About

Andrew Chapp, PhD, is an Assistant Professor in the Department of Neuroscience at the University of Minnesota. His current research focuses on how drugs of abuse, including cocaine, opioids, and alcohol, differentially impact behavior and neurophysiology among male and female rodents. He utilizes behavioral tests, optogenetics, and whole cell slice electrophysiology to investigate these effects.

Research topics

• Neuroscience
• Biology
• Medicine
• Biochemistry
• Psychiatry
• Psychology
• Pharmacology
• Chemistry
• Endocrinology
• Physiology
• Internal medicine

Selected publications

• Cocaine sensitization and accumbens shell plasticity depend on biological sex and gonadal hormones in C57BL/6J mice

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-15

  articleOpen access1st authorCorresponding

  Biological sex as a defining variable in drug sensitivity remains poorly understood. Here, we combine behavioral and electrophysiological analyses to examine the influence of sex and gonadal hormones on cocaine-induced psychomotor sensitization and nucleus accumbens shell (NAcSh) plasticity in the prominent C57BL/6J mouse strain. Males exhibited greater cocaine-evoked locomotor activity than females; castration attenuated responses, whereas ovariectomy enhanced them. This behavioral phenotype is opposite to what occurs in rats. A 10-14 day abstinence period abolished the sex difference in intact animals, and gonadectomy reduced cocaine-induced behavioral plasticity. Recordings from 309 medium spiny neurons revealed sex-dependent NAcSh plasticity. In males, cocaine decreased neuronal excitability, while in females it induced estrous cycle-dependent plasticity characterized by reduced excitability during diestrus relative to estrus. These effects were driven by cocaine-induced modulation of voltage-gated sodium channels. Cocaine potentiated glutamatergic strength in males but elicited estrous cycle-dependent depotentiation in females. These adaptations in excitability and glutamatergic strength were abolished by gonadectomy, and paralleled diminished behavioral plasticity during abstinence. These data illustrate that biological sex and hormonal milieu critically shape cocaine-induced plasticity, offering a more nuanced framework than the traditional notion of heightened female sensitivity to drugs of abuse.

  PublisherDOI

• Fundamental sex differences in cocaine-induced plasticity of D1R- and D2R-MSNs in the mouse nucleus accumbens core

