Biology subjects

Gipson, C. D.

Publications and source records attributed to Gipson, C. D..

5 recordsLinked to original sources

bioRxiv2025

Estrogen Receptor Beta Localized on Ventral Tegmental Area Dopamine Neurons Regulates Nicotine Self-Administration Acquisition in Ovary-Intact Female Rats

Women exhibit greater nicotine use vulnerability than men. High estradiol (E2) exacerbates nicotine use outcomes in women, effects which have been modeled in preclinical nicotine self-administration (SA) studies. Nicotine SA is maintained by dopamine (DA) release from the ventral tegmental area (VTA) to the nucleus accumbens (NA). E2 exerts its effects by binding to estrogen receptors (ER), including ER, ER{beta}, and G-protein coupled ER-1 (GPER-1)s. E2 action at ERs specifically has been shown to potentiate DA neuronal excitability within the VTA. Further, we have shown that ovariectomy decreases both nicotine use during SA and VTA ER{beta} protein. Despite clear evidence of mechanistic relationships between E2, ERs, DA, and nicotine, no studies to date have functionally evaluated the specific role of ER{beta} located on VTA DA cells in driving nicotine consumption during SA in females. There are currently no tools that allow for evaluations of relationships between nicotine neurobiology and ERs with cell-type specificity, as ER{beta} is also localized on other (non-DA) cell types within the VTA. As such, the goals of the present studies were (1) to build and validate a novel adeno-associated viral construct that produces long-term knockdown of ER{beta} specifically on VTA DA neurons, and (2) to determine if VTA DA ER{beta} viral knockdown reduces nicotine SA in ovary-intact female rats. Here we show that ER{beta} regulates VTA DA neuron excitability, and that ER{beta} knockdown in VTA DA neurons reduces DA neuron firing frequency. We also show that VTA ER{beta} knockdown in DA neurons reduces nicotine SA acquisition in ovary-intact female rats. Together, our results demonstrate a critical role of ER{beta} in driving nicotine use in females, underscoring the need for future studies to evaluate neurobehavioral mechanisms of smoking through the lens of sex differences.

neuroscience↗

bioRxiv2025

Utility of the Recombinase Driver CX3CR1::Cre Rat Strain to Evaluate Microglial Contributions to Nicotine Addiction

Smoking remains a leading preventable cause of death, and nicotine is the primary substance responsible for maintaining use of tobacco products. Preclinical rodent models have shown that neuroimmune signaling is dysregulated by nicotine self-administration (SA) within the nucleus accumbens core (NAcore), which is a key region within the mesolimbic brain reward pathway. Microglia are the resident brain immune cell and prior studies have shown that they play an important role in nicotine-related behaviors. However, while there are transgenic mouse lines that allow for specific evaluations of microglia to neurobiology and behavior, there are fewer tools available for rats as a model species thus limiting our ability to evaluate specific contributions of microglia to nicotine SA. Using transgenic rats expressing Cre under the control of the CX3CR1 promoter bred on a Long Evans (LE) background, we show that NAcore microglia can be specifically transduced with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). We further show that CX3CR1::Cre rats readily self-administer nicotine, and display a characteristic extinction curve that is not different from outbred LE or Cre-negative littermates. Together, these validation studies lay the foundation for future use of this transgenic rat line to evaluate the specific contributions of microglia in the brain to neurobehavioral underpinnings of nicotine addiction.

neuroscience↗

bioRxiv2023

Xylazine co-self-administration suppresses fentanyl consumption during self-administration and induces a unique sex-specific withdrawal syndrome that is not altered by naloxone in rats

Prescription and illicit opioid use are a public health crisis, with the landscape shifting to fentanyl use. Since fentanyl is 100-fold more potent than morphine, its use is associated with a higher risk of fatal overdose that can be remediated through naloxone (Narcan) administration. However, recent reports indicate that xylazine, an anesthetic, is increasingly detected in accidental fentanyl overdose deaths. Anecdotal reports suggest that xylazine may prolong the fentanyl "high", alter the onset of fentanyl withdrawal, and increase resistance to naloxone-induced reversal of overdose. To date no preclinical studies have evaluated the impacts of xylazine on fentanyl self-administration (SA; 2.5 g/kg/infusion) or withdrawal to our knowledge. We established a rat model of xylazine/fentanyl co-SA and withdrawal and evaluated outcomes as a function of biological sex. When administered alone, chronic xylazine (2.5 mg/kg, IP) induced unique sex-specific withdrawal symptomatology whereby females showed delayed onset of signs and a possible enhancement of sensitivity to the motor-suppressing effects of xylazine. Xylazine reduced fentanyl consumption both male and female rats regardless of whether it was experimenter-administered or added to the intravenous fentanyl product (0.05. 0.10, and 0.5 mg/kg/infusion) when compared to fentanyl SA alone. Interestingly, this effect was dose-dependent when self-administered intravenously. Naloxone (0.1 mg/kg, SC) did not increase somatic signs of fentanyl withdrawal, regardless of the inclusion of xylazine in the fentanyl infusion in either sex; however, somatic signs of withdrawal were higher across timepoints in females after xylazine/fentanyl co-SA regardless of naloxone exposure as compared to females following fentanyl SA alone. Together, these results indicate that xylazine/fentanyl co-SA dose-dependently suppressed fentanyl intake in both sexes, and induced a unique withdrawal syndrome in females which was not altered by acute naloxone treatment.

