{Reference Type}: Journal Article
{Title}: Arrestin-3-assisted activation of JNK3 mediates dopaminergic behavioral sensitization.
{Author}: Ahmed MR;Zheng C;Dunning JL;Ahmed MS;Ge C;Pair FS;Gurevich VV;Gurevich EV;
{Journal}: Cell Rep Med
{Volume}: 5
{Issue}: 7
{Year}: 2024 Jul 16
{Factor}: 16.988
{DOI}: 10.1016/j.xcrm.2024.101623
{Abstract}: In rodents with unilateral ablation of neurons supplying dopamine to the striatum, chronic treatment with the dopamine precursor L-DOPA induces a progressive increase of behavioral responses, a process known as behavioral sensitization. This sensitization is blunted in arrestin-3 knockout mice. Using virus-mediated gene delivery to the dopamine-depleted striatum of these mice, we find that the restoration of arrestin-3 fully rescues behavioral sensitization, whereas its mutant defective in c-Jun N-terminal kinase (JNK) activation does not. A 25-residue arrestin-3-derived peptide that facilitates JNK3 activation in cells, expressed ubiquitously or selectively in direct pathway striatal neurons, also fully rescues sensitization, whereas an inactive homologous arrestin-2-derived peptide does not. Behavioral rescue is accompanied by the restoration of JNK3 activity, as reflected by JNK-dependent phosphorylation of the transcription factor c-Jun in the dopamine-depleted striatum. Thus, arrestin-3-assisted JNK3 activation in direct pathway neurons is a critical element of the molecular mechanism underlying sensitization upon dopamine depletion and chronic L-DOPA treatment.