  Biology of Sex Differences · 2025-11-26 · 2 citations

  articleOpen access1st authorCorresponding

  BACKGROUND: Cocaine-induced changes in nucleus accumbens shell (NAcSh) medium spiny neurons (MSNs) differ based on dopamine receptor subtype expression, the sex of the animal, and for females, phase of the estrous cycle. These findings highlight the need to account for both sex and estrous cycle when studying drug-mediated alterations in neurophysiology. Whether MSNs of the nucleus accumbens core (NAcC), which serve different aspects of reward function, will exhibit similar sex and estrous cycle effects with cocaine administration was investigated. METHODS: Mice underwent a 5-day locomotor sensitization paradigm via daily cocaine administration (15 mg/kg, s.c.) followed by a 1- to 4-day drug-free abstinence period. We examined NAcC MSN excitability by obtaining ex vivo whole-cell recordings from differentially labeled dopamine D1-receptor expressing MSNs (D1R-MSNs) and dopamine D2-receptor expressing MSNs (D2R-MSNs) obtained from male mice or female mice that were either in estrus or diestrus. RESULTS: In this mouse strain, male and female mice sensitized to cocaine to a similar degree. In males, there were no cocaine-induced changes in NAcC D1R-MSN or D2R-MSN excitability. When comparing MSN subtypes, D2R-MSNs exhibited greater excitability. In saline-treated females, D1R-MSN excitability fluctuated across the estrous cycle with increased excitability during estrus. Following cocaine, estrous cycle-dependent D1R-MSN excitability was arrested, fixed at an intermediate value between estrus and diestrus when compared to saline controls. D2R-MSNs did not change across the estrous cycle or following cocaine. When comparing MSN subtypes, in diestrus, D2R-MSNs were more excitable under saline conditions, but indistinguishable from D1R-MSNs following cocaine. In contrast, during estrus, D1R- was indistinguishable from D2R-MSN excitability in saline treated animals, but with cocaine, D2R-MSNs displayed heightened excitability. CONCLUSIONS: There are fundamental sex differences in cocaine-induced changes to the excitability of D1R-MSNs in the NAcC. After cocaine exposure, female mice in diestrus saw a significant main effect change in MSN excitability, an inversion of what had previously been demonstrated in the NAcSh. These data suggest that there are fundamental sex differences in the neuropharmacological effect of cocaine in males versus females that are shell- and core-specific. HIGHLIGHTS: There are sex- and estrous-cycle dependent changes to D1R-MSNs in the NAcC that are sensitive to cocaine exposure. In males, cocaine has no effect on altering D1R- or D2R- MSNs excitability. During the estrous cycle, D1R-MSNs exhibit increased excitability during estrus. This fluctuation is halted by cocaine, such that D1R-MSNs recorded in diestrus show increased excitability following cocaine exposure whereas female D1R-MSNs recorded in estrus have decreased excitability. The nucleus accumbens core (NAcC) is a brain region associated with regulating motivated behavior. The primary neuronal populations of the NAcC are dopamine D1 receptor expressing medium spiny neurons (D1R-MSNs) and dopamine D2 receptor expressing medium spiny neurons (D2R-MSNs). No studies exist which examine sex differences and estrous cycle effects in the NAcC following cocaine administration. Using ex vivo electrophysiology, we found inherent sex- and estrous-cycle differences in cocaine-induced MSN neuroplasticity. Following cocaine exposure, D1R-MSN excitability was unaffected in males, increased in females recorded during the diestrus phase, and decreased in females recorded during estrus. This ran counter to estrous cycle effects under drug-naive conditions where D1R-MSN excitability was higher in estrus versus diestrus. The estrous cycle effects on D1R-MSNs were eliminated following cocaine administration. For both sexes, D2R-MSN excitability was not impacted following cocaine. These results highlight fundamental sex differences in neurophysiology that might underpin differences in addiction.

  PublisherOA PDFDOI

• Fundamental Sex Differences in Cocaine-Induced Plasticity of D1R-and D2R-MSNs in the Mouse Nucleus Accumbens Core

