Fundamental Sex Differences in Cocaine-Induced Plasticity of Dopamine D1 Receptor- and D2 Receptor-Expressing Medium Spiny Neurons in the Mouse Nucleus Accumbens Shell

Andrew D Chapp; Chinonso A Nwakama; Pramit P Jagtap; Chau-Mi H Phan; Mark J Thomas; Paul G Mermelstein

doi:10.1016/j.bpsgos.2024.100295

Fundamental Sex Differences in Cocaine-Induced Plasticity of Dopamine D1 Receptor- and D2 Receptor-Expressing Medium Spiny Neurons in the Mouse Nucleus Accumbens Shell

Biol Psychiatry Glob Open Sci. 2024 Feb 19;4(3):100295. doi: 10.1016/j.bpsgos.2024.100295. eCollection 2024 May.

Authors

Andrew D Chapp^{1

2}, Chinonso A Nwakama^{1

2

3}, Pramit P Jagtap¹, Chau-Mi H Phan¹, Mark J Thomas^{1

2

4}, Paul G Mermelstein^{1

2

4}

Affiliations

¹ Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota.
² Medical Discovery Team on Addiction, University of Minnesota, Minneapolis, Minnesota.
³ Medical Scientist Training Program, Icahn School of Medicine at Mount Sinai, New York, New York.
⁴ Center for Neural Circuits in Addiction, University of Minnesota, Minneapolis, Minnesota.

Abstract

Background: Cocaine-induced plasticity in the nucleus accumbens shell of males occurs primarily in dopamine D₁ receptor-expressing medium spiny neurons (D1R-MSNs), with little if any impact on dopamine D₂ receptor-expressing medium spiny neurons (D2R-MSNs). In females, the effect of cocaine on accumbens shell D1R- and D2R-MSN neurophysiology has yet to be reported, nor have estrous cycle effects been accounted for.

Methods: We used a 5-day locomotor sensitization paradigm followed by a 10- to 14-day drug-free abstinence period. We then obtained ex vivo whole-cell recordings from fluorescently labeled D1R-MSNs and D2R-MSNs in the nucleus accumbens shell of male and female mice during estrus and diestrus. We examined accumbens shell neuronal excitability as well as miniature excitatory postsynaptic currents (mEPSCs).

Results: In females, we observed alterations in D1R-MSN excitability across the estrous cycle similar in magnitude to the effects of cocaine in males. Furthermore, cocaine shifted estrous cycle-dependent plasticity from intrinsic excitability changes in D1R-MSNs to D2R-MSNs. In males, cocaine treatment produced the anticipated drop in D1R-MSN excitability with no effect on D2R-MSN excitability. Cocaine increased mEPSC frequencies and amplitudes in D2R-MSNs from females in estrus and mEPSC amplitudes of D2R-MSNs from females in diestrus. In males, cocaine increased both D1R- and D2R-MSN mEPSC amplitudes with no effect on mEPSC frequencies.

Conclusions: Overall, while there are similar cocaine-induced disparities regarding the relative excitability of D1R-MSNs versus D2R-MSNs between the sexes, this is mediated through reduced D1R-MSN excitability in males, whereas it is due to heightened D2R-MSN excitability in females.

Keywords: Cocaine; Estrous cycle; Excitability; Nucleus accumbens shell; Sex differences; mEPSCs.

Plain language summary

The nucleus accumbens shell (NAcSh) is a key brain region involved in motivation and reward. It is primarily composed of dopamine D₁ and D₂ receptor–expressing medium spiny neurons (D1R and D2R neurons). Previous studies in males demonstrated that D1R neurons undergo intrinsic plasticity following cocaine exposure, believed to underlie aspects of drug addiction. We confirmed this effect. It has also been generally assumed that females would show similar responses. However, this does not appear to be true, and our data indicate 2 novel findings. First, under baseline conditions, the estrous cycle produces recurring changes in D1R neuron excitability, with no changes observed in D2R neurons. Second, following cocaine exposure, D1R neuron plasticity is arrested, and D2R neurons begin to show estrous cycle effects on intrinsic excitability. These results indicate profound sex differences in the neurophysiological underpinnings of motivational behaviors including drug addiction.