Central amygdala mineralocorticoid receptors modulate alcohol self-administration

Makhijani, Viren H.; Irukulapati, Preethi; Voorhies, Kalynn Van; Fortino, Brayden; Besheer, Joyce

doi:10.1016/j.neuropharm.2020.108337

Cited by 14 publications

(6 citation statements)

References 56 publications

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“…Levels of aldosterone, a ligand for MR, increase with chronic alcohol exposure in monkeys and are associated with craving and alcohol intake in alcohol-dependent patients ( Aoun et al, 2018 ). Antagonizing MR also effectively reduced alcohol self-administration when administered systemically or directly into the central amygdala (CeA) of rats ( Makhijani et al, 2020 ). Steroid receptor co-activator 1 (SRC-1), a histone acetyltransferase, also regulates GR activity and may be an important epigenetic factor in the response of GR to alcohol ( Edwards et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Corticosterone Levels and Glucocorticoid Receptor Gene Expression in High Drinking in the Dark Mice and Their Heterogeneous Stock (HS/NPT) Founder Line

Savarese

Grigsby

Jensen

et al. 2022

Front. Behav. Neurosci.

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The High Drinking in the Dark (HDID-1) line of mice has been selectively bred for achieving high blood alcohol levels (BALs) in the Drinking in the Dark task, a model of binge-like drinking. Recently, we determined that glucocorticoid receptor (GR) antagonism with either mifepristone or CORT113176 (a selective GR antagonist) reduced binge-like ethanol intake in the HDID-1 mice, but not in their founder line, HS/NPT. Here, we examined whether the selection process may have altered glucocorticoid functioning by measuring (1) plasma corticosterone levels and (2) expression of the genes encoding GR (Nr3c1) and two of its chaperone proteins FKBP51 and FKBP52 (Fkbp5 and Fkbp4) in the brains (nucleus accumbens, NAc) of HDID-1 and HS/NPT mice. We observed no genotype differences in baseline circulating corticosterone levels. However, HDID-1 mice exhibited a greater stimulated peak corticosterone response to an IP injection (of either ethanol or saline) relative to their founder line. We further observed reduced basal expression of Fkbp4 and Nr3c1 in the NAc of HDID-1 mice relative to HS/NPT mice. Finally, HDID-1 mice exhibited reduced Fkbp5 expression in the NAc relative to HS/NPT mice following an injection of 2 g/kg ethanol. Together, these data suggest that selective breeding for high BALs may have altered stress signaling in the HDID-1 mice, which may contribute to the observed selective efficacy of GR antagonism in reducing binge-like ethanol intake in HDID-1, but not HS/NPT mice. These data have important implications for the role that stress signaling plays in the genetic risk for binge drinking.

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Section: Discussionmentioning

confidence: 99%

Corticosterone Levels and Glucocorticoid Receptor Gene Expression in High Drinking in the Dark Mice and Their Heterogeneous Stock (HS/NPT) Founder Line

Savarese

Grigsby

Jensen

et al. 2022

Front. Behav. Neurosci.

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“…In contrast, eplerenone is selective for MR and was used to evaluate the brain region-specific effects of an MR blockade on alcohol drinking. Similar to systemic spironolactone administration, the intra-CeA infusion of eplerenone reduced alcohol intake without affecting general locomotion, further highlighting the role of CeA MRs in alcohol intake.…”

Section: Aldosterone/mr System and Alcohol Usementioning

confidence: 87%

“…Systemic administration of the MR antagonist spironolactone significantly reduced alcohol self- administration in non-dependent female rats. 2 Spironolactone is a non-selective MR antagonist that also binds, with lower affinity, to both androgen and progesterone receptors. In contrast, eplerenone is selective for MR and was used to evaluate the brain region-specific effects of an MR blockade on alcohol drinking.…”

Section: ■ Aldosterone/mr System and Alcohol Usementioning

confidence: 99%

“…Later, work by Makhijani and colleagues evaluated whether pharmacologic manipulations of the aldosterone/MR system influence alcohol intake. Systemic administration of the MR antagonist spironolactone significantly reduced alcohol self-administration in non-dependent female rats . Spironolactone is a non-selective MR antagonist that also binds, with lower affinity, to both androgen and progesterone receptors.…”

Section: Aldosterone/mr System and Alcohol Usementioning

confidence: 99%

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The Mineralocorticoid Receptor: An Emerging Pharmacotherapeutic Target for Alcohol Use Disorder?

