mGlu5 inhibition in the basolateral amygdala prevents estrous cycle-dependent changes in cue-induced cocaine seeking

Corbett, Claire M.; Miller, Emily N D; Loweth, Jessica A.

doi:10.1016/j.addicn.2022.100055

Cited by 11 publications

(15 citation statements)

References 67 publications

(99 reference statements)

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“…Rats were group housed by sex during the initial acclimation period (5–7 days) and singly housed immediately following surgery and for the remainder of the experiment. Following the acclimation period, all rats underwent surgery to implant a catheter into the jugular vein [17, 18, 19, 23]. Rats were anesthetized with ketamine and xylazine (males: 80 mg/kg and 10 mg/kg, i.p.…”

Section: Methodsmentioning

confidence: 99%

“…To investigate this, we conducted ex vivo patch clamp recordings of BLA pyramidal neurons following 2–4 weeks withdrawal from extended-access cocaine self-administration or drug-naïve conditions in adult male and female rats and across the estrous cycle. Baseline changes in spontaneous excitatory postsynaptic currents (sEPSCs) and intrinsic excitability were assessed because these properties influence the spontaneous activity of BLA pyramidal neurons [21, 22] and because our recent behavioral studies are suggestive of an interaction between cocaine exposure and estrous cycle fluctuations on glutamatergic transmission in the BLA [18]. These studies will enhance our understanding of how cocaine exposure, sex, and estrous cycle fluctuations impact BLA physiology.…”

Section: Introductionmentioning

confidence: 99%

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Cocaine Exposure Increases Excitatory Synaptic Transmission and Intrinsic Excitability in the Basolateral Amygdala in Male and Female Rats and across the Estrous Cycle

Corbett,

Miller,

Wannen

et al. 2023

Neuroendocrinology

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Introduction: Sex and ovarian hormones influence cocaine seeking and relapse vulnerability, but less is known regarding the cellular and synaptic mechanisms contributing to these behavioral sex differences. One factor thought to influence cue-induced seeking behavior following withdrawal is cocaine-induced changes in the spontaneous activity of pyramidal neurons in the basolateral amygdala (BLA). However, the mechanisms underlying these changes, including potential sex or estrous cycle effects, are unknown. Methods: Ex vivo whole cell patch clamp electrophysiology was conducted to investigate the effects of cocaine exposure, sex and estrous cycle fluctuations on two properties that can influence spontaneous activity of BLA pyramidal neurons: 1). Frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) and 2). Intrinsic excitability. Recordings of BLA pyramidal neurons were conducted in adult male and female rats and across the estrous cycle following 2-4 weeks of withdrawal from extended-access cocaine self-administration (6h/day for 10 days) or drug-naïve conditions. Results: In both sexes, cocaine exposure increased the frequency, but not amplitude, of sEPSCs and neuronal intrinsic excitability. Across the estrous cycle, sEPSC frequency and intrinsic excitability were significantly elevated only in cocaine-exposed females in the estrus stage of the cycle, a stage when cocaine seeking behavior is known to be enhanced. Conclusions: Here we identify potential mechanisms underlying cocaine-induced alterations in the spontaneous activity of BLA pyramidal neurons in both sexes along with changes in these properties across the estrous cycle.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cocaine Exposure Increases Excitatory Synaptic Transmission and Intrinsic Excitability in the Basolateral Amygdala in Male and Female Rats and across the Estrous Cycle

Corbett,

Miller,

Wannen

et al. 2023

Neuroendocrinology

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“…New evidence also supports that distinct neural mechanisms mediate oestrous cycle‐dependent cocaine seeking. For example, injections of mGlu5 antagonist into basolateral amygdala decreased incubated cocaine seeking only in oestrus female rats, but not nonoestrus female or male rats 27 . In contrast, no effect of oestrous cycle is observed on incubation of heroin or sucrose craving 20,22 .…”

Section: Introductionmentioning

confidence: 94%

“…It is of note that for the analysis of oxycodone seeking data, we combined pro-oestrus, dioestrus, and metoestrus together as the nonoestrus stage, to be consistent with previous literature on cocaine and heroin seeking. 16,17,20,26,27,[32][33][34] To ensure that there were enough oestrus and nonoestrus females, we tested rats for oxycodone seeking on abstinence day 14, 15, or 16.…”

