Chronic baclofen treatment influences GABAB activation of G‐proteins and phosphorylation of FAK, GSK3β, and DARPP32 in mesocorticolimbic rat brain regions (1066.3)

Abstract

The GABAB receptor agonist baclofen is being explored as a potential treatment for cocaine addiction, as therapeutic activation of the GABAergic system is theorized to counterbalance over‐stimulation of the dopaminergic system in brain regions involved in reward. Rats acutely administered i.p. baclofen (5 mg/kg, single dose 15 min. prior to sacking) showed no immediate changes in GABAB‐stimulated GTPγS binding in any brain region but displayed significantly greater phosphorylation of focal adhesion kinase (FAK) in key mesocorticolimbic regions (caudate putamen, cortex, hippocampus, thalamus, and prefrontal cortex) compared to controls, as well as elevated levels of glycogen synthase kinase 3‐beta (GSK3β) phosphorylation in these and other regions (nucleus accumbens, septum, and globus pallidus). In contrast, GABAB‐stimulated GTPγS binding in rats administered chronic (5 mg/kg, t.i.d. for five days) baclofen was significantly lower in the prefrontal cortex, septum, amygdala, and parabrachial nucleus than in the controls. While chronically‐treated rats exhibited similar increases in FAK phosphorylation, they displayed attenuated levels of GSK3β phosphorylation and wide‐spread elevations in levels of DARPP32 phosphorylation compared to those treated acutely or with vehicle. These findings indicate a desensitization of GABAB‐mediated signal transduction in rats following chronic administration of baclofen.Grant Funding Source: Supported by the National Institute on Drug Abuse: R01‐DA03690 and P50‐DA006634.