Infralimbic D1 receptor agonist effects on spontaneous novelty exploration and anxiety-like defensive responding in CD-1 mice

Abstract

Mesocortical dopamine (DA) terminals in the ventromedial prefrontal cortex (vmPFC) integrate cognitive/emotional processing functions underlying adaptive and appropriate behavioral responding to stressful environmental events. Results from several studies have also shown that stressor-enhanced prefrontal DA activation exerts detrimental effects on cognitive performance. However, questions have arisen as to whether stressor-enhanced vmPFC DA transmission exerts direct control over conditioned or unconditioned responses to threatening events, or whether enhanced prefrontal DA transmission gates cognitive processing to facilitate adaptive responding in threatening situations. We have previously shown that infralimbic (IL) vmPFC dopamine D2 agonist and antagonist drug infusions reduced anxiety-like responding in the elevated plus-maze (EPM) and disrupted spontaneous exploration in the Y-maze in CD-1 mice. In the present study, the effects of IL vmPFC infusions of the specific D1 receptor agonist, SKF-81297, in CD-1 mice were evaluated on spontaneous exploration in the Y-maze, anxiety-like responding in a 2-trial elevated plus-maze procedure, and anti-predator defensive responding in the Mouse Defense Test Battery (MDTB). SKF-81297 infusions disrupted spontaneous alternation performance along with potentiated repetitive 2-arm responding in the Y-maze. In the elevated plus-maze, pre-trial 1 IL SKF-81297 infusions reduced anxiety-like responding (enhanced open arm entries and time ratio, unprotected stretch attends and head dips), and reduced closed arm time ratio and protected risk assessment activity (protected stretch attends). In trial 2, 24h later (no drug infusions), open arm entries, open time ratio, and unprotected head dips remained enhanced relative to trial 2 vehicle controls. In the MDTB, avoidance distance was enhanced in the approach test; risk assessment (approach) was enhanced in the closed alley test; and defensive threat (upright postures) was enhanced in the forced contact test. Results are discussed with respect to possible influences of IL vmPFC DA receptors on cognitively mediated responding to differing levels of threat in mice.