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 using self-administration of the psychostimulant cocaine withhold responding for the drug when it is not available (NoGo period). We then demonstrated that inactivation of a brain region known as the lateral habenula (LHb) prevents the inhibition of drug seeking (during NoGo periods), that inhibition of muscarinic acetylcholine receptors (mAChRs) also reduces this response inhibition and increases impulsivity. 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. Because the LHb is a brain area that contains a preponderance of excitatory glutamate neurons, and because there are few sources of synaptic inhibition within the LHb, we are conducting studies to identify brain regions that project to and inhibit the LHb to control impulsive behavior. Using retrograde neuroanatomical tracing and colocalization of cellular markers for GABA and the cannabinoid CB1 receptor (CB1R) we identified inhibitory inputs arising from an area of the basal forebrain (BF) that includes the ventral pallidum (VP) and nucleus accumbens shell (NAcs). After identification of this pathway, we explored its physiological properties and compared them to another input to the LHb arising from the ventral tegmental area (VTA),using viral expression of the excitatory ion channel, channelrhodopsin-2 (ChR2). We found that the BF GABAergic inputs more strongly inhibit LHb neuronal activity, compared to VTA inputs, and that this was inhibited by activation of CB1Rs, whereas those from VTA were unaffected by CB1R stimulation. Behavioral studies during either optogenetic activation or inhibition of the BF inputs to the LHb revealed that activation of this inhibitory input increased impulsive behavior in a food-reinforced operant task, whereas inhibition of this pathway had no effect on this behavior. Therefore, this study identifies an inhibitory LHb input that is controlled by CB1Rs that may be a target of cannabis use, and can control impulsive behavior. More recent studies are investigating the activity of LHb neurons during response inhibition using a virally-expressed fluorescent calcium sensor known as GCaMP8f. These studies so far show that LHb neurons increase their activity during the presence of a stimulus that predicts food availability. Additionally, we have observed a decrease in this LHb neuron excitation in rats injected with the primary psychoactive constituent of cannabis known as delta-9-tetrahydrocannabinol (THC), suggesting that its ability to increase impulsivity is related to its effects on LHb neuron activity.