance were assessed for all animals. Scopolamine decreased accuracy of signal detection but did not differentially affect gonadectomized and sham-treated animals. In Experiment 2, a new group of rats (not gonadectomized) was trained to perform the attention task and subsequently administered testosterone (0, 0.1, and 0.5 mg/kg) or dihydrotestosterone (0, 0.1, and 0.5mg/kg) prior to performing the standard version of the attention task and in the presence of a visual distractor. Testosterone (0.5 mg/kg) decreased accuracy on non-signal trials and, at 0.1 mg/kg, decreased latencies to retrieve a reward. Dihydrotestosterone (0.5 mg/kg) decreased accuracy on non-signal trials during visual distractor sessions. The present data do not support the hypothesis that alterations in attention critically mediate androgen-induced changes in mnemonic processing. Supra-physiological androgen levels appear to be capable of impairing attentional processing.     

Drug discrimination under a concurrent fixed-ratio fixed-ratio schedule.

Pigeons were trained to discriminate 5.0 mg/kg pentobarbital from saline under a two-key concurrent fixed-ratio 10 fixed-ratio 40 schedule of food presentation, in which the fixed-ratio component with the lower response requirement was programmed to reinforce responding on one key after drug administration (pentobarbital-biased key) and on the other key after saline administration (saline-biased key). After responding stabilized, pigeons averaged 98% of their responses on the pentobarbital-biased key during training sessions preceded by pentobarbital, and they averaged 90% of their responses on the saline-biased key during training sessions preceded by saline. In test sessions preceded by doses of pentobarbital, chlordiazepoxide, or ethanol, pigeons switched from responding on the saline-biased key at low doses to responding on the pentobarbital-biased key at higher doses (the dose-response curve was quantal). High doses of phencyclidine produced responding on both keys, whereas pigeons responded almost exclusively on the saline-biased key after all doses of methamphetamine. These and previous experiments using concurrent reinforcement schedules to study drug discrimination illustrate that the schedule of reinforcement is an important determinant of the shape of dose-effect curves in drug-discrimination experiments.     

Effects of amphetamine-CNS depressant combinations and of other CNS stimulants in four-choice drug discriminations

Three pigeons were trained to discriminate among 5 mg/kg pentobarbital, 2 mg/kg amphetamine, a combination of these two drugs at these doses, and saline using a four-choice procedure (amphetamine-pentobarbital group). Three other pigeons were trained to discriminate among 5 mg/kg morphine, 2 mg/kg methamphetamine, a combination of these two drugs at these doses, and saline (methamphetamine-morphine group). After 10 to 13 months of training, the pigeons averaged more than 90% of their responses on the appropriate key during training sessions. In subsequent testing, dose-response curves were determined for the individual drugs, for a wide range of dose combinations of the training drugs, and for two drugs to which the pigeons had not been exposed previously (pseudoephedrine and nicotine). After low test doses of the training drugs, pigeons responded on the saline key. As the dose increased, responding on the key associated with that drug during training sessions increased. When training drugs were combined at doses that were not discriminable when given alone, responding occurred on the saline key. When a discriminable dose of one training drug was combined with a nondiscriminable dose of the other training drug, responding occurred on the key associated with the discriminable dose. When both drugs were given at discriminable doses, responding almost always occurred on the drug-combination key. The response-rate decreasing effects of pentobarbital and amphetamine were mutually antagonized when the drugs were combined, but the rate-decreasing effects of morphine and methamphetamine were not. After low doses of pseudoephedrine and nicotine, pigeons in both groups responded on the saline key. After higher doses of pseudoephedrine and nicotine, responding in the amphetamine-pentobarbital group occurred primarily on the amphetamine key. In the methamphetamine-morphine group, higher doses of pseudoephedrine and especially nicotine engendered more responding on the combination key than had occurred in the other group. The four-choice procedure can reveal subtle effects in the discrimination of individual drugs and drug combinations that are not apparent with procedures offering fewer response alternatives.     

