Dopamine neurons projecting to medial shell of the nucleus accumbens drive heroin reinforcement

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.

One Is Not Enough: Understanding and Modeling Polysubstance Use

“…PKA, CREB), (2) Gβγ-mediated activation of G protein-coupled inwardly rectifying K + (GIRK) channels, (3) Gβγ-mediated inactivation of voltage-gated Ca 2+ channels, and (4) Gβγ-mediated inhibition of SNARE-dependent vesicle release (Bourinet et al, 1996;Blanchet and Lüscher, 2002;Blackmer et al, 2005;Al-Hasani and Bruchas, 2011;Zamponi and Currie, 2013). Acute exposure to opioids inhibits VTA GABA neurons (Johnson and North, 1992;Corre et al, 2018), resulting in subsequent disinhibition of VTA DA neurons and phasic DA release into the NAc (Hemby et al, 1995;Pontieri et al, 1995). Nonetheless, although opioids facilitate DA release into the striatum, whether this DA transmission is necessary for opioid reward remains a point of debate (Badiani et al, 2011).…”

TRPM8 as the rapid testosterone signaling receptor: Implications in the regulation of dimorphic sexual and social behaviors

“…54,55 We hypothesized that activation of TRPM8 by testosterone in the amygdala causes excitatory transmissions to the VTA, which further impacts dopamine release in the NAc. This represents the main pathway of endogenous reward mechanism 52 or drug-induced reinforcement, 56 known to impact sexual experience. 51 To test this hypothesis, we assessed activation of DA neurons before and immediately after mating events of age-matched TRPM8 +/+ and TRPM8 −/− littermates using cFos as a marker of neuron activation.…”

G‐protein‐coupled receptor‐based sensors for imaging neurochemicals with high sensitivity and specificity

“…In freely behaving mice, GPCR‐based sensors have been used to report sensory stimulation‒evoked acetylcholine release and behavior‐related dopamine and norepinephrine release using fiber photometry recording and in vivo two‐photon imaging (Fig. c and d) (Jing et al ; Sun et al ; Patriarchi et al ; Corre et al ; Dong et al ; de Jong et al ; Feng et al ; Mohebi et al ). In principle, the GPCR‐based sensors could also be used together with mini‐scopes to achieve real‐time imaging of neurochemicals in free‐behaving animals.…”