Abstract
The dopamine (DA) hypothesis posits the increase of mesolimbic dopamine levels as a defining commonality of addictive drugs, initially causing reinforcement, eventually leading to compulsive consumption. While much experimental evidence from psychostimulants supports this hypothesis, it has been challenged for opioid reinforcement. Here, we monitor genetically encoded DA and calcium indicators as well as cFos in mice to reveal that heroin activates DA neurons located in the medial part of the VTA, preferentially projecting to the medial shell of the nucleus accumbens (NAc). Chemogenetic and optogenetic manipulations of VTA DA or GABA neurons establish a causal link to heroin reinforcement. Inhibition of DA neurons blocked heroin self-administration, while heroin inhibited optogenetic self-stimulation of DA neurons. Likewise, heroin occluded the self-inhibition of VTA GABA neurons. Together, these experiments support a model of disinhibition of a subset of VTA DA neurons in opioid reinforcement.
Highlights
The DA hypothesis of drug reinforcement is rooted in the observation that electrical activation of the medial forebrain bundle leads to repetitive action (Olds and Milner, 1954)
We found that heroin increases DA in the nucleus accumbens (NAc) through the activation of a subset of VTA DA neurons located in the medial VTA, which preferentially project to the NAc medial shell
The VTA consists of DA (60–65%), GABA (30–35%), glutamate (2%) and neurons that express more than one marker (Margolis et al, 2006; Nair-Roberts et al, 2008; Roberts and Ribak, 1987; Steffensen et al, 1998; Yamaguchi et al, 2011)
Summary
The DA hypothesis of drug reinforcement is rooted in the observation that electrical activation of the medial forebrain bundle leads to repetitive action (Olds and Milner, 1954). Based on in vivo single unit and brain slice recordings, a disinhibition scenario of VTA DA neurons has been proposed (Gysling and Wang, 1983), whereby MOR activation inhibits GABA neurons (Johnson and North, 1992) through somatodendritic hyperpolarization and the reduction of the efferent release probability.
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