Regulation of cocaine seeking behavior by locus coeruleus noradrenergic activity in the ventral tegmental area is time- and contingency-dependent

Abstract

Substance use disorder is linked to impairments in the ventral tegmental area (VTA) dopamine (DA) reward system. Noradrenergic (NA) inputs from locus coeruleus (LC) into VTA have been shown to modulate VTA neuronal activity, and are implicated in psychostimulant effects. Phasic LC activity controls time- and context-sensitive processes: decision making, cognitive flexibility, motivation and attention. However, it is not yet known how such temporally-distinct LC activity contributes to cocaine seeking. In a previous study we demonstrated that pharmacological inhibition of NA signaling in VTA specifically attenuates cocaine-seeking. Here, we used virally-delivered opsins to target LC neurons for inhibition or excitation, delivered onto afferents in VTA of male rats seeking cocaine under extinction conditions. Optogenetic stimulation or inhibition was delivered in distinct conditions: upon active lever press, contingently with discreet cues; or non-contingently, i.e., throughout the cocaine seeking session. Non-contingent inhibition of LC noradrenergic terminals in VTA attenuated cocaine seeking under extinction conditions. In contrast, contingent inhibition increased, while contingent stimulation reduced cocaine seeking. These findings were specific for cocaine, but not natural reward (food) seeking. Our results show that NA release in VTA drives behavior depending on timing and contingency between stimuli – context, discreet conditioned cues and reinforcer availability. We show that, depending on those factors, noradrenergic signaling in VTA has opposing roles, either driving CS-induced drug seeking, or contributing to behavioral flexibility and thus extinction.

Exploring distinct and joint contributions of the Locus Coeruleus and the Substantia Nigra/Ventral Tegmental Area complex to reward and valence processing using high-resolution fMRI

“…Regarding the directionality of the influence, on the one hand it has been suggested based on animal models that the VTA triggers phasic activation of the LC in response to reward-predicting stimuli, which in turn serves further allocation of attention (Hofmeister & Sterpenich, 2015). On the other hand, animal addiction models posit that LC inputs to the VTA can modulate drug-seeking behaviour (Solecki et al, 2022) – which relies on the same dopaminergic circuits as reward processing. While these are interesting avenues for further research, the present data is considered merely exploratory in this regard.…”