TY - JOUR T1 - Nociceptin/Orphanin FQ Modulation of Ionic Conductances in Rat Basal Forebrain Neurons JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 188 LP - 195 DO - 10.1124/jpet.102.037945 VL - 303 IS - 1 AU - J. H. Chin AU - K. Harris AU - D. MacTavish AU - J. H. Jhamandas Y1 - 2002/10/01 UR - http://jpet.aspetjournals.org/content/303/1/188.abstract N2 - Nociceptin/orphanin FQ (N/OFQ) is an endogenous opioid-like heptadecapeptide that plays an important role in a variety of physiological functions. N/OFQ and its receptor opioid receptor-like orphan receptor-1 are abundant in the diagonal band of Broca (DBB), a basal forebrain nucleus where the loss of cholinergic neurons is linked to memory and spatial learning deficits. In the whole animal, central injections of N/OFQ have been shown to disrupt spatial learning. In this study, we investigated the basis for these behavioral observations by examining the cellular effects of N/OFQ on chemically identified DBB neurons. Whole cell patch-clamp recordings were performed on enzymatically dissociated DBB neurons. Under voltage-clamp conditions, bath application of N/OFQ (10 pM–1 μM) resulted in a dose-dependent depression of whole cell currents. Single cell reverse transcription-polymerase chain reaction analysis identified cholinergic and fewer GABAergic cells to be N/OFQ-responsive. [Nphe1]nociceptin-(1-13)-NH2 and CompB (J-113397) antagonized the N/OFQ response, but both compounds also displayed partial agonist activity. Using a combination of channel blockers we determined that the effects of N/OFQ were mediated via a suite of Ca2+ (N- and L-type) and Ca2+-dependent K+ (iberiotoxin-sensitive) conductances. In addition, biophysical analysis of voltage subtraction protocols revealed that N/OFQ reduces transient outward and the delayed rectifier K+ currents. Because N-type and L-type Ca2+ channels are important in the context of neurotransmitter release, our observations indicate that N/OFQ inhibition of Ca2+-dependent conductances in cholinergic neurons would be expected to result in depression of acetylcholine release, which may explain the behavioral actions of N/OFQ in the brain. The American Society for Pharmacology and Experimental Therapeutics ER -