Contribution of Opioid and Stress Systems to Impulsive Action in Rodent Models

Abstract

Impulsive action, the inability to withhold responding, is a primary symptom of many psychiatric disorders, including drug addiction. Impulsive action is mediated through a complex interplay of many different neurotransmitters. The purpose of the experiments presented in this thesis was to further elucidate the role of opioid activity and environmental influences (e.g., stress) on impulsive action. Chapters 2 – 4 extend previous findings showing mu and delta opioid receptor (M/DOR) involvement in impulsive action. In all experiments, animals were trained to withhold responding for sucrose until a discriminative stimulus (cue light) was presented. In Chapter 2, rats were tested in a Variable delay response inhibition (RI) task in which the pre-response (i.e., premature) phase ranged from 1-60 s; thus, animals could not predict the length of the premature phase. Following training, rats were tested for impulsive action following injections of the DOR agonist, SNC80, or the MOR agonist, morphine. SNC80 dose-dependently increased premature responding in the Variable delay task, whereas none of the morphine doses had any effect. SNC80-induced increases in premature responding were blocked by a highly specific DOR antagonist (naltrindole). Morphine had no effect on responding in the Variable delay task, so in Chapter 3 we tested the effects of morphine in two Fixed delay tasks (4- and 60-s). Morphine dose-dependently increased premature responding in both the Fixed 4s and 60s versions of the RI task, an effect blocked by MOR antagonism. In Chapter 4, we assessed impulsive action in mice conditionally lacking MORs or DORs located on GABAergic forebrain neurons (cKO), and in constitutive MOR or DOR knockout mice (KO). Surprisingly, neither cKO nor KO mice differed in impulsive responding compared to control mice. Finally, in Chapter 5, we examined whether the pharmacological stressor, yohimbine, increases impulsive action. Yohimbine dose-dependently increased impulsive action; however antagonism of stress (CRF and glucocorticoid receptors), noradrenergic, dopaminergic, or opioidergic systems did not alter this response. Collectively, these studies demonstrate an important role for both opioid systems and stress in impulsive action, but highlight the importance of methodological differences when interpreting pharmacological and genetic behavioural studies.