Section: Experiments 1: Effect Of Oestrous Cycle On Oxycodone Seeking...mentioning

confidence: 99%

“…For example, injections of mGlu5 antagonist into basolateral amygdala decreased incubated cocaine seeking only in oestrus female rats, but not nonoestrus female or male rats. 27 In contrast, no effect of oestrous cycle is observed on incubation of heroin or sucrose craving. 20,22 However, whether the oestrous cycle plays a role in incubated oxycodone seeking is unknown.…”

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confidence: 97%

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Role of oestrous cycle and orbitofrontal cortex in oxycodone seeking after 15‐day abstinence in female rats

Olaniran,

Altshuler,

Burke

et al. 2023

Addiction Biology

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Relapse to oxycodone seeking progressively increases after abstinence in rats, a phenomenon termed incubation of oxycodone craving. We have previously shown that the orbitofrontal cortex (OFC) plays a critical role in incubation of oxycodone craving in male rats. Here, we examined the effect of oestrous cycle on incubated oxycodone seeking in female rats, and whether the critical role of OFC in incubated oxycodone seeking generalizes to female rats. We first assessed oxycodone self‐administration and incubated oxycodone seeking on abstinence day 15 across the oestrous cycle. Next, we determined the effect of chemogenetic inactivation of OFC by JHU37160 (J60), a novel agonist for Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), on incubated oxycodone seeking on abstinence day 15. Finally, we determined the effect of J60 alone on incubated oxycodone seeking on abstinence day 15. We found no difference in oxycodone intake across oestrus, pro‐oestrus, and metoestrus stages during oxycodone self‐administration training. Incubated oxycodone seeking was also similar between nonoestrus and oestrus female rats. Moreover, chemogenetic inactivation of OFC by J60 decreased incubated oxycodone seeking on abstinence day 15, while J60 alone had no effect on incubated oxycodone seeking in no‐DREADD control rats. Taken together, results here show that the oestrous cycle has no effect on oxycodone intake and incubated oxycodone seeking in female rats under our experimental conditions. Furthermore, consistent with our previous findings in male rats, results here show that OFC also plays a critical role in incubated oxycodone seeking in female rats.

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The mGlu5 receptor negative allosteric modulator mavoglurant reduces escalated cocaine self-administration in male and female rats

Vendruscolo,

Whiting

et al. 2024

Psychopharmacology

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Rationale Cocaine use disorder (CUD) is a brain disorder for which there is no Food and Drug Administration-approved pharmacological treatment. Evidence suggests that glutamate and metabotropic glutamate receptor subtype 5 (mGlu5) play critical roles in synaptic plasticity, neuronal development, and psychiatric disorders. Objective In the present study, we tested the hypothesis that the mGlu5 receptor is functionally involved in intravenous cocaine self-administration and assessed the effects of sex and cocaine exposure history. Methods We used a preclinical model of CUD in rats that were allowed long access (LgA; 6 h/day) or short access (ShA; 1 h/day) to intravenous cocaine (750 µg/kg/infusion [0.1 ml]) self-administration. Rats received acute intraperitoneal or oral administration of the mGlu5 receptor negative allosteric modulator mavoglurant (1, 3, and 10 mg/kg) or vehicle. Results Both intraperitoneal and oral mavoglurant administration dose-dependently reduced intravenous cocaine self-administration in the first hour and in the entire 6 h session in rats in the LgA group, with no effect on locomotion. In the ShA group, mavoglurant decreased locomotion but had no effects on cocaine self-administration. We did not observe significant sex × treatment interactions. Conclusions These findings suggest that the mGlu5 receptor is involved in escalated cocaine self-administration. These findings support the development of clinical trials of mavoglurant to evaluate its potential therapeutic benefits for CUD.

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mGlu5 inhibition in the basolateral amygdala prevents estrous cycle-dependent changes in cue-induced cocaine seeking

Cited by 11 publications

References 67 publications

Cocaine Exposure Increases Excitatory Synaptic Transmission and Intrinsic Excitability in the Basolateral Amygdala in Male and Female Rats and across the Estrous Cycle

Cocaine Exposure Increases Excitatory Synaptic Transmission and Intrinsic Excitability in the Basolateral Amygdala in Male and Female Rats and across the Estrous Cycle

Role of oestrous cycle and orbitofrontal cortex in oxycodone seeking after 15‐day abstinence in female rats

The mGlu5 receptor negative allosteric modulator mavoglurant reduces escalated cocaine self-administration in male and female rats

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