Infralimbic kappa opioid and muscarinic M1 receptor interactions in the concurrent modulation of anxiety and memory

Rationale: Spontaneous working memory and anxiety-like behaviour can be concurrently influenced following kappa opioid or muscarinic M 1 antagonist infusions in the infralimbic (IL) area of the ventromedial prefrontal cortex (vmPFC) in CD-1 mice. Further dose-response analyses of our previous norBNI and pirenzepine data revealed significant dose x drug interactions on trial-1 and -2 anxiety-related elevated plus-maze indices. These data prompted us to evaluate the effects of simultaneous IL norBNI/pirenzepine infusions on anxiety and spontaneous working memory. Objective: The present study sought to evaluate whether (a) our previously reported anxiogenic and working memory disruptive effects of norBNI, and anxiolytic and working memory disruptive effects of pirenzepine data could be replicated using the most effective dose (10 nmol) of each drug and (b) IL infusions of mixed kappa/M1 receptor inhibitor drugs might interactively influence these cognitive, behavioural processes. Methods: Anxiety was evaluated in the elevated plus maze, and spontaneous alternation memory was evaluated in the Y-maze following pirenzepine, norBNI or two levels of norBNI/pirenzepine drug mix infusions in the IL vmPFC. Results: Pretreatment with the M 1 antagonist pirenzepine was anxiolytic in trial 1 (10 nmol) and trial 2 (no-injection) in the elevated plus maze 24 h later, and disrupted alternation performance and some aspects of attention in the Y-maze. Pretreatment with the kappa antagonist norBNI was anxiogenic in trial 1 (10 nmol) and trial 2 (no-injection) in the elevated plus maze 24 h later, and also disrupted alternation performance and some aspects of attention in the Y-maze. The norBNI-10 nmol/pirenzepine-10 nmol mixed drug infusion was somewhat anxiogenic in trial 1, exerted no carry-over effects in trial 2 in the elevated plus maze, and disrupted alternation memory and some aspects of attention in the Y-maze. The norBNI-5 nmol/pirenzepine-10 nmol drug mix had no effect on trial-1 or -2 anxiety measures in the elevated plus maze, yet also disrupted Y-maze spontaneous memory performance. Conclusions: (1) The effects of IL infusions of norBNI or pirenzepine (10 nmol/0.5 mul) alone on anxiety-like behaviour and aversive learning and memory in the elevated plus-maze replicated previously reported data. (2) Mixed M1/kappa receptor inhibition in the IL cortex exerted counteractive effects on anxiety-like behaviour and aversive learning in the elevated plus maze. (3) Mixed M1/kappa receptor inhibition appeared to exert additive disruptive effects on alternation performance and aspects of attention related to active working memory in the Y-maze.