cAMP-Fyn signaling in the dorsomedial striatum direct pathway drives excessive alcohol use

Abstract

Fyn kinase in the dorsomedial striatum (DMS) of rodents plays a central role in mechanisms underlying excessive alcohol intake. The DMS is comprised mostly of medium spiny neurons (MSNs) that are divided into dopamine D1 receptor expressing neurons (dMSNs), and dopamine D2 receptor expressing neurons (iMSNs). Here, we examined the cell-type specificity of Fyn's actions on the development of alcohol use. First, we knocked down Fyn selectively in DMS dMSNs or iMSNs of mice and measured the level of alcohol consumption. We found that downregulation of Fyn in dMSNs, but not in iMSNs, reduces excessive alcohol but not saccharin intake and preference. D1Rs are coupled to Gαs/olf, which activate cAMP signaling. To examine whether Fyn's actions are mediated through cAMP signaling, DMS dMSNs were infected with GαsDREADD, and the activation of Fyn signaling was measured following CNO treatment. We found that remote stimulation of cAMP signaling in DMS dMSNs activates Fyn and promotes the phosphorylation of the Fyn substrate, GluN2B. Next, we tested whether remote activation of GαsDREADD in DMS dMSNs or iMSNs alters alcohol intake, and observed that CNO-dependent activation of GαsDREADD in DMS dMSNs but not iMSNs increases alcohol but not saccharin intake and preference. Finally, we examined the contribution of Fyn to GαsDREADD-dependent increase in alcohol intake, and found that systemic administration of the Fyn inhibitor, AZD0503 blocks GαsDREADD-dependent increase in alcohol consumption.Our results suggest that the cAMP-Fyn axis in the DMS dMSNs is a molecular transducer of mechanisms underlying the development of excessive alcohol consumption.

The BDNF Val68Met polymorphism causes a sex specific alcohol preference over social interaction and also acute tolerance to the anxiolytic effects of alcohol, a phenotype driven by malfunction of BDNF in the ventral hippocampus of male mice

“…In addition, sex differences in social behavior have been widely described [57][58][59][60][61][62], and are likely to be caused by differences in neuronal activity, receptor density and hormonal signaling. However, further studies are needed to determine whether BDNF in female mice plays a role in other behaviors, including gating alcohol use [63], which is mediated in part via corticostriatal circuitries [31].…”

“…Met68BDNF mice (8-10 weeks old) underwent stereotaxic surgery as described in [14, 32] targeting the vHC (Franklin and Paxinos stereotaxic atlas, 3rd edition). Specifically, mice were anesthetized by vaporized isoflurane, and were placed in a digital stereotaxic frame (David Kopf Instruments, Tujunga, CA).…”

“…Characterization of infection and overexpression was performed as described previously [14, 32]. At the end of experiments animals were euthanized by cervical dislocation, and the brains were removed.…”