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

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.

The nucleus accumbens shell (NAcSh) is a key brain region involved in motivation and reward. It is primarily composed of dopamine D₁ and D₂ receptor­expressing 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.

Diabetes alters neuroeconomically dissociable forms of mental accounting.

Those with diabetes mellitus are at high-risk of developing psychiatric disorders, yet the link between hyperglycemia and alterations in motivated behavior has not been explored in detail. We characterized value-based decision-making behavior of a streptozocin-induced diabetic mouse model on a naturalistic neuroeconomic foraging paradigm called Restaurant Row. Mice made self-paced choices while on a limited time-budget accepting or rejecting reward offers as a function of cost (delays cued by tone-pitch) and subjective value (flavors), tested daily in a closed-economy system across months. We found streptozocin-treated mice disproportionately undervalued less-preferred flavors and inverted their meal-consumption patterns shifted toward a more costly strategy that overprioritized high-value rewards. We discovered these foraging behaviors were driven by impairments in multiple decision-making systems, including the ability to deliberate when engaged in conflict and cache the value of the passage of time in the form of sunk costs. Surprisingly, diabetes-induced changes in behavior depended not only on the type of choice being made but also the salience of reward-scarcity in the environment. These findings suggest complex relationships between glycemic regulation and dissociable valuation algorithms underlying unique cognitive heuristics and sensitivity to opportunity costs can disrupt fundamentally distinct computational processes and could give rise to psychiatric vulnerabilities.

Physiological acetic acid concentrations from ethanol metabolism stimulate accumbens shell medium spiny neurons via NMDAR activation in a sex-dependent manner.

Recent studies have implicated the ethanol metabolite, acetic acid, as neuroactive, perhaps even more so than ethanol itself. In this study, we investigated sex-specific metabolism of ethanol (1, 2, and 4 g/kg) to acetic acid in vivo to guide electrophysiology experiments in the accumbens shell (NAcSh), a key node in the mammalian reward circuit. There was a sex-dependent difference in serum acetate production, quantified via ion chromatography only at the lowest dose of ethanol (males > females). Ex vivo electrophysiology recordings of NAcSh medium spiny neurons (MSN) in brain slices demonstrated that physiological concentrations of acetic acid (2 mM and 4 mM) increased NAcSh MSN excitability in both sexes. N-methyl-D-aspartate receptor (NMDAR) antagonists, AP5 and memantine, robustly attenuated the acetic acid-induced increase in excitability. Acetic acid-induced NMDAR-dependent inward currents were greater in females compared to males and were not estrous cycle dependent. These findings suggest a novel NMDAR-dependent mechanism by which the ethanol metabolite, acetic acid, may influence neurophysiological effects in a key reward circuit in the brain from ethanol consumption. Furthermore, these findings also highlight a specific sex-dependent sensitivity in females to acetic acid-NMDAR interactions. This may underlie their more rapid advancement to alcohol use disorder and increased risk of alcohol related neurodegeneration compared to males.

Physiological acetic acid concentrations from ethanol metabolism stimulate accumbens shell neurons via NMDAR activation in a sex-dependent manner.

Recent studies have implicated the ethanol metabolite, acetic acid, as neuroactive, perhaps even more so than ethanol itself. In this study, we investigated sex-specific metabolism of ethanol (1, 2, and 4g/kg) to acetic acid in vivo to guide electrophysiology experiments in the accumbens shell (NAcSh), a key node in the mammalian reward circuit. There was a sex-dependent difference in serum acetate production, quantified via ion chromatography only at the lowest dose of ethanol (males>females). Ex vivo electrophysiology recordings of NAcSh neurons in brain slices demonstrated that physiological concentrations of acetic acid (2 mM and 4 mM) increased NAcSh neuronal excitability in both sexes. N -methyl- D -aspartate receptor (NMDAR) antagonists, AP5, and memantine robustly attenuated the acetic acid-induced increase in excitability. Acetic acid-induced NMDAR-dependent inward currents were greater in females compared to males. These findings suggest a novel NMDAR-dependent mechanism by which the ethanol metabolite, acetic acid, may influence neurophysiological effects in a key reward circuit in the brain.

Sex Differences in Cocaine Sensitization Vary by Mouse Strain.

INTRODUCTION: Preclinical literature, frequently utilizing rats, suggests females display a more rapid advancement of substance abuse and a greater risk of relapse following drug abstinence. In clinical populations, it is less clear as to what extent biological sex is a defining variable in the acquisition and maintenance of substance use. Even without considering environmental experiences, genetic factors are presumed to critically influence the vulnerability to addiction. Genetically diverse mouse models provide a robust tool to examine the interactions between genetic background and sex differences in substance abuse. METHODS: We explored mouse strain variability in male versus female behavioral sensitization to cocaine. Locomotor sensitization was observed following 5 consecutive days of subcutaneous cocaine across three genetically different mice strains: C57BL/6J, B6129SF2/J, and Diversity Outbred (DO/J). RESULTS: Sex differences in cocaine locomotor sensitization were dependent on mouse strain. Specifically, we observed opposing sex differences in locomotor sensitization, with male C57BL/6J and female B6129SF2/J mice displaying heightened activity compared to their opposite sex counterparts. Conversely, no sex differences were observed in the DO/J mice. Acute cocaine administration resulted in locomotor differences across strains in male, but not female, mice. The magnitude of sensitization (or lack thereof) also varied by genetic background. CONCLUSIONS: While sex differences in drug addiction may be observed, these effects can be mitigated, or even reversed, depending on genetic background. The clinical implications are that in the absence of understanding the genetic variables underlying vulnerability to addiction, sex provides little information regarding the predisposition of an individual to drug abuse.