We examined separate and combined effects of neonatal ventral hippocampal lesions (NVHLs)—a neurodevelopmental model of schizophrenia (vs. SHAM-operated control animals)—and a behaviorally sensitizing cocaine history (15 mg/kg/day × 5 days vs. saline injections) on acute cocaine-induced neural activation signaled by c-Fos expression. Stereological assessment of activation densities spanned six ventral to dorsal cortical-striatal compartments.
Cortically, NVHLs showed hypoactivation and decreased volume of the ventral medial prefrontal cortex. In contrast, cocaine history was only expressed subcortically and as a hyperactivating effect in the dorsal striatum where significant NVHL-induced hyperactivation also emerged. Across all subjects and brain regions, only dorsal striatal activation was correlated with differences in sensitized locomotion. However, this activation was tightly correlated to a simple multiplicative function of ventral medial prefrontal hypoactivation and cocaine history-related increases in striatal activation.
These findings suggest drug history and developmental temporal limbic abnormalities associated with prefrontal dysfunction produce compounding effects within cortical-striatal circuits as mechanistic basis for dual diagnosis.