Evaluation of pharmacological treatment of impulsivity in children with attention deficit hyperactivity disorder

We used an assessment that involved competing reinforcer dimensions in a concurrent-schedules arrangement to examine the effects of stimulant medication on impulsivity (i.e., sensitivity of choices to reinforcer immediacy relative to rate, quality, and effort) with 4 students with attention deficit hyperactivity disorder. The assessments were administered in the context of a double-blind, placebo-controlled, counterbalanced reversal design. Reinforcer immediacy was the most influential dimension for 3 of the students and the second most influential dimension for 1 of the students across placebo and medication conditions; medication did not affect these sensitivities.     

Behavioral pharmacology of methocinnamox: A potential new treatment for opioid overdose and opioid use disorder

Opioid overdose and opioid use disorder continue to be significant public health challenges despite the availability of effective medications and significant efforts at all levels of society. The emergence of highly potent and efficacious opioids such as fentanyl and its derivatives over the last decade has only exacerbated what was already a substantial problem. Behavioral pharmacology research has proven invaluable for understanding the effects of drugs as well as developing and evaluating pharmacotherapies for disorders involving the central nervous system, including substance abuse disorders. This paper describes a program of research characterizing a potent, selective, and long-lasting mu opioid receptor antagonist, methocinnamox, and evaluating its potential for treating opioid overdose and opioid use disorder. Studies in rodents and nonhuman primates demonstrate that methocinnamox prevents and reverses opioid-induced ventilatory depression and selectively blocks opioid self-administration. This work, taken together with rigorous in vitro and ex vivo studies investigating methocinnamox neuropharmacology, lays a solid foundation for the therapeutic utility of this potentially life-saving medication. Moreover, these studies demonstrate how rigorous behavioral pharmacological studies can be integrated in a broader drug discovery and development research program.     

Discriminative stimulus effects of diazepam and buspirone in normal volunteers.

A within-subject design was used to characterize the effects of dose manipulations on discriminative and self-reported effects of oral diazepam and buspirone. Subjects were trained to discriminate diazepam (10 mg) versus placebo (n = 10), or buspirone (10 or 15 mg) versus placebo (n = 9). The compounds were identified to subjects by letter code before discrimination training began. In later sessions, correct identifications at 2 hr after the oral administration of drug earned money. All subjects showed accurate discrimination performance during the test-of-acquisition phase. In a low-dose generalization phase, diazepam and buspirone produced dose-related increases in drug identifications across a four-fold range of doses. In a subsequent low-dose training phase, in which subjects were trained to discriminate progressively lower drug doses, the median lowest discriminable dose of diazepam and buspirone was 2.5 and 7.5 mg, respectively. Dose-response functions for drug identifications were shifted leftward in the low-dose training phase relative to the low-dose generalization phase, suggesting that reinforcement of progressively lower doses enhances drug discriminability. The self-reported effects of diazepam and buspirone were similar (e.g., both drugs increased ratings of drug strength and clumsy/uncoordinated) and different (e.g., diazepam but not buspirone increased ratings of drowsy/sleepy; buspirone but not diazepam increased ratings of tense/nervous). This study demonstrates discriminative and self-reported effects of diazepam and buspirone at doses lower than previously shown to be behaviorally active, and suggests that at commonly used clinical doses, diazepam is relatively more discriminable than buspirone.     

An evaluation of stimulant medication on the reinforcing effects of play

Although a vast literature has indicated that stimulant medications are effective for reducing inappropriate behavior in children with attention deficit hyperactivity disorder (ADHD), the effects of stimulant medication on ancillary behaviors (e.g., play) have yet to be investigated with the same rigor. We used a reinforcer assessment procedure to evaluate the effects of medication on the play and social behavior of 5 preschool children who had been diagnosed with ADHD. Conditions included (a) social reinforcement (i.e., playing with friends), (b) alone play, and (c) quiet time (i.e., resting). Results indicated that 1 of the 5 participants selected fewer social reinforcers and more nonsocial reinforcers (alone play or quiet time) while on medication. The findings indicate that the reinforcer assessment procedure may be a viable way to evaluate medication effects on an ongoing basis and to inform treatment decisions.     

Repeated diazepam administration: effects on the acquisition and performance of response chains in humans.

The effects of repeated diazepam administration (80 mg) were assessed across a 12-hr time course with humans responding under a two-component multiple schedule of repeated acquisition and performance of response sequences. Subjects resided in an inpatient clinical research ward for the duration of the study. In each component of the multiple schedule, subjects completed sequences of 10 responses in a predetermined order using three keys of a numeric keypad. In the acquisition component, a new response sequence was to be acquired each session. In the performance component, the response sequence always remained the same. After stable responding was obtained and the effects of the placebo assessed, diazepam was administered for 3 consecutive days. The effects of repeated diazepam administration on overall percentage of errors across the two components of the multiple schedule were selective. In the acquisition component, the first dose of diazepam increased percentage errors with the magnitude of effects decreasing across the second and third days of diazepam administration. In the performance component, the percentage of errors was either minimally affected across all 3 days of diazepam administration or substantively increased on Day 1 with subsequent diazepam administrations having minimal effects. Effects on response rate were not selective. Diazepam decreased rates of responding in both schedule components, with the magnitude of effects decreasing across successive administrations. These results replicate previous findings in humans and nonhumans on the selective effects of diazepam on acquisition versus performance baselines. Also, the results suggest that the selective effects do not result from differences in reinforcement rate. Finally, the present results demonstrate that the selective recovery from repeated drug administration previously demonstrated in nonhumans using a repeated acquisition arrangement has generality to human behavior.     

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.     

Emergent equivalence relations between interoceptive (drug) and exteroceptive (visual) stimuli.

Conditional "if-then" relations between drug (interoceptive) stimuli and visual (exteroceptive) stimuli were taught to 4 normal humans. Interoceptive stimuli were the effects produced by 0.32 mg/70 kg triazolam (a prototypical benzodiazepine) and placebo (lactose-filled capsules); exteroceptive stimuli were black symbols on white flash cards. Following the training of the prerequisite conditional relations, tests of emergent relations were conducted between exteroceptive stimuli and between interoceptive and exteroceptive stimuli. Equivalence relations emerged immediately without explicit training for all 4 subjects. Accuracy of responding during the interoceptive-exteroceptive equivalence tests and subjects' self-reports showed consistent discrimination between the drug effects of triazolam and placebo. Finally, a generalization test assessed whether a novel visual stimulus presented in the context of the placebo (i.e., no drug) would generalize to visual stimuli belonging to the placebo stimulus class. All 3 subjects who completed this test reliably chose the visual stimuli belonging to the placebo class and not the visual stimuli belonging to the triazolam stimulus class. The development of equivalence relations between interoceptive and exteroceptive stimuli demonstrates that private and public stimulus events can emerge as members of the same equivalence class. Theoretical and clinical implications are discussed.