Lékó

McGinn

Farokhnia

2022

ACS Chem. Neurosci.

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Despite the high prevalence and negative consequences associated with alcohol use disorder (AUD), currently available pharmacotherapies are limited in number and efficacy. Several neuroendocrine pathways have been identified and are under investigation as potential pharmacotherapeutic targets for AUD. Here, we present the promise of the mineralocorticoid receptor (MR) as a novel target and discuss associations between the aldosterone/MR system and AUD, the effects of MR antagonism on alcohol consumption, and the underlying neurobiology of these effects.

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“…Rats were trained to self-administer a 15% (v/v) alcohol on a fixed ratio 2 (FR2) schedule of reinforcement in 30-minute sessions, five days a week (M-F) via sucrose fading as described in (Randall et al, 2017;Randall et al, 2019;Makhijani et al, 2020;Ornelas et al, 2021). Sucrose fading began with self-administration of 10% sucrose and 2% alcohol (2A/10S), then 5A/10S, 10A/10S, 10A/5S, 15A/5S, 15A/2S on subsequent sessions, and then remained at 15A for the duration of training.…”

Section: Alcohol Self-administration Trainingmentioning

confidence: 99%

RTICBM-74 is a Brain-Penetrant CB₁Receptor Allosteric Modulator that Reduces Alcohol Intake in Rats

Lovelock

Nguyễn

Voorhies

et al. 2021

Preprint

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The endocannabinoid system is implicated in the neuronal mechanisms of alcohol use disorder (AUD), with the cannabinoid receptor subtype 1 (CB1) representing a promising target for AUD therapeutic interventions. We have previously shown negative allosteric modulators (NAMs) of the CB1 receptor attenuated the reinstatement of other drugs of abuse including cocaine and methamphetamine in rats; however, their effects on alcohol-related behaviors have not been investigated. Here, we tested the pharmacokinetic properties of one such CB1 NAM, RTICBM-74, and its effects on alcohol self-administration in rats. RTICBM-74 showed low aqueous solubility and high protein binding but had excellent half-life and low clearance against rat liver microsomes and hepatocytes, and excellent brain penetrance in rats. RTICBM-74 pretreatment specifically reduced alcohol intake across a range of doses in male or female Wistar or Long-Evans rats that were trained to self-administer alcohol. These effects were similar to the CB1 antagonist/inverse agonist rimonabant which was tested as a positive control. Importantly, RTICBM-74 was effective at reducing alcohol intake at doses that did not affect locomotion or sucrose self-administration. Our findings suggest that CB1 NAMs such as RTICBM-74 have promising therapeutic potential in treatment of AUD.

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Central amygdala mineralocorticoid receptors modulate alcohol self-administration

Cited by 14 publications

References 56 publications

Corticosterone Levels and Glucocorticoid Receptor Gene Expression in High Drinking in the Dark Mice and Their Heterogeneous Stock (HS/NPT) Founder Line

Corticosterone Levels and Glucocorticoid Receptor Gene Expression in High Drinking in the Dark Mice and Their Heterogeneous Stock (HS/NPT) Founder Line

The Mineralocorticoid Receptor: An Emerging Pharmacotherapeutic Target for Alcohol Use Disorder?

RTICBM-74 is a Brain-Penetrant CB₁Receptor Allosteric Modulator that Reduces Alcohol Intake in Rats

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Central amygdala mineralocorticoid receptors modulate alcohol self-administration

Cited by 14 publications

References 56 publications

Corticosterone Levels and Glucocorticoid Receptor Gene Expression in High Drinking in the Dark Mice and Their Heterogeneous Stock (HS/NPT) Founder Line

Corticosterone Levels and Glucocorticoid Receptor Gene Expression in High Drinking in the Dark Mice and Their Heterogeneous Stock (HS/NPT) Founder Line

The Mineralocorticoid Receptor: An Emerging Pharmacotherapeutic Target for Alcohol Use Disorder?

RTICBM-74 is a Brain-Penetrant CB1Receptor Allosteric Modulator that Reduces Alcohol Intake in Rats

Contact Info

Product

Resources

About

RTICBM-74 is a Brain-Penetrant CB₁Receptor Allosteric Modulator that Reduces Alcohol Intake in Rats