Optogenetic mimicry of drug action: Tools and models to dissect the dopamine-dependent core of addiction.

Drug addiction is characterized by compulsive drug use despite negative consequences, reflecting maladaptive changes in brain circuits. Elucidating the underlying neural mechanisms relies on animal models that capture core features of the disorder. Here, we review optogenetic mimicry mouse models that leverage a defining core of addictive drugs-their ability to elevate mesolimbic dopamine. Analogous to gold-standard pharmacological self-administration paradigms, these models allow animals to self-induce dopamine transients either directly, via optogenetic activation of ventral tegmental area dopamine neurons, or indirectly, via optogenetic inhibition of midbrain GABA interneurons. Both protocols are robustly reinforcing and induce lasting behavioral and synaptic adaptations. We compare these adaptations with those observed in established rodent models of psychostimulant and opioid addiction. We argue that optogenetic mimicry of drug-evoked mesolimbic dopamine transients recapitulates key features of addiction while uniquely enabling cell-type- and circuit-specific mechanistic investigations of reinforcement and maladaptive plasticity.