Cortical-Striatal Integration of Cocaine History and Prefrontal Dysfunction in Animal Modeling of Dual Diagnosis

Abstract

Background High rates of substance disorders in schizophrenia and other mental illnesses may reflect biological vulnerabilities to the addiction process. Interactions between addictive drug effects and mental illness involving circuits that generate motivated behavior may underpin this vulnerability. Methods We examined separate and combined effects of neonatal ventral hippocampal lesions (NVHL)—a neurodevelopmental model of schizophrenia (vs. SHAM-operated controls)—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 6 ventral to dorsal cortical-striatal compartments. Results Cortically, NVHLs showed hypo-activation and decreased volume of the ventral-medial prefrontal cortex. In contrast, cocaine history was only expressed sub-cortically, and as a hyper-activating effect in the dorsal striatum where significant NVHL-induced hyper-activation 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 hypo-activation and cocaine history-related increases striatal activation. Conclusions 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.

Histological correlates of N40 auditory evoked potentials in adult rats after neonatal ventral hippocampal lesion: animal model of schizophrenia

“…Reports in the literature of a reduced number of neurons in the cortex of NVHL rats support this possibility (Halim and Swerdlow, 2000;Flores et al, 2005;Tseng et al, 2008 andFrancois et al, 2009). A deficit in dendritic complexity after NVHL must also be considered (Chambers et al, 2010). This atrophy could be determined by the loss of the neurotrophic effect of glutamate, since the neuronal outputs of the ventral hippocampus are primarily glutamatergic (Bardgett and Henry, 1999).…”

MRI and X-ray scanning images of the brain of 3-, 6- and 9-month-old rats with bilateral neonatal ventral hippocampus lesions

“…Reports in the literature of a reduced number of neurons in the cortex of NVHL rats support this assessment (Halim and Swerdlow, 2000;Flores et al, 2005;François et al, 2009;Tseng et al, 2008). A deficit in dendritic complexity must also be considered (Chambers et al, 2010). This atrophy could be determined by the loss of the neurotrophic effect of glutamate, the neuronal outputs of the ventral hippocampus being mostly glutamatergic (Bardgett and Henry, 1999).…”

Cocaine self-administration differentially modulates the expression of endogenous cannabinoid system-related proteins in the hippocampus of Lewis vs. Fischer 344 rats

“…In these cells and other brain-associated cells, CB 2 is expressed and modulated according to cell activation state during inflammation and have recently been linked to schizophrenia-like symptoms (Ortega-Alvaro et al, 2011). Moreover, microglial cells play a role in several psychiatric disorders such as schizophrenia (Munn, 2000), whose expression is also known to be exacerbated by concomitant cocaine addiction (Green and Brown, 2006 ;Chambers et al, 2010). CB 2 gene expression is thought to be involved in the effects of abused substances, including cocaine, in rodents (Onaivi et al, 2008).…”