Pyk2 in D1 receptor-expressing neurons of the nucleus accumbens modulates the acute locomotor effects of cocaine

Abstract

The striatum is a critical brain region for locomotor response to cocaine. Although the D1 receptor-expressing neurons are centrally involved in mediating the locomotor effects of cocaine, the molecular pathways controlling this response are not fully understood. Here we studied the role of Pyk2, a non-receptor calcium-dependent protein-tyrosine kinase, in striatum-related functions. We discovered that cocaine injection increases Pyk2 phosphorylation in the striatum of mice in vivo. Pyk2-deficient mice displayed an altered locomotor response to acute cocaine injection. In contrast, they developed normal locomotor sensitization and cocaine-conditioned place preference. Accordingly, a cocaine-activated signaling pathway essential for these late responses, ERK phosphorylation, was not altered.Specific deletion of Pyk2 in the nucleus accumbens or in D1 neurons reproduced this phenotype, whereas deletion of Pyk2 in the dorsal striatum or in A2A receptor-expressing neurons did not. Mice lacking Pyk2 in D1-neurons also displayed lower locomotor response to the D1 receptor agonist SKF-81297 but not to an anticholinergic drug. Our results identify Pyk2 as a regulator of acute locomotor responses to psychostimulants and suggest that changes in Pyk2 expression or activation may alter specific responses to drugs of abuse, or possibly other behavioral responses linked to dopamine action.

Pyk2 Stabilizes Striatal Medium Spiny Neuron Structure and Striatal-Dependent Action

“…A Western blot analysis was used to evaluate the relative expression levels of Pyk2 in the striatum vs. other regions of the brain. As demonstrated in Figure 1 A, and in agreement with previous studies [ 29 , 30 , 31 ], Pyk2 is highly expressed in the striatum relative to thalamus, dorsal raphe nucleus, or hypothalamus, and similar in expression levels to the thymus, a hematopoietic organ in which Pyk2 is highly expressed.…”

“…A Western blot analysis was used to evaluate the relative expression levels of Pyk2 in the striatum vs. other regions of the brain. As demonstrated in Figure 1A, and in agreement with previous studies [29][30][31], Pyk2 is highly expressed in the striatum relative to thalamus, dorsal raphe nucleus, or hypothalamus, and similar in expression levels to the thymus, a hematopoietic organ in which Pyk2 is highly expressed. Next, we measured PSD-95, a post-synaptic marker, in the striatum of Ptk2b −/− mice, revealing lower levels (t 4 = 3.319, p = 0.04) (Figure 1B), as also occurs in the Ptk2b −/− hippocampus [12].…”