Differential effects of intra-RMTg infusions of pilocarpine or 4-DAMP on regulating depression- and anxiety-like behaviors

Depression and anxiety are associated with dysfunction of the mesolimbic dopamine system. The rostromedial tegmental nucleus (RMTg) is predominantly composed of GABAergic neurons that exhibit dense projections and strongly inhibit mesolimbic dopaminergic neurons, proposed as a major "brake" for the system. Consequently, the RMTg may be a crucial brain region for regulating these emotions. The central cholinergic system, particularly the muscarinic receptors, plays an important regulatory role in depression and anxiety. M3 muscarinic receptors are distributed on GABAergic neurons in the RMTg, but their involvement in the regulation of depression and anxiety remains uncertain. This study aimed to examine the effects of RMTg M3 muscarinic receptors on regulating depression- and anxiety-like behaviors in adult male Wistar rats, as assessed through the forced swim, tail suspension, and elevated plus maze tests. The results showed that intra-RMTg injections of the M1/M3 muscarinic receptors agonist, pilocarpine (3, 10, and 30 mu g/side), or the M3 muscarinic receptors antagonist, 4-DAMP (0.5, 1, and 2 mu g/side), did not alter the immobility time in the forced swim and tail suspension tests. Additionally, pilocarpine (30 mu g/side) decreased time spent in open arms and increased time in closed arms in the elevated plus maze; while 4-DAMP (1 and 2 mu g/side) played the opposite role by increasing time spent in open arms and decreasing time in closed arms. These findings suggest that RMTg M3 muscarinic receptors have differential effects on regulating depression- and anxiety-like behaviors. Enhancing or inhibiting these receptors can produce anxiogenic or anxiolytic effects, but have no impact on depression-like behavior. Therefore, RMTg M3 muscarinic receptors are involved in regulating anxiety and may be a potential therapeutic target for anxiolytic drugs.