Null Mutation of 5α-Reductase Type I Gene Alters Ethanol Consumption Patterns in a Sex-Dependent Manner

Ford, Matthew M.; Nickel, Jeffrey D.; Kaufman, Moriah N.; Finn, Deborah A.

doi:10.1007/s10519-014-9694-2

Cited by 10 publications

(5 citation statements)

References 67 publications

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“…Importantly, knocking out the gene encoding the 5a‐reductase type I gene, essential in the synthesis of allopregnanolone, increased ethanol consumption in female mice (Ford et al . ). While the relationship between alcohol intake and neurosteroid signalling is complex, the observation that tolerance to the alcohol‐induced increase in neurosteroid levels developed in alcohol‐dependent animals (Khisti et al .…”

Section: Integrating the Human Genetic And Animal Studiesmentioning

confidence: 97%

GABA_A receptor subtype involvement in addictive behaviour

Stephens

King

Lambert

et al. 2016

Genes Brain and Behavior

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GABA A receptors form the major class of inhibitory neurotransmitter receptors in the mammalian brain. This review sets out to summarize the evidence that variations in genes encoding GABA A receptor isoforms are associated with aspects of addictive behaviour in humans, while animal models of addictive behaviour also implicate certain subtypes of GABA A receptor. In addition to outlining the evidence for the involvement of specific subtypes in addiction, we summarize the particular contributions of these isoforms in control over the functioning of brain circuits, especially the mesolimbic system, and make a first attempt to bring together evidence from several fields to understanding potential involvement of GABA A receptor subtypes in addictive behaviour. While the weight of the published literature is on alcohol dependency, the underlying principles outlined are relevant across a number of different aspects of addictive behaviour.Keywords: Alcohol, animal model, benzodiazepine, conduct disorder, electrophysiology, gene association, gene knockout, impulsivity, nucleus accumbens, psychostimulant, reward Received 31 May 2016, revised 19 July 2016, accepted for publication 15 August 2016Both human and animal studies have implicated GABA A receptors in addiction processes. This article sets out to review the evidence for GABA A receptor involvement in relation to alcoholism and addiction to other drugs of abuse. It will begin with a summary of the structure and function of GABA A receptors and their subtype diversity, before reviewing the human and animal literature providing genetic and behavioural evidence for the role of GABA A receptors in addictive behaviour. Finally, we will attempt to integrate these data into our understanding of addiction processes, and their underlying neurobiology. While the review concerns itself broadly with GABAergic systems and addictive behaviour, the weight of the published literature is on alcohol dependency. Nevertheless, the underlying principles outlined are relevant across a number of different aspects of addictive behaviour.

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Section: Integrating the Human Genetic And Animal Studiesmentioning

confidence: 97%

GABA_A receptor subtype involvement in addictive behaviour

Stephens

King

Lambert

et al. 2016

Genes Brain and Behavior

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“…During 2BC sessions, mice had access to a 10% v/v ethanol bottle (Supplementary Methods) and a water bottle. Drinking patterns were acquired by lickometer circuits and recorded via MED-PC IV software (MED Associates, Inc., St. Albans, VT USA) [28]. Lick events were analyzed by custom R scripts (www.r-project.org), and a 'bout' was defined as ≥20 licks with <5-min pause between consecutive licks.…”

Section: Drinking Paradigmsmentioning

confidence: 99%

Modulation of Gpr39, a G-protein coupled receptor associated with alcohol use in non-human primates, curbs ethanol intake in mice

Carlson

Ford

Carlson

et al. 2019

Neuropsychopharmacol.

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Alcohol use disorder (AUD) is a chronic condition with devastating health and socioeconomic effects. Still, pharmacotherapies to treat AUD are scarce. In a prior study aimed at identifying novel AUD therapeutic targets, we investigated the DNA methylome of the nucleus accumbens core (NAcc) of rhesus macaques after chronic alcohol use. The G-protein coupled receptor 39 (GPR39) gene was hypermethylated and its expression downregulated in heavy alcohol drinking macaques. GPR39 encodes a Zn 2+-binding metabotropic receptor known to modulate excitatory and inhibitory neurotransmission, the balance of which is altered in AUD. These prior findings suggest that a GPR39 agonist would reduce alcohol intake. Using a drinking-in-the-dark two bottle choice (DID-2BC) model, we showed that an acute 7.5 mg/kg dose of the GPR39 agonist, TC-G 1008, reduced ethanol intake in mice without affecting total fluid intake, locomotor activity or saccharin preference. Furthermore, repeated doses of the agonist prevented ethanol escalation in an intermittent access 2BC paradigm (IA-2BC). This effect was reversible, as ethanol escalation followed agonist "wash out". As observed during the DID-2BC study, a subsequent acute agonist challenge during the IA-2BC procedure reduced ethanol intake by~47%. Finally, Gpr39 activation was associated with changes in Gpr39 and Bdnf expression, and in glutamate release in the NAcc. Together, our findings suggest that GPR39 is a promising target for the development of prevention and treatment therapies for AUD.

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“…Illustrating this approach, two companion papers in this Special Issue examine the effects of a specific gene, Srd5a1 , which is involved in the synthesis of allopregnanolone (a neuroactive steroid that is synthesized from progesterone), on alcohol use behavior in an animal model (Ford, Nickel, Kaufman, and Finn, 2015; Tanchuck-Nipper et al, 2015). Two other papers use family designs to examine the links between hormonal processes and (latent) genetic risks for psychopathology.…”

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confidence: 99%