Hearing, M. C. | Search bioRxiv

bioRxiv2026

Remifentanil self-administration promotes circuit- and sex-specific adaptations within the prefrontal-accumbens pathways

The nucleus accumbens (NAc) and its excitatory input from the medial prefrontal cortex (mPFC) form a critical circuit underlying drug-induced plasticity associated with addiction-related behaviors. However, baseline differences in excitatory signaling across NAc subcircuits and sex-specific neuroadaptations following opioid self-administration remain poorly understood. Here, we examined synaptic signaling in mPFC-NAc pathways in drug-naive mice and after abstinence from remifentanil self-administration. Under drug-naive conditions, AMPA receptor- mediated glutamatergic signaling was generally elevated in D2 medium spiny neurons (MSNs) of both the NAc core and shell across sexes, while females exhibited greater excitatory signaling in D1 MSNs of the NAc core compared with males. Pathway-specific analyses revealed that prelimbic cortex (PL) inputs to NAc core D2 MSNs displayed enhanced calcium-permeable AMPA receptor (CP-AMPAR) signaling and increased presynaptic release relative to D1 MSNs. Following abstinence from remifentanil self-administration, miniature excitatory postsynaptic current analyses showed increased excitatory drive at D1 MSNs and decreased drive at D2 MSNs, largely restricted to the NAc core. At PL-Core D1 MSN synapses, remifentanil reduced AMPA/NMDA ratios, consistent with increased CP-AMPAR incorporation in males and females, while increasing presynaptic signaling exclusively in males. In contrast, PL-Core D2 MSN synapses showed a reduction in presynaptic signaling across sex, while ostensibly weakening postsynaptic signaling selectively in males through reductions in CP-AMPAR signaling. At infralimbic cortex (IL)-shell inputs, a reduction in AMPAR rectification indices at D1 MSN synapses was produced by remifentanil, while release probability was decreased at D2 MSN synapses in males only. Together, these findings reveal sex- and pathway-specific synaptic adaptations within mPFC-NAc circuits that may be obscured by global measures of excitatory transmission and identify baseline circuit differences that may shape opioid-induced plasticity.

neuroscience↗

bioRxiv2024

Aversion-induced drug taking and escape behavior involve similar nucleus accumbens core dopamine signaling signatures

Dopamine release in the nucleus accumbens core (NAcC) has long been associated with the promotion of motivated behavior. However, inhibited dopamine signaling can increase behavior in certain settings, such as during drug self-administration. While aversive environmental stimuli can reduce dopamine, it is unclear whether such stimuli reliably engage this mechanism in different contexts. Here we compared the physiological and behavioral responses to the same aversive stimulus in different designs to determine if there is uniformity in the manner that aversive stimuli are encoded and promote behavior. NAcC dopamine was measured using fiber photometry in male and female rats during cocaine self-administration sessions in which an acutely aversive 90 dB white noise was intermittently presented. In a separate group of rats, aversion-induced changes in dopamine were measured in an escape design in which operant responses terminated aversive white noise. Aversive white noise significantly reduced NAcC dopamine and increased cocaine self-administration in both male and female rats. The same relationship was observed in the escape design, in which white noise reduced dopamine and promoted escape attempts. In both designs, the magnitude of the dopamine reduction predicted behavioral performance. While prior research demonstrated that pharmacologically reduced dopamine signaling can promote intake, this report demonstrates that this physiological mechanism is naturally engaged by aversive environmental stimuli and generalizable to non-drug contexts. These findings illustrate a common physiological signature in response to aversion that may promote both adaptive and maladaptive behavior.

neuroscience↗