Effects of protein kinase A inhibitor and activator on rewarding effects of SKF-82958 microinjected into nucleus accumbens shell of ad libitum fed and food-restricted rats

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Abstract
Rationale Previous studies indicate that the rewarding effect of D-1 dopamine receptor stimulation in nucleus accumbens (NAc) shell is greater in food-restricted (FR) than in ad libitum fed (AL) rats. The D-1 receptor is positively coupled to adenylyl cyclase and activates protein kinase A (PKA). Objectives The purpose of this study was to determine whether PKA is involved in the rewarding effect of D-1 receptor stimulation and, if so, whether it is involved in the enhanced response of FR rats. Materials and methods Rats were stereotaxically implanted with microinjection cannulae in NAc shell and a stimulating electrode in lateral hypothalamus. The rewarding effects of SKF-82958 (1.5 or 3.0 μg, bilaterally) in the presence and absence of PKA inhibitor, Rp-cAMPS (8.9 μg), and PKA activator, Sp-cAMPS (8.9 μg), were assessed using the curve-shift method of intracranial self-stimulation (ICSS). Basal NAc levels of DARPP-32 phosphorylated on Thr34 and Thr75 were measured. Results Rp-cAMPS increased the rewarding effect of SKF-82958 in AL but not FR rats, doubling the ICSS threshold-lowering effect of the 3.0-μg dose. Sp-cAMPS decreased the rewarding effect of SKF-82958 in FR but not AL rats. Levels of phospho-DARPP-32 (Thr75), which inhibits PKA, were higher in FR than AL rats. Conclusions Results indicate that inhibition of PKA enhances the unconditioned rewarding effect of D-1 receptor stimulation and that decreased PKA may be involved in the effect of FR on drug reward. Evidence for involvement of D-2 receptor-expressing neurons in the enhancing effect of PKA inhibition is discussed.

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