In mammalian studies of nicotine addiction, nicotinic acetylcholine receptor activation reportedly acts to disinhibit reward signaling by suppressing GABA release (D'Souza and Markou, 2011). As well, it has been recently reported that a subset of neurons in the rodent hippocampus co-release GABA and acetylcholine (Saunders et al, 2015). Thus, it is of interest to describe how nicotinic receptor activation and GABA signaling may interact in neurons. C. elegans is an ideal model as both GABA and acetylcholine receptors are co-expressed at the NMJ. Mobility resulting from NMJ signaling has been well-described as relying on alternating activation of cholinergic and GABA receptors to produce contraction and simultaneous relaxation of opposing body wall muscles, respectively. Thus, the C. elegans NMJ is a site where direct interaction between excitatory cholinergic and inhibitory GABAergic signaling likely occurs. Studies from other labs confirm that cholinergic NMJ signaling can be modulated, seen as altered surface expression of acr-16 nicotinic Ach receptors (Jensen et al., 2012). Previous studies from this lab have quantified changes in nicotinic Ach and GABA receptor transcripts in adult worms following exposure to nicotine during development (Rose et al., 2013). More recently, we have found in adult worms that application of nicotine (30 microM) for 24 hours significantly increases UNC-49::GFP GABA receptor expression (p<0.05) while SNB-1::GFP synaptobrevin expression in motor neurons appears relatively unchanged. Conversely, exposure to the inhalant drug toluene (a GABA agonist) results in increased SNB-1::GFP expression in motor neurons (p<0.05) with seemingly no change in UNC-49::GFP expression. This increase in presynaptic GABA elements was further supported using qRT-PCR where a significant increase in unc-47 (vesicular GABA transporter) transcripts was found (p<0.01). With regards to mobility, these differences in expression appear to correlate with decreased swim motion (measured as body bends) following application of either nicotine or toluene (p<0.05 compared to controls). Interestingly, application of nicotine following toluene exposure seems to rescue the toluene-induced decrease in mobility. This suggests that the effects of one drug may offset the effects of the other potentially by returning to balance the drug altered pre- and post-synaptic GABA signaling elements. Taken together, these results demonstrate a potential role for GABA in both nicotine and toluene addiction. Funding support from WWU Research and Sponsored Programs Project Development Award..

Affiliation:
- Behavioral Neuroscience Program and Dept Psychology, Western Washington University, BELLINGHAM, WA