Cannabinoid and opioid modulation of impulsive behavior and drug addiction

Occasionally, it happens to all of us: you speak out of turn during a meeting or you make a comment and immediate realize that you shouldn't have said it. Or you buy an expensive pair of shoes even though you actually cannot afford them. Two examples of daily‐live impulsive behavior, and more specifically of impulsive action (acting without forethought) and impulsive choice (preferring immediate gratification over a delayed reward). When somebody is hyper‐impulsive, this personality trait can negatively affect that person's life. Failure to suppress impulsive behavior (failing impulse control) is a well‐known endophenotype in people suffering from Attention‐ Deficit/Hyperactivity Disorder (ADHD) or drug addiction, but also, for instance, in people with a bipolar disorder (during the manic phases). Hyper‐impulsivity results from abnormal brain functioning. However, to date, the exact malfunctions in the 'impulsive brain' remain largely unknown, thereby hampering effective treatment of this maladaptive behavior. An important aim of this Ph.D. thesis was to gain more insight into the neurobiology of impulsivity. In addition, this thesis examines some aspects of the neurobiology of drug addiction, a psychiatric disorder that, as mentioned before, is in most patients characterized by impulse control‐related problems, particularly during the abstinence phase when drug addicts have been drug‐ free for some time and try to prevent relapse. By using rat behavioral models combined with various pharmacological approaches, we have studied the neurobiology of impulsivity and relapse to drug seeking, in search of putative 'targets' for novel medication against hyper‐impulsivity and/or drug addiction. Thereby, we focused specifically on the cannabinoid and opioid neurotransmitter systems, as previous studies had already suggested a role for these two neurotransmitter systems in regulating both impulsive behavior and relapse to drug seeking. Cannabinoid and opioid modulation of impulsive behavior For the impulsivity project (Chapters 2‐4), the main aim was to elucidate under which conditions, and via which neuronal mechanisms, the endogenous cannabinoid and opioid systems can mediate two types of impulsive behavior. To this end, different groups of rats were trained for 2‐3 months in either a 5‐choice serial reaction time task (5‐CSRTT), to measure an aspect of impulsive action (the inability to inhibit inappropriate responses), or a delayed reward task (DRT), to assess impulsive choice (inability to wait for a larger but delayed reward). Subsequently, the role of various receptor subtypes of cannabinoid and opioid receptors in mediating impulsive action and impulsive choice was determined. In a series of test …