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-23

  preprintOpen access1st authorCorresponding

  ABSTRACT BACKGROUND Previous studies have shown that cocaine-induced changes in nucleus accumbens shell (NAcSh) medium spiny neurons (MSNs) differ based on dopamine receptor subtype expression, the sex of the animal, and for females, phase of the estrous cycle. These findings highlight the need to account for both sex and estrous cycle when studying drug-mediated alterations in neurophysiology. Whether MSNs of the nucleus accumbens core (NAcC), which serve different aspects of addiction, will exhibit similar sex and estrous cycle effects with cocaine administration was investigated. METHODS Mice underwent a 5-day locomotor sensitization paradigm via daily cocaine administration (15 mg/kg, s.c.) followed by a 1-to 4-day drug-free abstinence period. We examined NAcC MSN excitability by obtaining ex vivo whole-cell recordings from differentially labeled dopamine D1-receptor expressing MSNs (D1R-MSNs) and dopamine D2-receptor expressing MSNs (D2R-MSNs) obtained from male mice or female mice that were either in estrus or diestrus. RESULTS In this genetic background of mice, both male and female mice sensitized to cocaine in a similar manner. In males, there were no cocaine-induced changes in D1R-MSN or D2R-MSN excitability, with D2R-MSNs exhibiting greater excitability. In saline-treated females, D1R-MSN excitability fluctuated across the estrous cycle with increased excitability during estrus. Following cocaine, estrous cycle-dependent D1R-MSN excitability was arrested, fixed at an intermediate value between estrus and diestrus when compared to saline controls. D2R-MSNs did not change either across the estrous cycle or following cocaine. When comparing MSN subtypes, in diestrus, D2R-MSNs were more excitable under saline conditions, but indistinguishable from D1R-MSNs following cocaine. In contrast, during estrus, D1R-and D2R-MSN excitability was similar in saline treated animals, but with cocaine, D2R-MSNs displayed heightened excitability. CONCLUSIONS There are fundamental sex differences in cocaine-induced changes to the excitability of D1R-MSNs in the NAcC. After cocaine exposure, female mice in diestrus exhibited a significant main effect change in MSN excitability, an inversion of what had previously been demonstrated in the NAcSh where no cocaine-induced changes were observed. These data suggest that there are distinct differences in the neuropharmacological effect of cocaine in males versus females that are shell and core specific. Abstract Figure HIGHLIGHTS There are sex-and estrous-cycle dependent changes to D1R-MSNs in the NAcC that are sensitive to cocaine exposure. In males, cocaine has no effect on D1R-or D2R-MSNs excitability. During the estrous cycle, D1R-MSNs exhibit increased excitability during estrus. This fluctuation is halted by cocaine, such that D1R-MSNs recorded in diestrus show increased excitability following cocaine exposure whereas female D1R-MSNs recorded in estrus have decreased excitability. PLAIN LANGUAGE SUMMARY The nucleus accumbens core (NAcC) is a brain region associated with regulating motivated behavior. The primary neuronal populations of the NAcC are dopamine D1 receptor expressing medium spiny neurons (D1R-MSNs) and dopamine D2 receptor expressing medium spiny neurons (D2R-MSNs). No studies exist which examine sex differences and estrous cycle effects in the NAcC following cocaine administration. Using ex vivo electrophysiology, we found inherent sex-and estrous-cycle differences in cocaine-induced changes in MSN neuroplasticity. D1R-MSN excitability was unaffected in males, increased in females recorded during the diestrus phase, and decreased in females recorded during estrus following cocaine exposure. This ran counter to estrous cycle effects under drug-naive conditions where D1R-MSN excitability was higher in estrus versus diestrus. The estrous cycle effects on D1R-MSNs were eliminated following cocaine administration. For both sexes, D2R-MSN excitability was not impacted following cocaine. These results highlight fundamental sex differences that might underpin differences in substance abuse.

  PublisherOA PDFDOI

• Acetic Acid: An Underestimated Metabolite in Ethanol-Induced Changes in Regulating Cardiovascular Function

  Antioxidants · 2024-01-23 · 9 citations

  reviewOpen access1st authorCorresponding

  Acetic acid is a bioactive short-chain fatty acid produced in large quantities from ethanol metabolism. In this review, we describe how acetic acid/acetate generates oxidative stress, alters the function of pre-sympathetic neurons, and can potentially influence cardiovascular function in both humans and rodents after ethanol consumption. Our recent findings from in vivo and in vitro studies support the notion that administration of acetic acid/acetate generates oxidative stress and increases sympathetic outflow, leading to alterations in arterial blood pressure. Real-time investigation of how ethanol and acetic acid/acetate modulate neural control of cardiovascular function can be conducted by microinjecting compounds into autonomic control centers of the brain and measuring changes in peripheral sympathetic nerve activity and blood pressure in response to these compounds.

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

  Biological Psychiatry Global Open Science · 2024-02-19 · 9 citations

  articleOpen access1st author

  Background: 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.

  PublisherDOI

• Sympathoexcitation and pressor responses induced by acetate, an ethanol metabolite in the hypothalamic paraventricular nucleus involves activation of NMDA receptors in rats

