UC San Diego

Natural rewards and addictive drugs increase the release of dopamine (DA) in the brain's reward circuit by augmenting the activity of dopaminergic neurons in the ventral tegmental area (VTA). Exposure to drugs of abuse produces persistent adaptations in neural signaling, both excitatory and inhibitory. G protein-gated inwardly rectifying potassium (GIRK or Kir3) channels activate a slow inhibitory postsynaptic current in dopamine neurons mediated by GABA(B) or D2 receptors and are involved in the response to multiple drugs of abuse. How the psychostimulants methamphetamine or cocaine affect GIRK channel signaling, however, remains unclear. This thesis describes novel mechanisms of GIRK channel plasticity and regulation in VTA dopamine and GABA neurons in response to methamphetamine. Activation of dopamine neurons induces a biphasic response of GABA(B)R-GIRK signaling in VTA, with short-term drug exposure down-regulating GABA(B)R-GIRK signaling in GABA neurons, increasing VTA inhibition, while repeated methamphetamine exposure down-regulates GABA(B)R-GIRK currents in DA neurons through a mechanism involving GIRK3-containing channels, dis-inhibiting DA neurons. SNX27 is an endosomal trafficking protein that regulates the surface expression and signaling of GIRK3 channels and is inducible by repeated exposure to psychostimulants. Through conditional deletion of SNX27, I describe the first neuronal function of a sorting nexin in vivo, which is regulation of GABA(B)R-GIRK signaling and inhibitory control of VTA DA neurons. Mice lacking SNX27 in DA neurons display hyperlocomotion in a novel environment and an enhanced sensitivity to the locomotor- stimulant effects of cocaine, suggesting that SNX27 regulation of GIRK channel signaling is involved in addictive behaviors. The data presented in this dissertation thus identify novel mechanisms of psychostimulant-induced plasticity in the VTA and highlight SNX27 and GIRK channels as promising therapeutic targets for addiction and other complex psychiatric disorders