Reduced dopamine release in the nucleus accumbens core of adult rats following adolescent binge alcohol exposure: age and dose-dependent analysis

Abstract

Rationale Alcohol use in adolescence is one of the most significant predictors of alcohol dependence in adulthood, yet the neurochemical mechanisms underlying this heightened vulnerability remain unknown. Whereas research has focused on characterizing adaptations in the mesolimbic dopamine (DA) system following ethanol exposure in adolescence, whether these changes persist into adulthood has yet to be determined. Objectives To investigate the effects of binge-intermittent ethanol administration in adolescence (P30-50) or early adulthood (P60-80) on DA in the nucleus accumbens (NAc) core after an ethanol challenge in adulthood following a period of abstinence. Methods Male Sprague Dawley rats (n=160) were administered intermittent ethanol injections, 1 g/kg or 3 g/kg, intraperitoneally (i.p.) every other day for 20 days starting on either P30 or 60. Following an ethanol-free period of either 7, 14 or 28 days, we measured DA efflux following an ethanol challenge (3 g/kg, i.p.) using electrochemical recording electrodes bilaterally implanted into the NAc core. Results Moderate dose ethanol administration (1 g/kg, i.p.) during adolescence significantly decreased ethanol-evoked DA release in adulthood at 7 and 14 days, but not 28 days, following pretreatment exposure compared to saline controls. Relative to rats pretreated with ethanol in adulthood, moderate dose ethanol in adolescence significantly reduced DA efflux at all time points measured. Additionally, adult rats pretreated with high dose ethanol administration (3 g/kg, i.p.) displayed significantly decreased DA compared to adolescents after 28 days of withdrawal. Conclusions Binge-intermittent ethanol administration during adolescence may induce age-dependent neuroadaptations in the mesolimbic DA system compared to ethanol-treated adults during protracted ethanol withdrawal.

Reward-centricity and attenuated aversions: An adolescent phenotype emerging from studies in laboratory animals

“…Given the normative course of development of this region throughout adolescence, it is not surprising that adolescents exhibit ontogenetic alterations in many aspects of reward-related behavior that are thought to be influenced by dopaminergic activity in the nAc such as enhanced goal-directed behavior (e.g., Anderson et al, 2013; Serlin and Torregrossa, 2015), expending more effort for larger rewards (e.g., Friemel et al, 2010; Stolyarova and Izquierdo, 2015), and altered responding to drug- and reward-associated cues (e.g., Anderson et al, 2013; Doherty et al, 2009; Li and Frantz, 2009). Furthermore, the responsiveness of dopaminergic activity in the nAc to drug-related rewards (for review see Volkow and Morales, 2015) is consistent with evidence that this region may be especially vulnerable to lasting modification by adolescent exposure to drugs of abuse (e.g., Catlow and Kirstein, 2007; Smith et al, 2015; Zandy et al, 2015), as well as to natural rewards, such as sucrose overconsumption (e.g., Naneix et al, 2016). …”

Differential behavioral and molecular alterations upon protracted abstinence from cocaine versus morphine, nicotine, THC and alcohol

“…Diminished neuronal activation in this region, a likely result of sustained stimulation during drug exposure and withdrawal (Luscher and Malenka, 2011), reduces striatal dopamine (DA) release and may contribute to lower reward sensitivity in addiction (Volkow et al, 2010). Remarkably, decreased DA release in the nucleus accumbens (NAc) was evidenced as a long-term consequence of adolescent binge alcohol exposure (Zandy et al, 2015). Moreover, social interactions recruit brain reward circuitry (Becker et al, 2014; Gunaydin et al, 2014; Trezza et al, 2010).…”

Juvenile Traumatic Brain Injury Increases Alcohol Consumption and Reward in Female Mice

“…[29][30][31] This pattern of responses is highly consistent with the alterations in the dopaminergic system following adolescent but not adult exposure to bingelike levels of ethanol. 32,33 Exposure to alcohol during early adolescence strongly drives dopamine release. However, adolescent alcohol appears to blunt dopaminergic signaling and responses to alcohol in adulthood.…”

“…33,34 Importantly, this effect was highly age specific as exposure to alcohol during later developmental stages reduced both the immediate dopamine efflux and the sensitization of the dopaminergic system to later ethanol exposure. 32 It seems possible, therefore, that the injury-induced surge of dopamine release throughout the forebrain sensitizes reward circuitry in a similar manner. Combining these data with the evidence for later long-term hypodopaminergia following TBI strongly suggests that increases in alcohol drinking behavior are mediated by three overlapping events.…”

“…Taken together, these events would produce a brain that is highly vulnerable to high levels of alcohol consumption. 32,35,36 Conversely, environmental enrichment, which has been shown to normalize dopaminergic tone following brain injury, blocked enhanced drinking. 37 Although the neuroprotective effect of environmental enrichment on TBI outcome is well documented, this is the first report indicating environmental enrichment as a method for reducing post-TBI alcohol consumption.…”