Sex differences in adolescent ethanol drinking to behavioral intoxication

Rodent models have been especially useful for investigating adolescent ethanol exposure. However, there is a paucity of studies examining sex differences in behavioral intoxication from adolescent ethanol drinking. Here, we used an ethanol drinking model to investigate if adolescent rats of both sexes readily drink ethanol to measurable behavioral intoxication, indicated by increased impulsive action and motor incoordination. Beginning on postnatal day (P) 28, male and female Long‐Evans rats were given 30‐min access to a solution of sucrose (20%) or sweetened ethanol (20% sucrose +15% ethanol) every other day until P60 and once after 2 weeks of forced abstinence (on P75). On alternate (nondrinking) days, rats were reinforced with a food pellet for making a cued nosepoke response. Beginning on P56, rats were tested in this task after drinking sessions to assess ethanol‐induced changes in impulsive action, defined as premature responding prior to cue presentation. Motor coordination was assessed before and after drinking sessions using an incline plane test. Adolescent male and female rats readily consumed ethanol to behavioral intoxication, measured as reduced motor coordination. Following forced abstinence, females displayed greater ethanol‐induced impulsive action. These studies provide evidence for sex differences in behavioral intoxication following adolescent ethanol drinking.     

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.     

Reinforcing effects of caffeine in coffee and capsules.

In a residential research ward the reinforcing and subjective effects of caffeine were studied under double-blind conditions in volunteer subjects with histories of heavy coffee drinking. In Experiment 1, 6 subjects had 13 opportunities each day to self-administer either a caffeine (100 mg) or a placebo capsule for periods of 14 to 61 days. All subjects developed a clear preference for caffeine, with intake of caffeine becoming relatively stable after preference had been attained. Preference for caffeine was demonstrated whether or not preference testing was preceded by a period of 10 to 37 days of caffeine abstinence, suggesting that a recent history of heavy caffeine intake (tolerance/dependence) was not a necessary condition for caffeine to function as a reinforcer. In Experiment 2, 6 subjects had 10 opportunities each day to self-administer a cup of coffee or (on different days) a capsule, dependent upon completing a work requirement that progressively increased and then decreased over days. Each day, one of four conditions was studied: caffeinated coffee (100 mg/cup), decaffeinated coffee, caffeine capsules (100 mg/capsule), or placebo capsules. Caffeinated coffee maintained the most self-administration, significantly higher than decaffeinated coffee and placebo capsules but not different from caffeine capsules. Both decaffeinated coffee and caffeine capsules were significantly higher than placebo capsules but not different from each other. In both experiments, subject ratings of "linking" of coffee or capsules covaried with the self-administration measures. These experiments provide the clearest demonstrations to date of the reinforcing effects of caffeine in capsules and in coffee.     

Oral self-administration of pentobarbital by rhesus monkeys: relative reinforcing effects under concurrent fixed-ratio schedules.

During daily 3-hr sessions, orally delivered pentobarbital solutions and water, or two separate pentobarbital solutions, were concurrently available to rhesus monkeys according to fixed-ratio schedules of mouth contacts with a spout. First water, and then each of four "comparison-concentration" pentobarbital solutions (0.0625, 0.25, 1, and 4 mg/mL), was successively available from one spout for a block of sessions under a fixed-ratio-64 (three monkeys) or fixed-ratio-16 (one monkey) schedule. Under an identically sized fixed-ratio schedule, deliveries of a "standard-concentration" pentobarbital solution were concurrently available from a second spout. The concentration of the standard solution remained unchanged throughout testing of the series of comparison solutions. Each of three pentobarbital concentrations (4, 1, and 0.25 mg/mL) in turn served as the standard concentration. Within each pair of concurrently available solutions, the higher drug concentration maintained more behavior than the lower concentration. Thus when monkeys were provided with concurrent access to different pentobarbital concentrations, relative reinforcing effects were directly related to drug concentration. Further, the amount of behavior maintained by a particular drug concentration was dependent on the concentration of the concurrently available drug solution. Thus, the relative effectiveness of a reinforcer in maintaining behavior is a function of both the reinforcer's magnitude and the availability of alternative reinforcers in the environment.     

Analysis of fixed-ratio behavior maintained by drug reinforcers.

Behavior maintained by intravenously delivered alfentanil, cocaine, or ketamine was assessed using a fixed-ratio schedule of reinforcement. As the dose of each drug was increased, rate of responding also increased up to a maximum. Further increases in dose resulted in decreased response rates (inverted U-shaped curve). An analysis of postreinforcement-pause-time and run-time measures for the ascending limb of the inverted U-shaped functions revealed that behavior was characterized by systematic decreases in both pause time and run time as dose and rate increased. An examination of the descending limb of the dose-response functions revealed that lowered response rates for cocaine and ketamine were correlated with increases in run time and small and inconsistent effects on postreinforcement pause time. Behavior maintained by rate-reducing doses of alfentanil was characterized by lengthened postreinforcement pauses with small increases in run time. These data suggest that at larger doses, drug reinforcers may have unconditioned or direct effects on the behavior that the drug is maintaining, and more important, that the nature of these unconditioned effects depends on the drug that is maintaining behavior.     

