Ethanol sensitization in a neurodevelopmental lesion model of schizophrenia in rats

Abstract

Substance use disorder comorbidity in schizophrenia may reflect dysfunctional cortical-striatal-limbic circuitry commonly involved in the addiction process and the pathogenesis of schizophrenia. Rats with neonatal ventral hippocampal lesions (NVHL) demonstrate post-adolescent onset of schizophrenia-like symptoms and increased addiction vulnerability in paradigms using cocaine in adulthood. Here, we investigated response profiles of young adult NVHL vs. SHAM rats to ethanol, an addictive drug with many psychopharmacological effects divergent from those of cocaine, in a locomotor sensitization paradigm. Over 15 days of daily injections of saline, low (0.15 g/kg) or high (1.0 g/kg) doses of ethanol, NVHL rats showed stimulatory effects at the low dose compared to saline and high-dose conditions, while SHAM rats showed expected patterns of dose-dependent suppression of locomotor activity. In a challenge session 2 weeks later in which a moderate dose (0.25 g/kg) of ethanol was given to all subjects, NVHL rats with history of prior ethanol exposure showed greater locomotor activity consistent with installment of alcohol-induced sensitization not present in SHAMs. These findings provide further evidence of enhanced short- and long-term responsivity to abused drugs in a neurodevelopmental model of schizophrenia, and may reflect potentiation of common mechanisms of addiction shared between pharmacologically diverse addictive drugs.

Fig. 1

Experimental timeline with respect to rat age. All rats received 0.25 g/kg ethanol in the challenge session.

Fig. 2

Photomicrographs of coronal sections through the hippocampus of SHAM and NVHL rats.

Fig. 3

Pre-injection distance traveled during the initial locomotor sensitization session for SHAM and NVHL rats. No significant differences were found between NVHL and SHAM rats. Data are expressed as group means of distance traveled (cm)±SEM.

Fig. 4

Post-injection distance traveled during the 15-session injection series. NVHL and SHAM rats are depicted separately for clarity but all data was examined in one analysis. An overall repeated measures ANOVA revealed a main effect of dose [F(2,34)=13.7, p<0.001] and a significant interaction of lesion status and dose [F(2,34)=3.3, p<0.05]. In post-hoc testing, the 0.15 g/kg dose stimulated activity compared to saline in NVHL rats (p<0.05) but not in SHAM rats. The 1.0 g/kg dose was sedating compared to saline for both SHAM and NVHL groups (p<0.05). Data are expressed as group means of distance traveled (cm)±SEM.

Fig. 5

Postinjection distance traveled during the challenge session, in which all groups received 0.25 g/kg ethanol. Two-way ANOVA revealed a significant effect of Lesion Status [F(1,34)=7.3, p<0.05]. Post-hoc analysis showed that NVHL rats with a history of receiving repeated doses of either 0.15 g/kg or 1.0 g/kg ethanol had significantly greater locomotor activation than SHAM rats with a history of 0.15 g/kg doses (*p<0.05), whereas NVHL and SHAM rats with a history of saline did not differ. Data are expressed as group means of distance traveled (cm)±SEM.