Increased Alcohol Seeking in Mice Lacking Gpr88 Involves Dysfunctional Mesocorticolimbic Networks

Hamida, Sami Ben; Mendonça-Netto, Sueli; Arefin, Tanzil Mahmud; Nasseef, Taufiq; Lj, Boulos; McNicholas, Michael; Ehrlich, Aliza T.; Clarke, Ellie; Moquin, Luc; Gratton, Alain; Darcq, Emmanuel; Harsan, Laura‐Adela; Maldonado, Rafaël; Bl, Kieffer

doi:10.1016/j.biopsych.2018.01.026

Cited by 48 publications

(70 citation statements)

References 75 publications

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“…Because GPR88 KO mice showed enhanced motivation for alcohol drinking and seeking behaviors, 23 we sought to determine whether RTI-13951-33 would be effective in vivo to alter operant alcohol self-administration. Female Long Evans rats were trained to self-administer alcohol, as described in our recent publications (15% alcohol [v/v] + 2% [w/v] sucrose vs inactive lever).…”

Section: Resultsmentioning

confidence: 99%

“…18–22 Interestingly, a recent GPR88 KO study demonstrated that the GPR88-deficient mice displayed enhanced voluntary alcohol drinking in both moderate and excessive drinking paradigms compared with wild-type (WT) mice. 23 No alterations in water intake, palatability, and alcohol metabolism were observed in these mice. 23 Moreover, mice lacking the GPR88 gene showed enhanced motivation for alcohol drinking and seeking behaviors using operant self-administration.…”

Section: Introductionmentioning

confidence: 82%

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Discovery of a Potent, Selective, and Brain-Penetrant Small Molecule that Activates the Orphan Receptor GPR88 and Reduces Alcohol Intake

et al. 2018

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The orphan G-protein-coupled receptor GPR88 is highly expressed in the striatum. Studies using GPR88 knockout mice have suggested that the receptor is implicated in alcohol seeking and drinking behaviors. To date, the biological effects of GPR88 activation are still unknown due to the lack of a potent and selective agonist appropriate for in vivo investigation. In this study, we report the discovery of the first potent, selective, and brain-penetrant GPR88 agonist RTI-13951-33 (6). RTI-13951-33 exhibited an EC50 of 25 nM in an in vitro cAMP functional assay and had no significant off-target activity at 38 GPCRs, ion channels, and neurotransmitter transporters that were tested. RTI-13951-33 displayed enhanced aqueous solubility compared to (1R,2R)-2-PCCA (2) and had favorable pharmacokinetic properties for behavioral assessment. Finally, RTI-13951-33 significantly reduced alcohol self-administration and alcohol intake in a dose-dependent manner without effects on locomotion and sucrose self-administration in rats when administered intraperitoneally.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 82%

Discovery of a Potent, Selective, and Brain-Penetrant Small Molecule that Activates the Orphan Receptor GPR88 and Reduces Alcohol Intake

et al. 2018

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“…Bmal1SKO and Per2SKO mice and their respective HET counterparts have only one functional copy of Gpr88 in MSNs since one copy is modified to drive Cre and GFP expression. Complete deletion of Gpr88 has been shown to augment alcohol intake in male mice [47,48], raising the possibility that the changes in alcohol consumption seen in striatal Bmal1SKO and striatal Per2SKO were due, at least in part, to a contributory effect of Gpr88 monoallelic expression. To study this possibility, we compared alcohol intake and preference between Gpr88+/+ mice (males, n = 7; females, n = 10) and Gpr88Cre/+ mice (males, n = 7; females, n = 12).…”

Section: Gpr88 Monoallelic Expression Does Not Affect Alcohol Intakementioning

confidence: 99%

Sexually dimorphic influence of the circadian clock geneBmal1in the striatum on alcohol intake

