Nicotinic and muscarinic acetylcholine receptors are expressed throughout the human central and peripheral nervous systems, where they are important for many processes including cognition and cardiovascular function. Arecoline, a widely consumed recreational drug, is known as an agonist for cholinergic muscarinic receptors and acts as a neurological stimulant. Although arecoline and other muscarinic agonists have been pursued as treatments for several diseases, the side effects of these drugs, including heart arrythmias and even chronic epilepsy, often prohibit further medical application. In C. elegans arecoline activates the excitatory neuronal muscarinic receptor
gar-3, affecting the pharyngeal and motor circuits(Steger et al, Genetics 2003; Chan et al, G&D. 2012). Here, we show that arecoline treatment ameliorates excitation/inhibition imbalance in the locomotor circuit. We have studied a gain-of-function mutation in the nicotinic receptor
acr-2 that mimics a similar mutation found in certain heritable epilepsies (Jospin et al, PlosB. 2009).
acr-2(gf) animals exhibit spontaneous whole-body convulsion, as the result of a hyperactive channel. Strikingly, arecoline treatment suppresses
acr-2(gf) behavioral defects. We have determined that this suppression likely involves action of arecoline on the inhibitory GABA neurons, because mutation of either
unc-25/GAD or
unc-49/GABAR completely blocks the arecoline-induced effect. Mutation of
gar-3 does not affect suppression of
acr-2(gf) by arecoline. Moreover, pre-treatment of animals with the specific muscarinic antagonist atropine does not block effect of arecoline on
acr-2(gf) behavior, supporting a non-cholinergic mechanism for this phenomenon. To identify relevant factors involved in the suppression of
acr-2(gf) by arecoline, we have performed a forward genetic screen and isolated several mutants that blocked or reduced suppression of
acr-2(gf) on arecoline. At least three mutants are alleles of
unc-49, validating the specificity of the screen and emphasizing the involvement of GABA function. Together, our results suggest a model in which the cholinergic agonist arecoline acts through the GABA system to modulate excitation/inhibition balance in the motor circuit. Our studies will elucidate novel pathways modulated by muscarinic agonists, with relevance to human neurological disorders.