Navigation in the Morris swim task as a baseline for drug discrimination: a demonstration with morphine

A morphine versus saline discrimination was demonstrated using the Morris swim task as the behavioral baseline. The apparatus was a large circular pool filled with water made opaque by floating polypropylene pellets. Rats were placed in the tank in randomly selected locations (12 trials per session) and could escape by swimming to a platform submerged 2 cm below the surface. Morphine (5.6 mg/kg) or saline was injected prior to training sessions. The position of the platform in a given session depended on the drug condition, thus forming the basis for discriminative responding. Three of the 4 rats acquired the discrimination, as evidenced by direct swims to the condition-appropriate platform. Generalization probe sessions were conducted following acquisition. Probe sessions were preceded by injections of morphine (0, 1.0, 3.0, 5.6, or 10.0 mg/kg) and involved placing the rat in the pool for 1 min without a platform. Swim patterns revealed a gradient, with probe swimming more concentrated in the area of the morphine platform position after higher morphine doses. In addition, dose-dependent increases in the likelihood of swimming first to the morphine-associated platform location were obtained. These results illustrate the generality of drug discrimination across different behavioral procedures, and of particular interest with respect to spatial learning, demonstrate interoceptive stimulus control of navigation.     

Discrimination of methadone and cocaine by pigeons without explicit discrimination training.

Pigeons were trained to peck a key on a variable-interval 2-min schedule of food reinforcement. Prior to each session, either 2.0 mg/kg methadone (n = 3), 3.0 mg/kg cocaine (n = 4), or 5.6 mg/kg cocaine (n = 2) was administered. When each pigeon's rate of pecking was stable, a range of doses of the training drug and saline were administered prior to 20-min extinction sessions separated by at least four training sessions. Rate of pecking during these extinction tests was generally an increasing function of dose, with the lowest rates obtained following saline and low doses and the highest rates obtained following doses near the training doses. Dose functions from pigeons trained with 5.6 mg/kg cocaine were steeper than those from pigeons trained with 3.0 mg/kg cocaine. Pigeons trained with methadone or 3.0 mg/kg cocaine were then given discrimination training, in which food reinforcement followed drug administration and 20-min extinction sessions followed saline administration. Rates of pecking under these conditions quickly diverged until near-zero rates were obtained following saline and high rates were obtained following drug. Discrimination training steepened dose functions for the training drugs, and the effects of several other substituted drugs depended on the pharmacology of the training drug. The pigeons trained with 5.6 mg/kg cocaine were tested with d-amphetamine, methadone, and morphine prior to discrimination training. d-Amphetamine increased rates dose dependently, and methadone and morphine did not. The results suggest that discriminative control by methadone and cocaine was established without explicit discrimination training.     

Time of supplemental feeding alters the effects of cocaine on lever pressing of rats

The present experiment assessed the effects of cocaine on the lever pressing of 4 rats maintained during 15-min sessions by a fixed-ratio 50 schedule of food reinforcement. Across phases, supplemental food was provided either immediately or 2 hr after sessions. Two rats began the experiment in the delayed-feeding condition, and 2 began the experiment in the immediate-feeding condition. Rates of lever pressing of 2 rats sometimes decreased to low levels near the ends of sessions when supplemental feeding was provided immediately, but were consistently high throughout sessions when supplemental feeding was delayed. Cocaine (1.0 to 17.0 or 30.0 mg/kg) was administered intraperitoneally 15 min prior to test sessions. In most cases, cocaine suppressed response rates at lower doses under immediate-feeding conditions. Decreases in overall response rates were correlated with dosedependent increases in the time rats spent not responding. It is suggested that delaying the time of postsession feeding increased response strength, as indicated by greater resistance to the rate-suppressive effects of cocaine.     

