Sex differences in the glutamate system: Implications for addiction

Abstract

Clinical and preclinical research have identified sex differences in substance use and addiction-related behaviors. Historically, substance use disorders are more prevalent in men than women, though this gap is closing. Despite this difference, women appear to be more susceptible to the effects of many drugs and progress to substance abuse treatment more quickly than men. While the glutamate system is a key regulator of addiction-related behaviors, much of the work implicating glutamate signaling and glutamatergic circuits has been conducted in men and male rodents. An increasing number of studies have identified sex differences in drug-induced glutamate alterations as well as sex and estrous cycle differences in drug seeking behaviors. This review will describe sex differences in the glutamate system with an emphasis on implications for substance use disorders, highlighting the gaps in our current understanding of how innate and drug-induced alterations in the glutamate system may contribute to sex differences in addiction-related behaviors.

Keywords: Addiction; Alcohol; Cocaine; Estrous cycle; Glutamate; Nicotine; Sex differences; Substance use disorders.

Figure 1.. Sex- and estrous cycle-dependent alterations in hippocampal glutamate receptor expression.

Sex differences in expression of both metabotropic and ionotropic glutamate receptors have been identified within the hippocampus. The metabotropic receptors mGluR2/3 and mGluR5 are expressed at higher levels in females than males (Wang et al., 2015), but how this varies by estrous phase has not been investigated. Conversely, females express lower levels of ionotropic receptors within the hippocampus, but this appears mostly specific to the estrus phase of the estrous cycle (Palomero-Gallagher et al., 2003). Expression levels of ionotropic receptors have not been assessed for the either proestrus or metestrus, thus it remains unclear how the surge in estradiol and progesterone that occur during proestrus may alter expression patterns. These sex- and estrous cycle-dependent differences may underlie differential risk for addictive behavior and/or variance in response to treatment. Lines represent approximate increases or decreases in glutamate receptor expression in the hippocampus in males versus females and across the estrous cycle. Dashed lines represent receptor expression levels for which estrous cycle has not been assessed.

Figure 2.. State of knowledge about sex differences in ethanol-induced glutamatergic alterations.

Research investigating glutamatergic projections and alterations in glutamate levels, uptake, and receptor expression implicated in ethanol seeking and exposure for which no sex differences are present (green), for which sex differences have been identified (purple), and for which sex differences have not been investigated (blue). Identification of drug exposure-related sex differences in the glutamate system have been limited primarily to glutamate receptor subunit (Devaud and Morrow, 1999, Devaud and Alele, 2004) and transporter (Alele and Devaud, 2005) expression in the hippocampus and chronic ethanol exposure- induced effects on glutamate release in the amygdala. However, some receptor subunit alterations are observed in both sexes (Devaud and Alele, 2004). Pharmacological manipulation of glutamate uptake in the PFC and NAc also alters ethanol consumption similarly in both males and females Sari et al., 2011, 2013; Qrunfleh et al., 2013; Alhaddad et al., 2014; Rao and Sari, 2014). In general, the roles of specific projections in ethanol-seeking behaviors have not been investigated in females (Gass et al., 2011, Pati et al., 2016, Keistler et al., 2017, Millan et al., 2017, Millan and McNally, 2011).