  Physiology · 2023-05-01

  article

  Alcohol abuse plays a crucial role in the prevalence of cardiovascular and neuronal degenerated diseases. However, the central mechanism that mediates these effects are not fully understood. It has been well know that autonomic hypothalamic paraventricular nucleus (PVN) play an important role in regulating sympathetic outflow and arterial blood pressure (ABP). Moreover, it has been demonstrated that the increased glutamatergic activity among PVN neurons contributed to the sympathoexcitation and development of hypertension. Furthermore, we have reported that ethanol and acetate increase sympathetic outflow and arterial pressure, which may involve the activation of NMDA receptors in autonomic central nucleus of amygdala. Combing with the fact that autonomic PVN neurons are abundantly expressed NMDA receptors, we hypothesize that acetate, the metabolic products from alcohol, activates the PVN neurons through the increase in glutamatergic activity and contributes to the sympathoexcitation and development of chronic diseases, such as hypertension. In anesthetized rats, the effect of acetate microinjected in the PVN on the renal sympathetic nerve activity (RSNA) and arterial blood pressure (ABP) was determined. The PVN acetate microinjection increased sympathoexcitatiory and pressor response in a dose dependent dose-dependent (1.5mm, 0.5mm, 2.0mm, 7.5mm) manner, and 2mm of acetate showed a minimum dose evoked a maximal response. To determine the role of acetate-stimulated glutamatergic receptor activation in driving sympathoexcitatory and pressor responses, either 2mm acetate or pre-treatment of Kynurenic acid (KYN, 7.2mm) ionotropic excitatory amino acid receptor blocker, or D-2-amino-5-phosphopentanoate (AP5, 3.0mm), a N-methyl-D-aspartate (NMDA) receptor antagonist, followed by 2mm acetate were microinjected into the PVN of male Sprague Dawley rats (300-500g, n= 6-9/ group). RSNA and ABP responses were compared among vehicle (saline) and 2mm acetate, pre-treatment of KYN and 2mm acetate, or pre-treatment AP5 and 2mm acetate protocols. 2mm acetate significantly increased RSNA (60-70% baseline, p < 0.001) and mean arterial pressure (MAP, 10-12mmHg, p < 0.05). Non-selective glutamatergic receptor antagonist, KYN significantly blocked the sympathoexcitatory (RSNA, p < 0.05) and pressor response (MAP, p < 0.05) evoked by 2mm acetate in the PVN. Furthermore, selective NMDA receptor antagonist, AP5 significantly attenuates the sympathoexcitatory response induced by PVN 2mm acetate (RSNA, P < 0.05 and MAP, p < 0.01). These data indicate acetate can increase glutamatergic activity and excitability of pre-sympathetic PVN neurons via activation of local NMDA receptors. The metabolism of ethanol to acetate following by alcohol consumption may contribute, in part, to the development of neurogenic hypertension and/or other cardiovascular diseases associated with increased sympathetic outflow. R15HL145655, R15HL150703 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

  PublisherDOI

• Sex differences in mouse infralimbic cortex projections to the nucleus accumbens shell

  Biology of Sex Differences · 2023-12-11 · 8 citations

  articleOpen access

  BACKGROUND: The nucleus accumbens (NAc) is an important region in motivation and reward. Glutamatergic inputs from the infralimbic cortex (ILC) to the shell region of the NAc (NAcSh) have been implicated in driving the motivation to seek reward through repeated action-based behavior. While this has primarily been studied in males, observed sex differences in motivational circuitry and behavior suggest that females may be more sensitive to rewarding stimuli. These differences have been implicated for the observed vulnerability in women to substance use disorders. METHODS: We used an optogenetic self-stimulation task in addition to ex vivo electrophysiological recordings of NAcSh neurons in mouse brain slices to investigate potential sex differences in ILC-NAcSh circuitry in reward-seeking behavior. Glutamatergic neurons in the ILC were infected with an AAV delivering DNA encoding for channelrhodopsin. Entering the designated active corner of an open field arena resulted in photostimulation of the ILC terminals in the NAcSh. Self-stimulation occurred during two consecutive days of testing over three consecutive weeks: first for 10 Hz, then 20 Hz, then 30 Hz. Whole-cell recordings of medium spiny neurons in the NAcSh assessed both optogenetically evoked local field potentials and intrinsic excitability. RESULTS: Although both sexes learned to seek the active zone, within the first day, females entered the zone more than males, resulting in a greater amount of photostimulation. Increasing the frequency of optogenetic stimulation amplified female reward-seeking behavior. Males were less sensitive to ILC stimulation, with higher frequencies and repeated days required to increase male reward-seeking behavior. Unexpectedly, ex vivo optogenetic local field potentials in the NAcSh were greater in slices from male animals. In contrast, female medium-spiny neurons (MSNs) displayed significantly greater intrinsic neuronal excitability. CONCLUSIONS: Taken together, these data indicate that there are sex differences in the motivated behavior driven by glutamate within the ILC-NAcSh circuit. Though glutamatergic signaling was greater in males, heightened intrinsic excitability in females appears to drive this sex difference.

