| Despite decades of research and billions of dollars spent on prevention and treatment, drug addiction remains a significant societal problem. Recent work indicates that addiction involves long-lasting changes in neuronal circuits. This involves cellular mechanisms common to other well-characterized forms of synaptic plasticity, such as regulated trafficking of AMPA-type glutamate receptors in and out of synapses. I developed a novel protein crosslinking assay to monitor redistribution of AMPA receptors between intracellular and cell surface compartments as a result of in vivo treatments. The assay was applied to an animal model of addiction termed behavioral sensitization in which repeated cocaine exposure leads some animals to develop enhanced or sensitized responses to cocaine. Incentive motivational effects of cocaine also undergo sensitization. Rats that developed behavioral sensitization exhibited a shift of AMPA receptors from intracellular compartments to the cell surface. This emerged early in withdrawal and was maintained for weeks. However, a single cocaine injection during withdrawal reversed the effect. As AMPA receptor transmission in the nucleus accumbens is required for drug-seeking behavior, increased AMPA receptor surface expression may explain increased drug-seeking behavior in cocaine sensitized rats. Signaling pathways that might underlie AMPA receptor redistribution were examined. Increased AMPA receptor surface expression was accompanied by activation of extracellular signal-regulated protein kinase 2 throughout the withdrawal period. Gradually developing changes in protein kinase A signaling were also observed. Finally, surface expression of particular transmembrane AMPA receptor regulatory proteins (TARPs) was increased in association with increased AMPA receptor surface expression during withdrawal. TARPs are required for AMPA receptor surface and synaptic expression, so cocaine effects on TARPs may underlie increased AMPA receptor surface expression. These results characterize a novel cellular adaptation in the nucleus accumbens that may underlie sensitization of incentive-motivational effects of cocaine. |
