Optogenetic stimulation of transmission from prelimbic cortex to nucleus accumbens core overcomes resistance to venlafaxine in an animal model of treatment-resistant depression

Our earlier study demonstrated that repeated optogenetic stimulation of afferents from ventral hippocampus (vHIP) to the prelimbic region of medial prefrontal cortex (mPFC) overcame resistance to antidepressant treatment in Wistar-Kyoto (WKY) rats. These results suggested that antidepressant resistance may result from an insufficiency of transmission from vHIP to mPFC. Here we examined whether similar effects can be elicited from major output of mPFC; the pathway from to nucleus accumbens core (NAc). WKY rats were subjected to Chronic Mild Stress and were used in two sets of experiments: 1) they were treated acutely with optogenetic stimulation of afferents to NAc core originating from the mPFC, and 2) they were treated with chronic (5 weeks) venlafaxine (10 mg/kg) and/or repeated (once weekly) optogenetic stimulation of afferents to NAc originating from either mPFC or vHIP. Chronic mild stress procedure decreased sucrose intake, open arm entries on elevated plus maze, and novel object recognition test. Acute optogenetic stimulation of the mPFC-NAc and vHIP-NAc pathways had no effect in sucrose or plus maze tests, but increased object recognition. Neither venlafaxine nor mPFC-NAc optogenetic stimulation alone was effective in reversing the effects of CMS, but the combination of chronic antidepressant and repeated optogenetic stimulation improved behaviour on all three measures. The synergism between venlafaxine and mPFC-NAc optogenetic stimulation supports the hypothesis that the mechanisms of non-responsiveness of WKY rats involves a failure of antidepressant treatment to restore transmission in the mPFC-NAc pathway. Together with earlier results, this implicates insufficiency in a vHIP-mPFC-NAc circuit in non-responsiveness to antidepressant drugs. •Chronic mild stress procedure causes anhedonia, anxiety and cognitive deficit in Wistar-Kyoto rats.•None of these effects are reversed by chronic administration of venlafaxine.•. Repeated optogenetic stimulation of medial prefrontal cortex to nucleus accumbens pathway enables response to venlafaxine•These results implicate insufficiency in a vHIP-mPFC-NAc circuit in non-responsiveness to antidepressant drugs.