Zavalía¹,

Schöttner²,

Goldsmith³

et al. 2020

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SummaryThe clock gene Bmal1 plays an obligatory role in the generation of circadian rhythms in gene expression, physiology, and behavior in mammals [1–4]. In mice, perturbations in Bmal1 expression in the brain are associated with loss of circadian rhythmicity and various physiological and behavioral disturbances, including disrupted sleep architecture and deficits in cognitive and affective behaviors [5–14]. Gene association studies in both humans and animals suggest that Bmal1 may also play a role in the control of appetitive behaviors such as alcohol preference and consumption [15–19]. Although there is evidence that genes that interact with Bmal1 in the molecular circadian clock, such as Per2 and Clock influence alcohol intake and preference [15, 20–23], experimental evidence of a causal role of Bmal1 is lacking. In addition, the specific brain regions where Bmal1 might affect alcohol consumption are not known. We investigated voluntary alcohol consumption in conditional knockout mice that lack BMAL1 protein exclusively in the striatum, which is an important structure in the control of alcohol intake and preference [24–29]. Particular emphasis was attributed to the investigation of male and female mice because of known sex differences in alcohol intake and preference [30–32], and the impact of a sexually dimorphic constitution of circadian clocks on behavior [33, 34]. We found that deletion of BMAL1 from the principal medium spiny neurons (MSNs) of the striatum significantly altered voluntary alcohol intake and preference, without affecting total fluid intake, sucrose preference, body weight, or circadian rhythms in behavior. Strikingly, there were major sex differences in the effect of striatal BMAL1 deletion on alcohol consumption. While striatal BMAL1 deletion augmented alcohol intake and preference in males, the same deletion suppressed intake and preference in females. Interestingly, striatal deletion of PER2, a clock gene that interacts with Bmal1 in the circadian clock, and which has been shown to limit alcohol consumption in mice [22], mimicked the effect of striatal BMAL1 deletion, albeit only in males. Together, our results reveal that BMAL1 in MSNs of the striatum plays a sexually dimorphic role in the control of alcohol intake in mice, restraining consumption in males, possibly by interacting with PER2, and promoting intake in females, independently of PER2. We therefore hypothesize that a sex-specific mechanism in the function of BMAL1 in MSNs of the striatum regulates differences between male and female mice in the propensity to consume alcohol.

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“…Importantly, several of these GPCRs modulate behaviors related to drugs of abuse. For example, the receptor for melanin-concentrating hormone (MCHR1) modulates responses to psychostimulants, and the orphan GPCR, GPR88, modulates alcohol intake [16,[19][20][21][22]. To date, however, the role or necessity of neuronal cilia in responses to drugs of abuse is essentially unknown.…”

Section: Introductionmentioning

confidence: 99%

Neuron-specific cilia loss alters locomotor responses to amphetamine

Ramos

Roberts

Jasso

et al. 2020

Preprint

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The neural mechanisms that underlie responses to drugs of abuse are complex, and impacted by a number of neuromodulatory peptides. Within the past ten years it has been discovered that several of the receptors for neuromodulators are enriched in the primary cilia of neurons.Primary cilia are microtubule-based organelles that project from the surface of nearly all mammalian cells, including neurons. Despite what we know about cilia, our understanding of how cilia regulate neuronal function and behavior is still limited. The primary objective of this study was to investigate the contributions of primary cilia on specific neuronal populations to behavioral responses to amphetamine. To test the consequences of cilia loss on amphetamineinduced locomotor activity we selectively ablated cilia from dopaminergic or GAD2-GABAergic neurons in mice. Cilia loss had no effect on baseline locomotion in either mouse strain. Both female and male mice lacking cilia on dopaminergic neurons showed significantly reduced responses to acute administration of 3.0 mg/kg amphetamine compared to wildtype mice. In contrast, changes in the locomotor response to amphetamine in mice lacking cilia on GAD2-GABAergic neurons were primarily driven by reductions in locomotor activity in males. Following repeated amphetamine administration (1.0 mg/kg/day over 5 days), mice lacking cilia on GAD2-GABAergic neurons exhibited enhanced sensitization of the locomotor stimulant response to the drug, whereas mice lacking cilia on dopaminergic neurons did not differ from their wildtype controls. These results indicate that cilia play neuron-specific roles in both acute and neuroplastic responses to psychostimulant drugs of abuse.

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Increased Alcohol Seeking in Mice Lacking Gpr88 Involves Dysfunctional Mesocorticolimbic Networks

Cited by 48 publications

References 75 publications

Discovery of a Potent, Selective, and Brain-Penetrant Small Molecule that Activates the Orphan Receptor GPR88 and Reduces Alcohol Intake

Discovery of a Potent, Selective, and Brain-Penetrant Small Molecule that Activates the Orphan Receptor GPR88 and Reduces Alcohol Intake

Sexually dimorphic influence of the circadian clock geneBmal1in the striatum on alcohol intake

Neuron-specific cilia loss alters locomotor responses to amphetamine

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