Enhanced attention in rhesus monkeys as a common factor for the cognitive effects of drugs with abuse potential.

Abstract

One of the common neurochemical features of many drugs of abuse is their ability to directly or indirectly enhance dopaminergic activity in the brain, particularly within the ventral tegmental-nucleus accumbens pathway. Dopaminergic pathways in the frontal and limbic cortex also may be targets for these agents, where pharmacological effects could result in heightened attention and/or support self-administration behavior. The purpose of this study was to determine whether drugs from differing pharmacological classes that exhibit abuse potential would share the ability to counter distractability in the delayed matching task. Well trained mature macaques performed a computer-assisted delayed matching-to-sample task which included trials associated with three delay intervals and randomly interspersed task-relevant distractors. Drug regimens included four to five doses and subjects were tested no more than twice per week. All but one of the six compounds (tomoxetine), on average, increased task accuracy for either non-distractor or distractor trials. It was evident that for several compounds, doses required to improve accuracy for non-distractor trials were routinely greater than the doses required to improve accuracy for distractor trials. Data for the individualized Best dose (based upon the subject's optimal level of accuracy during distractor trials) revealed statistically significant distractor-related improvements in task accuracy for the same five compounds. The relative efficacy for reversing distractor-induced decrements in task accuracy was estimated by the level of improvement with respect to baseline: nomifensine (31%)>nicotine (22%) approximately morphine (19%) approximately caffeine (19%) approximately methylphenidate (22%) >tomoxetine (9%). Tomoxetine (noradrenergic preferring) was the only compound that did not produce a significant improvement in accuracy. These results provide pharmacological support for the concept that attentional mechanisms may play an important role in the "environmental" associative aspects of drug seeking behavior, and as such they may provide the basis for treatment strategies aimed at preventing relapse in detoxified addicts.