Sex differences in behavior and neural development and their role in adolescent vulnerability to substance use

Abstract

Adolescents are especially prone to risky behavior and to the emergence of psychological disorders like substance abuse, anxiety and depression. However, there is a sex (or gender) difference in this vulnerability, with females being more prone to developing internalizing disorders and males being more likely to engage in risky behavior and drug use. While several researchers have proposed that there is a relationship between corticolimbic circuit development and adolescent vulnerability, the current proposed models do not take sex differences into account. In this review, we explore recent findings from both human and rodent studies of sex differences during adolescence. In particular, we consider epidemiological studies on the factors that contribute to the development of substance abuse and internalizing disorders, laboratory studies on reward-related and decision-making behavior, and neuroanatomical studies on the development of several structures in the corticolimbic circuit (i.e., prefrontal cortex [PFC], amygdala and striatum). We then integrate these recent findings into models of adolescent vulnerability to substance use that have previously not addressed sex differences. Lastly, we discuss methodological considerations for the interpretation and design of studies on sex (or gender) differences during adolescence while highlighting some opportunities for future investigations.

Adolescent impulsivity as a sex- and subtype-dependent predictor of impulsivity, alcohol drinking, and dopamine D2 receptor expression in adult rats

“…We have previously hypothesized that drinking is more strongly related to impulsivity in males (Hammerslag & Gulley 2016), while anxiety may be a better predictor of drinking for females (Varlinskaya et al 2015;Hammerslag & Gulley 2016). In this study the relationship between impulsive action and drinking was significant only in males, however there was a trend toward the same relationship in females and thus the importance of this sex difference is unclear.…”

D1 receptor-mediated inhibition of medial prefrontal cortex neurons is disrupted in adult rats exposed to amphetamine in adolescence

“…Thus, the ability of drugs of abuse to alter the normal developmental trajectory of prefrontal circuitry may be a principal mechanism through which adolescent drug exposure can lead to longstanding, if not permanent, changes in prefrontal control over behavior. It will be important for future studies to determine the precise mechanisms that underlie drug-induced plasticity leading to vulnerability, as well as understand what factors might lead to resilience to the effects of drugs (Hammerslag and Gulley, 2016). …”

Timing of amphetamine exposure in relation to puberty onset determines its effects on anhedonia, exploratory behavior, and dopamine D1 receptor expression in young adulthood

“…It has been shown that the continuous maturation of dopamine function in the mPFC throughout late-adolescence to adulthood coincides with improvement or emergence of complex cognitive behavior (Naneix et al, 2012). Thus, disruption of such delayed development by drug exposure during adolescence may induce specific neural and behavioral adaptations that contribute to a heightened vulnerability to addiction and comorbid mental disorders (Gulley and Juraska, 2013; Hammerslag and Gulley, 2016). An early study (Brandon et al, 2001) showing that exposure to methylphenidate during adolescence led to cross-sensitization to cocaine and increased cocaine self-administration in adulthood is consistent with this hypothesis.…”

“…Empirical evidence suggests that illicit substance use during adolescence may profoundly alter brain development (Gulley and Juraska, 2013; Spear, 2015) and potentially increase the risk of future substance abuse and addiction (Paus et al, 2008; Hammerslag and Gulley, 2016). Amphetamine (AMPH) is among the most widely abused drugs and it has been estimated that about 10.3% of the US population has used AMPH at least once by the 10 th grade (UNODC, 2010).…”