Nicotine trained as a negative feature passes the retardation-of-acquisition and summation tests of a conditioned inhibitor

Nicotine functions as a negative feature in a Pavlovian discriminated goal-tracking task. Whether withholding of responding to the conditional stimulus (CS) reflects nicotine functioning as a conditioned inhibitor is unknown. Accordingly, the present research sought to determine whether nicotine trained as a negative feature passed the retardation-of-acquisition and summation tests, thus characterizing it as a pharmacological (interoceptive) conditioned inhibitor. In the retardation test, rats received either nicotine (0.4 mg/kg) or chlordiazepoxide (5 mg/kg) negative feature training in which the drug state signaled when a 15-sec light CS would not be paired with sucrose; light was paired with sucrose on intermixed saline sessions. Following acquisition of the discrimination, both groups received nicotine CS training in which sucrose was intermittently available on nicotine but not intermixed saline sessions. Acquisition of conditioned responding to the nicotine CS was slower in the nicotine negative feature group than in the chlordiazepoxide negative feature group. In the summation test, rats were assigned to either the nicotine negative feature group or a pseudoconditioning control. In this control, the light CS was paired with sucrose on half the nicotine and half the saline sessions. Both groups also received excitatory training in which a white noise CS was paired with sucrose. The summation test consisted of presenting the white noise in conjunction with nicotine. Conditioned responding evoked by the white noise was decreased in the negative feature but not the pseudoconditioning group. Combined, the results provide the first evidence that an interoceptive stimulus (nicotine) can become a conditioned inhibitor.     

Neuroleptic-induced attenuation of brain stimulation reward in rats.

In 30-min free-operant tests, the dopamine receptor blockers pimozide (.125, .25, and .50 mg/kg) and (+)-butaclamol (.1, .2, and .4 mg/kg) attenuated lever pressing for lateral hypothalamic brain stimulation. When discrete self-stimulation trials were offered in a straight alleyway, pimozide increased start box latencies, slowed running speeds, and reduced lever-pressing rates. However, performance early in both lever-pressing and runway sessions was normal; performance deteriorated as testing progressed, following patterns that paralleled those seen when animals were tested with reductions in the amplitude of stimulating current. Spontaneous recovery was obtained in both situations; experimenter-imposed 10-min time-outs caused renewed lever pressing and running. In contrast, alpha-noradrenergic receptor blockade by phenoxybenzamine (5, 10, and 20 mg/kg) failed to produce extinction-like response patterns. These data support the view that central dopaminergic systems are important components of the neural mechanisms mediating reward.     

Responding to a positive stimulus by “satiated” pigeons

Skinner (1938) found that rats given discrimination training (Phase I) and then reinforced to “satiation” for responses in the presence of the negative stimulus (S?) (Phase II), began to respond again when the positive stimulus (S+) was reintroduced (Phase III). Experiment I replicated Skinner's finding with pigeons, alternating S+ and S? presentations during Phase III. In Experiment II, Phase II was extended, and Phase III results were similar to those of Experiment I, demonstrating that the recovery of S+ responding could not be attributed to a lax Phase II satiation criterion. In Experiment III, a uniform schedule of reinforcement was maintained throughout the three phases, and results similar to those of Experiment I were found, indicating that renewed S+ responding was not due to the shift in schedule between phases. In Experiment IV, Phase I consisted of discrimination training with two positive stimuli (S+_s and S+_n), and Phase II consisted of reinforcement for responses in the presence of S? and S+_s. During Phase III, significantly more responding was found to S+_s and S+_n than to S?, but no difference in responding was found between the two positive stimuli. In Experiment V, Phase I consisted of simple discrimination training, and during Phase II, responses in the presence of both S? and a novel stimulus (So) were reinforced. During Phase III, significantly more responding was found to S+ than to either S? or So, with no difference found between S? and So responding. Renewed responding to S+ during Phase III in the present experiments is best explained by behavioral contrast developed during Phase I.     

Within-session Analysis Of Visual Discrimination

Within-session changes in responding by pigeons during a maintained successive discrimination procedure were examined in four experiments. In the first two experiments, which involved discrimination of visual flicker rate, within-session changes in responding were minimal or absent. A third experiment, which examined discrimination of rectangular forms, demonstrated that the absence of within-session changes in responding was not limited to flicker-rate stimuli. A fourth experiment showed that the absence of within-session changes in responding was not due to high task difficulty in the previous experiments. For the group of subjects in each experiment, within-session changes in responding did not influence discrimination performance. Therefore, measures of overall response rate accurately represented responding both within and across sessions. The occasional appearance of within-session decreases in responding for a few birds may be attributable to satiation.     

