Effects of brief inhibition of the ventral tegmental area dopamine neurons on the cocaine seeking during abstinence

Abstract

Preclinical studies strongly suggest that cocaine seeking depends on the neuronal activity of the ventral tegmental area (VTA) and phasic dopaminergic (DA) signaling. Notably, VTA pharmacological inactivation or dopamine receptor blockade in the forebrain may induce behavioral inhibition in general and acute aversive states in particular, thus reducing cocaine seeking indirectly. Such artifacts hinder successful translation of these findings in clinical studies and practice. Here, we aimed to evaluate if dynamic VTA manipulations effectively reduce cocaine seeking. We used male tyrosine hydroxylase (TH) IRES-Cre + rats along with optogenetic tools to inhibit directly and briefly VTA DA neurons during conditioned stimulus (CS)-induced cocaine seeking under extinction conditions. The behavioral effects of optogenetic inhibition were also assessed in the real-time dynamic place aversion, conditioned place aversion, and CS-induced food-seeking tests. We found that brief and nondysphoric/nonsedative pulses of VTA photo-inhibition (1 s every 9 s, ie, for 10% of time) attenuated CS-induced cocaine seeking under extinction conditions in rats expressing archaerhodopsin selectively on the TH + neurons. Furthermore, direct inhibition of the VTA DA activity reduced CS-induced cocaine seeking 24 hours after photo-modulation. Importantly, such effect appears to be selective for cocaine seeking as similar inhibition of the VTA DA activity had no effect on CS-induced food seeking. Thus, briefly inhibiting VTA DA activity during CS-induced cocaine seeking drastically and selectively reduces seeking without behavioral artifacts such as sedation or dysphoria. Our results point to the therapeutic possibilities of coupling nonpharmacologic treatments with extinction training in reducing cocaine addiction. KEYWORDS cocaine craving, cue-evoked cocaine seeking, dopamine, photo-inhibition, ventral tegmental area 1 | INTRODUCTION Drug craving, defined as an overwhelming desire or drive to take the drug, is increasingly understood as a crucial psychopathological component of substance use disorder (SUD), where it drives substance abuse and impedes treatment by decreasing the motivation for abstinence. 1,2 Cravings usually emerge during periods of drug abstinence and are potently evoked by both discreet and contextual cues previously associated with the drug. Thus, exposure to drugassociated conditioned stimuli (CSs) during abstinence actively

The Role of Dorsal Raphe Serotonin Neurons in the Balance between Reward and Aversion

“…A previous report has shown that lowering the activity of VTA dopamine neurons can induce aversive response and behavior [57]. Moreover, Solecki et al have shown that photoinhibition of VTA dopamine neurons reduced the motivation to seek cocaine [58]. Taken together with our result indicating that inhibition of 5-HT projection from the DRN to the VTA is aversive, it is possible that craving-like behavior induced by drugs of abuse may be suppressed by drugs that selectively inhibit 5-HT neurons projecting from the DRN to the VTA.…”

Gene Expression Changes in the Ventral Tegmental Area of Male Mice with Alternative Social Behavior Experience in Chronic Agonistic Interactions

“…The VTA is one of the major sites of dopamine synthesis. The VTA dopaminergic neurons are implicated in the regulation of emotional and motivational behaviors and are involved in the development of psychopathologies including depression [ 50 ], aggression [ 51 ], and addictions [ 52 , 53 ]. So, it was important to check if the prioritized genes could be implicated in VTA dopaminergic signaling.…”

Cell-type specialization in the brain is encoded by specific long-range chromatin topologies

“…In mESCs, about one fifth of genes are marked by H3K27me3, a repressive histone mark catalysed by Polycomb Repressor Complex 2 (PRC2), which partially resolves through neuronal differentiation 26 (GO:0007611), both critical functions of PGNs 29,30 . Polycomb-classified DN-specific genes in cluster 7 have GO terms including 'response to cocaine' (GO:0042220) and 'response to alcohol' (GO:0097305), highlighting their role in dopamine-receptor responses related to reward-based learning 39,40 . Together, these data suggest that many differentially expressed genes critical for cell specialization can be found within compartment A irrespectively of cell type, and are regulated through specialized mechanisms such as Polycomb repression.…”