  PublisherOA PDFDOI

• Fundamental Sex Differences in Cocaine-Induced Plasticity of D1- and D2-MSNs in the Mouse Nucleus Accumbens Shell

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-06-30 · 7 citations

  preprintOpen access1st author

  ABSTRACT Cocaine-induced plasticity in the nucleus accumbens shell of males occurs primarily in D1 dopamine receptor expressing neurons (D1-MSNs), with little if any impact on D2 dopamine receptor neurons (D2-MSNs). Using ex vivo whole cell recordings in male and female mice, we observe alterations in D1-MSN excitability across the estrous cycle similar in magnitude to the actions of cocaine in males. Furthermore, cocaine shifts estrous cycle-dependent plasticity from intrinsic excitability changes in D1-MSNs to D2-MSNs. Overall, while there are similar cocaine-induced disparities regarding the relative excitability of D1-MSN versus D2-MSN between the sexes, in males this is mediated through reduced D1-MSN excitability, whereas in females it is due to heightened D2-MSN excitability.

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• 67 Prospective Memory Accuracy and Speed in Mild Cognitive Impairment and Alzheimer's Disease

  Journal of the International Neuropsychological Society · 2023-11-01

  articleOpen access

  Objective: Prospective memory (PM) is the ability to execute a planned action in the future (e.g., remembering to take medication before going to bed). Prior work has suggested that PM failure can account for 50-80% of reported memory problems. Research has also shown that PM becomes increasingly impaired in the Alzheimer's disease (AD) process. To our knowledge, most PM studies use PM accuracy as a measure of PM performance. However, examining the speed of the response as it relates to the AD process remains relatively unexplored. In this study, we examined both PM accuracy and speed in healthy aging, mild cognitive impairment (MCI), and AD. Participants and Methods: Participants included healthy older controls (N=65), persons with MCI (N=70), and persons with AD (N=11). The PM task was embedded within a working memory task as PM demands often occur during an ongoing activity in everyday life. For the working memory component of the PM task, participants were shown a series of words and asked to continuously monitor the words while maintaining the last 3 in memory. All words were displayed within 1 of 6 background patterns. For the PM component, participants were asked to press "1" on the keyboard whenever they were shown a particular background pattern on the screen. PM abilities were measured using the median response time and total accuracy. Results: Age was correlated with PM accuracy. An ANCOVA, controlling for age, and examining the impact of diagnosis on PM accuracy, was significant. Post-hoc tests revealed a trend toward the AD and MCI groups being less accurate than healthy controls. In contrast to accuracy, age was not related to PM speed. An ANOVA examining the impact of diagnosis on PM accuracy found that the AD group responded faster than healthy controls. The MCI group did not show differences in speed from the healthy control and AD groups. Conclusions: Overall, the pattern of results differed in accuracy and speed of PM performance. There was a trend for the MCI and AD groups being less accurate than the controls, with no difference in performance between the MCI and AD groups. However, the AD group responded more quickly than the controls, which may have impacted their accuracy. These findings indicate that PM performance differences among groups can be detected by examining speed and not just accuracy. As speed appears to be an essential aspect involved in PM performance, future research should consider incorporating speed as a measure of PM performance when examining PM differences in populations.

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• Sex Differences in Cocaine Sensitization Vary by Mouse Strain

  Neuroendocrinology · 2023 · 11 citations

  1st authorCorresponding
  • Internal medicine
  • Physiology
  • Psychology

  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.

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Frequent coauthors

• Qing‐Hui Chen

  Michigan Technological University

  32 shared

• Zhiying Shan

  Michigan Technological University

  28 shared

• Le Gui

  Western University

  19 shared

• Robert A. Larson

  18 shared

• Michael Huber

  RWTH Aachen University

  17 shared

• Jessica E. Behnke

  Michigan Technological University

  12 shared

• Kyle M. Driscoll

  Michigan Technological University

  10 shared

• Jianhua Zhu

  9 shared