State-dependent recall decrements with moderate doses of alcohol

Thirty-two adult volunteers were asked to memorize a simplified geographical map, visually displayed, together with an auditorially presented 19-item set of instructions regarding a particular route. During this session, half the subjects were sober and half were under the effects of a moderate dose of alcohol (mean blood alcohol concentration = 81mg/100ml). Twenty-four hours later they were tested under the same or different conditions. Learning performance on Day 1 was unaffected by alcohol. Learning transfer (tested on Day 2) was equally good when subjects were intoxicated during both sessions or were sober during both sessions. There were significant decrements in recall on Day 2, when subjects were in a different drug state. This ‘dissociation of learning’ was found to be symmetrical in that the recall decrement was the same whether the initial learning was acquired in a sober or a drugged state.     

Interaction of methadone, reinforcement history, and variable-interval performance.

In the present study, we examined how a reinforcement schedule history that generated high or low rates of responding influenced the effects of acute (Experiment 1) and chronic (Experiment 2) methadone administration. Initially, key-peck responses of pigeons were maintained under a variable-interval 90-s schedule of food presentation, and a methadone dose-response curve was determined with doses of 0.6, 1.2, and 2.4 mg/kg. The pigeons were then exposed, for at least 40 sessions, to either a fixed-ratio 50 schedule or a differential-reinforcement-of-low-rate 10-s schedule, or were given continued exposure to the variable-interval schedule. The methadone dose-response curve was redetermined after all pigeons again were responding under the variable-interval schedule. The effects of two different daily methadone doses (9.0 and 12.0 mg/kg/day) and withdrawal precipitated by naloxone also were assessed. Experience with a fixed-ratio or differential reinforcement of low rate schedule did not result in significantly different response rates under the variable-interval schedule and, in general, the acute effects of methadone did not have differential effects correlated with schedule history. However, for 2 of 4 subjects the rate-decreasing effects of methadone on rates of key pecking were greater following a history of low-rate responding, suggesting a possible interaction between schedule history and effects of methadone. Daily methadone administration under the variable-interval schedule revealed that pigeons with experience under the differential reinforcement of low rate schedule developed more rapid and complete tolerance to the rate-decreasing effects of methadone. Three of the 4 subjects in this group showed rate increases above drug-free baselines during chronic methadone dosing. Pigeons with a history of fixed-ratio responding also developed tolerance to the rate-decreasing effects of methadone but without the subsequent rate increases seen by subjects with low-rate histories. No subjects with variable-interval histories showed complete recovery of drug-free baselines, suggesting that interpolated training under other schedules may attenuate the rate-altering effects of chronically administered drugs. Naloxone (1.0 mg/kg), administered during the chronic methadone phase, resulted in greater disruption of responding by pigeons with a history of low-rate responding, as compared to subjects in the other two groups.(ABSTRACT TRUNCATED AT 400 WORDS)     

Enhancement of progressive-ratio performance by chlordiazepoxide and phenobarbital

The key pecking of two pigeons was reinforced with food on a progressive-ratio schedule, which required an increasing number of responses for each successive reinforcement: 8, 16, 24, 32, etc. When the subject failed to complete the next ratio in the sequence within 60 min, the session terminated. The number of responses in the final completed ratio was defined as the "breaking point". After the breaking point had stabilized (60 sessions), it served as a baseline to assess the effects of varying doses (5 to 80 mg/kg) of chlordiazepoxide and phenobarbital, administered intramuscularly 30 min before the sessions. Both drugs increased the breaking point. The dose-effect curves were inverted U-shaped, with maximum enhancement of performance occurring at 20 mg/kg for chlordiazepoxide and at 40 mg/kg for phenobarbital. A comparable enhancement was not obtained during a non-drug "probe" session, which was conducted after the subjects' body weights had been temporarily reduced from 80% to 70% of their free-feeding weights. The drug-induced enhancement of breaking point was related to the initial values of the performance and may represent a reduction in the aversiveness of the schedule.