Opposing Estrous Cycle-Dependent Norepinephrine and Dopamine Regulation in Response to Methamphetamine

The central catecholamine systems, norepinephrine and dopamine, play a critical role in encoding the valence of environmental stimuli to promote engagement in behaviors that potentiate an organism's survival. Furthermore, both neurochemicals in limbic brain areas such as the nucleus accumbens (NAc) and bed nucleus of the stria terminalis (BNST) are major targets of stimulant drugs. Canonically, limbic norepinephrine signaling is enhanced in the presence of aversive or noxious stimuli whereas dopamine transmission is generally considered to increase in response to appetitive or rewarding stimuli. However, it remains to be elucidated whether sex differences, especially at different stages of the estrous cycle, distinctly regulate catecholamine transmission in vivo. In this study we (i) identified estrous cycle-dependent changes in catecholamine regulation via their transporters and autoreceptors in the BNST and NAc of anesthetized rats and (ii) determined how the psychostimulant methamphetamine (METH) impacts norepinephrine and dopamine transmission in the BNST and NAc, respectively, in male and freely cycling female rats using in vivo fast-scan cyclic voltammetry. Our results demonstrate electrically evoked BNST norepinephrine levels are increased by METH the greatest during the non-estrus (diestrus/proestrus) stages while NAc dopamine release evoked by electrical stimulation and METH is heightened in estrus. This limbic norepinephrine and dopamine regulation suggests a critical role of estrous cycle stage on catecholamine dynamics. These findings offer new insights into the role of estrous cycle stage on how the brain encodes environmental stimuli and provide a new framework for sex-specific therapies for targeting the central catecholamine systems in health and disease ranging from drug use disorders to obesity.