Role of the lateral habenula in impulsive behavior

National Institute On Drug Abuse

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Abstract

In the past few years we have made much progress using a behavior model of impulsive drug seeking in rats in which rats trained to self-administer the psychostimulant cocaine are subsequently trained to withhold responding for the drug when the absence of a stimulus (light on) indicates that it is not available (NoGo period). Thus, the rats learn that cocaine reinforcement is only available when the stimulus is present (Go) and they learn to withhold the response during this period. We then demonstrated that inhibition of a brain region known as the lateral habenula (LHb) prevented this response inhibition during NoGo periods and later, that inhibition of muscarinic acetylcholine receptors (mAChRs) also prevented this response inhibition. Because of these results we have expanded these studies to define cellular mechanisms of acetylcholine (ACh) action in the LHb, as well as investigated a role for the endogenous cannabinoid (eCB) system in this response. To date, our work shows that endogenous ACh acts to facilitate impulse control in the LHb by stimulating an M2 mAChR subtype, and that activation of LHb cannabinoid type 1 receptors (CB1Rs) by delta-9-THC, the psychoactive molecule found in the cannabis plant, increases impulsive cocaine seeking behavior. These studies are important because impulsive behavior is a major impediment to abstinence from drug use and because impulsivity is linked to many psychiatric conditions, such as attention-deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). Moreover, impulsive behavior is also often observed following traumatic brain injury (TBI) in both soldiers and civilians, and therefore is relevant to acute brain damage. We have recently published our work implicating mAChRs in the LHb in impulsive behavior relating to cocaine seeking, and we are currently investigating the role of the LHb and this system in impulsive behavior in non-drug addiction models in rats.