Sex-dependent effects of vasopressin microinjections in CA3 on nucleus accumbens neurochemical modulation and amphetamine-induced behavior.

Addiction to psychostimulants, such as amphetamine (AMPH), disrupts mesolimbic dopaminergic circuits, and effective pharmacological treatments remain limited. AMPH enhances dopamine (DA) release in the nucleus accumbens (NAc), a process tightly linked to context-dependent reinforcement. Emerging evidence implicates the dorsal CA3 subregion of the hippocampus (CA3d) in modulating reward-related processes through its interactions with limbic and mesolimbic circuits. While vasopressin (AVP) signaling has been shown to regulate addictive-like behaviors via extra-hypothalamic regions, its functional role within hippocampal circuits remains poorly understood. Here we investigated whether AVP modulates reward-related processes through actions in the CA3d and whether such modulation differs between sexes. We show that microinjection of AVP into the CA3d significantly attenuates AMPH-induced conditioned place preference (CPP) in both male and female rats. Neurochemical analyses revealed sex-dependent downstream effects in the NAc. In males, AVP administration resulted in a sustained reduction in accumbal DA levels. In contrast, females exhibited a pronounced phasic increase in DA accompanied by a marked reduction in glutamate levels. Despite these divergent neurochemical profiles, behavioral sensitivity to AMPH was similarly reduced across sexes, indicating that distinct neurochemical mechanisms converge on a shared behavioral outcome. Together, these findings identify hippocampal AVP signaling within the CA3d as a critical modulator of mesolimbic function and drug-associated contextual learning. Our results further demonstrate that sex-dependent neurochemical pathways can support equivalent behavioral effects, underscoring the importance of considering sex as a biological variable when investigating the neurobiological mechanisms underlying psychostimulant addiction.