These observations are indicative of an innate upregulation of the N/OFQ-NOP system in msP rats. However, while a consistent up-regulation of NOP receptor expression, binding and signaling was observed in msP rats in a majority of brain regions, a distinct and unexpected pattern of differences was found in the CeA. In this brain region, N/OFQ-stimulated [35S]GTPγS binding was significantly lower in msP than in Wistars despite elevated NOP receptor expression and binding in the msP line. This finding suggests that although the N/OFQ system is generally upregulated in msP rats, “uncoupling” of the NOP receptor from G-protein-mediated signal transduction in CeA leads to a regionally-selective dysfunction of the N/OFQ system in the CeA. Consistent with the reduction of ethanol intake by N/OFQ in msP rats, the hypofunction of the system in the CeA may facilitate alcohol drinking in this line of rats. This hypothesis is supported by data showing that stimulation of NOP receptors in the CeA by site-specific microinjection of N/OFQ reduces alcohol self-administration in msP rat (Economidou et al., 2008).
