The Mesolimbic Dopamine Activity Signatures of Relapse to Alcohol-Seeking

Abstract

The mesolimbic dopamine system comprises distinct compartments supporting different functions in learning and motivation. Less well understood is how complex addiction-related behaviors emerge from activity patterns across these compartments. Here we show how different forms of relapse to alcohol-seeking in male rats are assembled from activity across the VTA and the nucleus accumbens. First, we used chemogenetic approaches to show a causal role for VTA TH neurons in two forms of relapse to alcohol-seeking: renewal (context-induced reinstatement) and reacquisition. Then, using gCaMP fiber photometry of VTA TH neurons, we identified medial and lateral VTA TH neuron activity profiles during self-administration, renewal, and reacquisition. Next, we used optogenetic inhibition of VTA TH neurons to show distinct causal roles for VTA subregions in distinct forms of relapse. We then used dLight fiber photometry to measure dopamine binding across the ventral striatum (medial accumbens shell, accumbens core, lateral accumbens shell) and showed complex and heterogeneous profiles of dopamine binding during self-administration and relapse. Finally, we used representational similarity analysis to identify mesolimbic dopamine signatures of self-administration, extinction, and relapse. Our results show that signatures of relapse can be identified from heterogeneous activity profiles across the mesolimbic dopamine system and that these signatures are unique for different forms of relapse.

Phasic inhibition of dopamine neurons is an instrumental punisher

“…Whole-cell patch-clamp recordings from made from eNpHR3.0-expressing VTA neurons in vitro from TH::Cre+ rats to confirm the inhibitory nature of the photostimulation and its effectiveness across the durations to be used in later behavioral experiments ( Figure 1A,B). We have previously reported that eNpHR3.0 expression is specific to VTA TH+ neurons in this rat line (Liu et al, 2020). The recorded neurons (12 neurons from 3 rats)…”

“…We have previously shown that Cre−dependent AAV expression is limited to TH+ neurons in the VTA of the TH-Cre rat (Liu et al, 2020). Here eYFP and mCherry labelling was detected using single-colour peroxidase immunohistochemistry.…”

Associative processes in addiction relapse models: A review of their Pavlovian and instrumental mechanisms, history, and terminology

“…They found that inactivation of the prelimbic cortex reduced contextual renewal but increased responding during reacquisition [60]. These neurobiological differences were recently extended to the pattern of activation in the mesolimbic dopamine system, such as the medial ventral tegmental area, which was required for reacquisition but not renewal [61]. While rapid reacquisition is generally an underutilised paradigm in drug self-administration studies [62], these neurobiological findings indicate that contextual renewal and rapid reacquisition are dissociable, suggesting that mechanisms other than renewal contribute to rapid reacquisition.…”

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.…”