The lateral habenula (LHb) is a brain structure receiving inputs from limbic forebrain areas and innervating major midbrain monoaminergic nuclei. Evidence indicates LHb involvement in sleep control, reward-based decision making, avoidance of punishment, and responses to stress. Additional work has established that the LHb mediates negative feedback in response to aversive events. As a hallmark of drug addiction is the inability to limit drug use despite negative consequences, we hypothesize that LHb dysfunction may have a role in the lack of control over drug seeking. Here we examine the effects of LHb inactivation in control over drug seeking in several cocaine self-administration (SA) paradigms in rats. We find that inhibition of the LHb with GABAergic agonists did not alter cocaine SA under progressive ratio or seeking/taking chained reinforcement schedules, or during punishment-induced suppression of cocaine-reinforced responding. In contrast, LHb inhibition increased cocaine seeking when the drug was not available in rats trained to discriminate its presence using an environmental cue. This effect of LHb inhibition was selective for cocaine, as it did not impair responding for sucrose reinforcement. The effect of LHb injection of GABA agonists was mimicked by intra-LHb muscarinic cholinergic (mACh) antagonist injection, and activation of mACh receptors excited a majority of LHb neurons in in vitro electrophysiology experiments. These results indicate that the LHb participates in the suppression of impulsive responding for cocaine through the activation of a cholinergic circuit, and they suggest that LHb dysfunction may contribute to impaired impulse control associated with drug addiction.

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The ability of neurons to dynamically and flexibly encode synaptic inputs via short-and long-term plasticity is critical to an organism's ability to learn and adapt to the environment. Whereas synaptic plasticity may be encoded by pre-or postsynaptic mechanisms, current evidence suggests that optimization of learning requires both forms of plasticity. Endogenous cannabinoids (eCBs) play critical roles in modulating synaptic transmission via activation of cannabinoid CB1 receptors (CB1Rs) in many central nervous system (CNS) regions, and the eCB system has been implicated, either directly or indirectly, in several forms of synaptic plasticity. Because of this, perturbations within the eCB signaling system can lead to impairments in a variety of learned behaviors. One agent of altered eCB signaling is exposure to "exogenous cannabinoids" such as the primary psychoactive constituent of cannabis, Δ 9 -THC, or illicit synthetic cannabinoids that in many cases have higher potency and efficacy than Δ 9 -THC. Thus, by targeting the eCB system, these agonists can produce widespread impairment of synaptic plasticity by disrupting ongoing eCB function. Here, we review studies in which Δ 9 -THC and synthetic cannabinoids impair synaptic plasticity in a variety of neuronal circuits and examine evidence that this contributes to their well-documented ability to disrupt cognition and behavior. This is an update to a previous article published in Cold Spring Harbor Perspectives in Medicine [Hoffman and Lupica (2013). Cold Spring Harb Perspect Med 3: a012237.