animal behavior and cognition↗

bioRxiv2020

Accumbens cholinergic interneurons mediate cue-induced nicotine seeking and associated glutamatergic plasticity

Nicotine, the primary addictive substance in tobacco, is widely abused. Relapse to cues associated with nicotine results in increased glutamate release within nucleus accumbens core (NAcore), modifying synaptic plasticity of medium spiny neurons (MSNs) which contributes to reinstatement of nicotine seeking. However, the role of cholinergic interneurons (ChIs) within the NAcore in mediating these neurobehavioral processes in unknown. ChIs represent less than 1% of the accumbens neuronal population yet are activated during drug seeking and reward-predicting events. Thus, we hypothesized that ChIs may play a significant role in mediating glutamatergic plasticity that underlies nicotine seeking behavior. Using chemogenetics transgenic rats that express Cre under the control of the choline acetyltransferase (ChAT) promoter, ChIs were bi-directionally manipulated prior to cue-induced reinstatement. Following nicotine self-administration and extinction training, ChIs were activated or inhibited prior to a cue reinstatement session. Following reinstatement, whole-cell electrophysiology from NAcore MSNs was used to assess changes in plasticity, measured via -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) / N-Methyl-D-Aspartate (NMDA) (A/N) ratios. Chemogenetic inhibition of ChIs inhibited cued nicotine seeking and resulted in decreased A/N, whereas activation of ChIs had no effect, demonstrating that ChI inhibition prevents transient synaptic potentiation (t-SP) associated with cue-induced nicotine seeking. To assess potential underlying mechanisms, accumbens 4{beta}2- and 7-containing nicotinic ACh receptors (nAChRs) were pharmacologically inhibited and MSN synaptic morphology was assessed following reinstatement. Inhibition of both nAChR subtypes prevented cue-induced nicotine seeking and t-SP (measured via changes in spine head diameter). Together, these results demonstrate that these neurons mediate cue-induced nicotine reinstatement and underlying synaptic plasticity within the NAcore.

neuroscience↗

bioRxiv2020

Establishing Preclinical Withdrawal Syndrome Symptomatology Following Heroin Self-Administration in Male and Female Rats

Opioid use disorder (OUD) is a significant health problem, and understanding mechanisms of various aspects of OUD including drug use and withdrawal is important. Preclinical models provide an ideal opportunity to evaluate mechanisms underlying opioid withdrawal. Current models are limited by their reliance upon forced opioid administration, focus on the acute (and not protracted) syndrome, and exclusion of females. In this study, male and female rats self-administered heroin (maintenance dose of 12.5 g/kg/infusion) opioid withdrawal following abrupt discontinuation was measured. In Phase 1, acute withdrawal symptoms were rated in male and female rats at 0, 16, 48, and 72 hrs following the last self-administration session. Total somatic signs increased until 48 hrs (predominantly in females), and heroin intake positively correlated with total somatic signs at the 48 and 72 hr timepoints. Measures of hyperactivity and anxiety-like behavior increased by 16 and 48 hrs, respectively. In Phase 2, symptoms were assessed at baseline, acute, and protracted (168 and 312 hrs after self-administration) timepoints in a subset of male and female rats from Phase 1. The total number of somatic signs did not differ across timepoints, though females displayed significantly higher body temperature at all timepoints compared to males, indicating sex-specific protracted withdrawal symptomatology. These data provide a thorough characterization of rodent opioid withdrawal symptomatology following self-administration and abrupt discontinuation that serve as a foundation for future studies designed to mimic the human experience, and demonstrate the importance of characterizing acute and protracted withdrawal with sex-specificity in preclinical models of opioid self-administration.

animal behavior and cognition↗