Behavioral economics of drug self-administration and drug abuse policy.

The concepts of behavioral economics have proven useful for understanding the environmental control of overall levels of responding for a variety of commodities, including reinforcement by drug self-administration. These general concepts are summarized for application to the analysis of drug-reinforced behavior and proposed as the basis for future applications. This behavioral agenda includes the assessment of abuse liability, the assay of drug-reinforcer interactions, the design of drug abuse interventions, and the formulation of drug abuse public policy. These separate domains of investigation are described as part of an overall strategy for designing model projects to control drug use and testing public policy initiatives.     

Choice between food and heroin: effects of morphine, naloxone, and secobarbital.

Baboons responded on a choice task on which discrete trials involved choosing between an intravenous injection of heroin (.32 or 1.0 mg/kg) or the availability of food pellets. An intertrial interval of three hours followed the completion of each trial. Under baseline conditions baboons consistently completed the eight available trials each day. Typically, animals chose heroin on three or four trials a day and food on the remaining trials. Animals tended to space the selection of heroin rather than choosing heroin on consecutive trials. A series of single-day experimental manipulations was undertaken to characterize performance further. Manipulation of the heroin dose produced shifts in the relative frequency of choosing the drug option which were inversely related to dose. Manipulation of number of pellets per food trial produced little change in distribution of choices. Noncontingent administration of morphine produced dose-related decreases in relative frequency of heroin choices, and a higher dose decreased the number of trials completed. Noncontingent naloxone produced dose-related increases in the relative frequency of heroin choices. Noncontingent secobarbital had no effect on distribution of choices, and high doses reduced the number of trials completed per day. The results suggest that morphine and naloxone produce shifts in this choice behavior by selectively interacting with the reinforcing properties of the option involving heroin.     

Preference in rhesus monkeys given a choice between cocaine and d,l-cathinone

Previous experiments have shown that both cocaine and d,l-cathinone can function as positive reinforces when delivered intravenously to rhesus monkeys. However, the relative reinforcing efficacies of these compounds have not been established. In the present experiment, three rhesus monkeys were allowed to choose between saline and several doses of d,l-cathinone or cocaine as well as between several doses of both drugs in a discrete-trial choice procedure. Sufficient doses (.05 to .2 mg/kg/injection) of either drug maintained self-administration and the higher doses were reliably preferred to saline. Doses of d,l-cathinone that were preferred to saline were then compared to a range of cocaine doses in drug-drug choice. As the dose of d,l-cathinone that was available was increased, an increase in cocaine dose was necessary to maintain cocaine preference. Comparison of drug-drug choice data to dose combinations predicted to be chosen with equal frequency revealed that the reinforcing efficacy of d,l-cathinone was equivalent to that of cocaine.     

Pentobarbital self-administration in rhesus monkeys: drug concentration and fixed-ratio size interactions.

Performances of three rhesus monkeys were reinforced by the oral delivery of pentobarbital and studied as functions of fixed-ratio size and drug concentration. Pentobarbital solutions and water were concurrently available on identical reinforcement schedules from separate liquid-delivery systems during 3-hour sessions. Under a fixed-ratio 16 schedule of drug availability, a descending series of drug concentrations was tested (4, 2, 1, 0.5, 0.25, 0.125, and 0.0625 mg/ml, followed by a retest at 4 mg/ml). Partial concentration series beginning with the highest concentration were repeated with fixed-ratios of 32 and 64, with a fixed-ratio 128 for two monkeys, and with fixed-ratio 256 for one. At each fixed-ratio value, response rate and number of drug deliveries were inverted U-shaped functions of pentobarbital concentration. Drug intake (mg/kg/session) increased directly with drug concentration. As the fixed-ratio size was increased, the number of liquid deliveries decreased. For each drug concentration, when the numbers of drug deliveries at fixed-ratios of 32, 64, and 128 responses were plotted as percentages of those obtained at fixed-ratio 16, the following orderly relationship emerged: the higher the drug concentration, the less that drug deliveries were decreased by increases in fixed-ratio size. This relationship indicates an increase in reinforcing efficacy with increases in pentobarbital concentration.     

Rate dependency, behavioral mechanisms, and behavioral pharmacology.

Behavioral pharmacology has become increasingly independent of the experimental analysis of behavior. At its beginning, behavioral pharmacology was closely related to the experimental analysis of behavior, with developments in each field aiding the other. Early attempts to systematize data in behavioral pharmacology culminated with the development of the rate-dependency concept, but as this principle was found to have more limited generality than originally was hoped, a theoretical void developed. This circumstance was followed by increased reliance on pharmacological theory as a basis for experimentation and interpretation, with an attendant decrease in emphasis on environmental variables and behavioral interpretations. Lack of interplay between behavioral pharmacology and the experimental analysis of behavior is detrimental to both disciplines because each could contribute significantly to the other. The current trend might be reversed if more research were directed at elucidating behavioral mechanisms of drug action.