Dissociable mesolimbic dopamine circuits control responding triggered by alcohol-predictive discrete cues and contexts

Abstract

Context can influence reactions to environmental cues and this elemental process has implications for substance use disorder. Using an animal model, we show that an alcohol-associated context elevates entry into a fluid port triggered by a conditioned stimulus (CS) that predicted alcohol (CS-triggered alcohol-seeking). This effect persists across multiple sessions and, after it diminishes in extinction, the alcohol context retains the capacity to augment reinstatement. Systemically administered eticlopride and chemogenetic inhibition of ventral tegmental area (VTA) dopamine neurons reduce CS-triggered alcohol-seeking. Chemogenetically silencing VTA dopamine terminals in the nucleus accumbens (NAc) core reduces CS-triggered alcohol-seeking, irrespective of context, whereas silencing VTA dopamine terminals in the NAc shell selectively reduces the elevation of CS-triggered alcohol-seeking in an alcohol context. This dissociation reveals new roles for divergent mesolimbic dopamine circuits in the control of responding to a discrete cue for alcohol and in the amplification of this behaviour in an alcohol context.

Dopamine Circuit Mechanisms of Addiction-Like Behaviors

“…Under periods of abstinence, VTA activity and NAC DA release facilitates relapse to cocaine, heroin, and alcohol in the presence of these cues ( Shaham et al, 2003 ; Saunders et al, 2013 ; Corre et al, 2018 ; Mahler et al, 2019 ). Conversely, drug seeking is reduced by inactivation of the mesolimbic pathway ( McFarland and Kalivas, 2001 ; Chaudhri et al, 2009 ; Saunders et al, 2013 ; Corre et al, 2018 ; Mahler et al, 2019 ; Valyear et al, 2020 ). These data fit within the framework of mesostriatal DA primarily controlling cue-guided or goal-directed drug seeking motivation.…”

Neurobiology of alcohol seeking behavior

“…Inhibition of inputs from the VTA to the NAc core reduced alcohol seeking triggered by an alcohol associated cue, irrespective of context. In contrast, silencing terminals of VTA inputs to the NAc shell selectively reduced cue-induced alcohol seeking in an alcohol-associated context (Valyear et al, 2020). If activation of GABA B receptors can attenuate activity of VTA neurons that belong to both these populations, it may therefore be able to broadly prevent relapse both when induced by discrete cues, and by contextual stimuli.…”

Dopamine and relapse to drug seeking

“…To be sure, activity in VTA dopamine neurons is important for relapse. VTA dopamine neuron activity is obligatory for cue-induced reinstatement of cocaine-seeking (Mahler et al, 2014) as well as cue (Valyear et al, 2020) and context-induced reinstatement of alcohol-seeking (Liu et al, 2020) because chemogenetic inhibition of these neurons prevents these forms of relapse. However, although important because they causally link reinstatement to the activity of VTA dopamine neurons, these kinds of global manipulations of VTA dopamine neurons obscure important findings.…”

“…stress, cue, discriminative cue, context) to seeking a variety of drugs (opiates, psychostimulants, ethanol) (Bossert et al, 2007(Bossert et al, , 2013Chaudhri et al, 2009;Mahler et al, 2014;Marchant & Kaganovsky, 2015;McFarland & Kalivas, 2001;Schmidt et al, 2005). Indeed, electrically evoked dopamine transients in the AcbC is itself sufficient to cause drug-seeking (Phillips et al, 2003) and chemogenetic inhibition of VTA dopamine terminals in the accumbens reduces alcohol-seeking (Valyear et al, 2020). However, the precise roles of AcbSh and AcbC in different forms or relapse remain less well understood.…”