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Repeated administration of low doses of ethanol gradually increases locomotor responses to ethanol in adult Swiss mice. This phenomenon is known as behavioral sensitization. However, we have shown that adolescent Swiss mice show either behavioral tolerance or no sensitization after repeated ethanol injections. Although the mesolimbic dopamine system has been extensively implicated in behavioral sensitization, several studies have demonstrated an important role of glutamatergic transmission in this phenomenon. In addition, relatively few studies have examined the role of developmental factors in behavioral sensitization to ethanol. To examine the relationship between age differences in behavioral sensitization to ethanol and the neurochemical adaptations related to glutamate within nucleus accumbens (NAc), in vivo microdialysis was conducted in adolescent and adult Swiss mice treated with ethanol (1.8 g/kg) or saline for 15 days, and subsequently challenged with an acute dose (1.8 g/kg) of ethanol six days later. Consistent with previous findings, only adult mice demonstrated evidence of behavioral sensitization. However, ethanol-treated adolescent mice demonstrated a 196.1 ± 40.0% peak increase in extracellular levels of glutamate in the NAc following ethanol challenge in comparison with basal values, whereas ethanol-treated adult mice demonstrated a 52.2 ± 6.2% reduction in extracellular levels of glutamate in the NAc following ethanol challenge. These observations suggest an age-dependent inverse relationship between behavioral and glutamatergic responses to repeated ethanol exposure.

Behavioral sensitization has been suggested to contribute to uncontrolled alcohol consumption. The aim of this study was to investigate the effects of repeated ethanol administration in adolescent and adult mice on subsequent ethanol consumption and conditioned place preference (CPP). Mice were administered ethanol for 15 consecutive days. This ethanol regimen induced behavioral sensitization to a lesser degree in adolescents than in adults. Following ethanol treatment, mice were subjected to CPP procedure, or given a free choice between water and ethanol solutions. While ethanol-pretreated adult mice did not display a robust ethanol-induced CPP, ethanol induced a significant CPP in mice pretreated with ethanol during adolescence. Ethanol pretreated mice, regardless of age, showed higher ethanol intake to saline-treated mice. The present findings suggest that ethanol-induced neuroadaptations underlying behavioral sensitization may activate mechanisms responsible for enhanced ethanol intake, and also reveals that ethanol pre-exposure during adolescence increases ethanol reward as measured by CPP.

Background Increasing evidence shows that excessive alcohol consumption during adolescence increases vulnerability to alcohol use disorders in adulthood. The aim of this study was to examine differences between adolescent and adult C57BL/6 mice in drinking behavior and blood ethanol concentrations (BECs) after chronic ethanol exposure and withdrawal. Methods Male adolescent (PND=28–30) and adult (PND=70) C57BL/6J mice were allowed to consume ethanol in a two-bottle choice paradigm (15% ethanol vs. water) for three weeks (Baseline Drinking, Test 1, and Test 2), which were interspersed with 2 cycles (Cycles I and II) of chronic ethanol vapor or air inhalation (16 h) and withdrawal (8 h). Blood ethanol concentrations (BECs) were determined during both cycles. Results Chronic ethanol exposure led to increased ethanol intake during Test 1 and Test 2 in both adolescent and adult mice compared to air exposed controls, and no differences between age groups were observed. During Cycle I adult mice showed higher BECs compared to adolescents. During Cycle II, BECs were lower in adult mice as compared to Cycle I, and BECs in adolescent mice did not change between the two cycles. Conclusions Chronic ethanol exposure followed by withdrawal periods increases ethanol consumption similarly in both adolescent and adult mice, despite differences in BECs.

Behavioral sensitization is a process of neuroadaptation characterized by a gradual increase in motor behaviors. The major neural substrates involved in the behavioral sensitization lie on the dopaminergic mesocorticolimbic pathway, which is still under development during adolescence. To investigate age-differences in ethanol behavioral sensitization and dopamine levels in distinct brain regions of the reward system, adolescent and adult mice were repeatedly pretreated with saline or ethanol (2.0 g/kg i.p.) during 15 consecutive days and challenged with saline or ethanol 5 days after pretreatment. Dopamine and its metabolites were measured in tissue samples of the prefrontal cortex (PFC), nucleus accumbens (NAc) and striatum by HPLC analysis. While repeated ethanol administration resulted in the development of locomotor sensitization in both adult and adolescent mice, only the adults expressed sensitization to a subsequent ethanol challenge injection. Neurochemical results showed reduced dopamine levels in adolescents compared to adults. Specifically, mice pretreated with ethanol during adolescence displayed lower dopamine levels in the PFC compared to the respective adult group in response to an ethanol challenge injection, and preadolescent mice exhibited lower dopamine levels in the NAc following an acute ethanol treatment compared to adults. These findings suggest that adolescent mice are not only less sensitive to the expression of ethanol-induced sensitization than adults, but also show lower dopamine content after ethanol exposition in the PFC and NAc.