THE MEMBRANE HYPERPOLARIZATION OF RAT DORSOLATERAL SEPTAL NUCLEUS NEURONS IS MEDIATED BY A NOVEL NICOTINIC RECEPTOR

The pharmacology, calcium dependence and G protein mediation of the me mbrane hyperpolarization of rat dorsolateral septal nucleus (DLSN) neu rons in response to nicotinic agonists was examined to classify the ni cotinic receptor mediating the response. Intracellular recording from DSLN neurons in a brain slice preparation was used to determine whethe r chlorisondamine, trimethaphan, cytisine or strychnine inhibited the membrane hyperpolarization in response to application of the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP). Chlorisondamine was found to block the response only at a high concentration (500 mu M) a lthough strychnine (100 mu M) was without effect, Cytisine was neither an effective agonist nor an antagonist (500 mu M). Surprisingly, trim ethaphan appeared to act as an agonist, rather than an antagonist, wit h a potency and efficacy similar to that reported for nicotine at this receptor. The response was dependent on intracellular calcium stores because it persisted in the absence of extracellular calcium but was b locked by intracellular injection of ,2-bis(2-aminophenoxy)ethane-N,N, N',N'-tetraacetic acid (BAPTA). Injection of GTP gamma S into the neur ons blocked the nicotinic response. Apamin, iberiotoxin and charybdoto xin reduced but did not block the response at concentrations that sele ctively block calcium-dependent potassium channels. These results indi cate that the nicotinic response in DLSN neurons may be mediated by a metabotropic nicotinic receptor coupled to a calcium-dependent potassi um channel through the activation of a G-protein and release of intrac ellular calcium stores. The unusual pharmacology of the nicotinic rece ptor on DLSN neurons indicates that it may be a novel receptor which h as yet to be cloned.