Activation of mACh Receptors, but Not the nACh Receptors, in VTA Ameliorates Anxiety-Like Behaviors in PTSD Model Rats

Accumulating preclinical and clinical evidence implicates ventral tegmental area (VTA) dysfunction in post-traumatic stress disorder (PTSD) onset and progression. The VTA receives abundant cholinergic afferent innervations and expresses multiple cholinergic receptors. Nonetheless, it is unclear how cholinergic tone in the VTA modulates PTSD-related behaviors. In this study, we examined the effects of cholinergic modulation in the VTA on PTSD-like behaviors in rats. Rats were subjected to single-prolonged stress for PTSD modeling and cannulae implantation into the bilateral VTA for infusion of nicotinic and muscarinic cholinergic drugs. Animals receiving cholinergic drug or vehicle (control) infusion were then examined for PTSD-associated anxiety behaviors in the open field (OF) and elevated plus maze (EPM). Compared to vehicle infusion, the muscarinic cholinergic receptor (mAChR) agonist oxotremorine-M enhanced distance travelled and central time in the OF as well as open arm time and distance in the EPM, while the nicotinic cholinergic receptor (nAChR) agonist nicotine had no detectable effect on behaviors in either test. Conversely, the mAChR antagonist atropine tended to reduce distance travelled and central time in the OF as well as open arm time and distance in the EPM. Thus, mAChR activation rescued while mAChR inactivation exacerbated PTSD-associated anxiety phenotypes. These findings provide a rationale for clinical trials examining enhanced VTA mAChR activation as a treatment strategy for PTSD.