Systemic Administration of the Cyclin‐Dependent Kinase Inhibitor (S)‐CR8 Selectively Reduces Escalated Ethanol Intake in Dependent Rats

Autor: Giordano de Guglielmo, Olivier George, Lieselot L. G. Carrette, Candice Contet, Scott P. Goulding
Rok vydání: 2019
Předmět:
Male
endocrine system
Alcohol Drinking
Pyridines
030508 substance abuse
Medicine (miscellaneous)
Self Administration
Pharmacology
Toxicology
Article
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Extended amygdala
Cyclin-dependent kinase
Administration
Inhalation
mental disorders
Roscovitine
medicine
Animals
Enzyme Inhibitors
Phosphorylation
Rats
Wistar
Protein Kinase Inhibitors
Saccharin
reproductive and urinary physiology
Dose-Response Relationship
Drug
Ethanol
biology
Kinase
Cyclin-dependent kinase 5
Central Nervous System Depressants
Cyclin-Dependent Kinase 5
Amygdala
Rats
Alcoholism
Psychiatry and Mental health
Stria terminalis
medicine.anatomical_structure
nervous system
chemistry
Purines
biology.protein
Conditioning
Operant
0305 other medical science
030217 neurology & neurosurgery
CDK inhibitor
Basolateral amygdala
Zdroj: Alcohol Clin Exp Res
ISSN: 1530-0277
0145-6008
Popis: BACKGROUND. Chronic exposure to ethanol and other drugs of abuse can alter the expression and activity of cyclin-dependent kinase 5 (CDK5) and its cofactor p35, but the functional implication of CDK5 signaling in the regulation of ethanol-related behaviors remains unknown. In the present study, we sought to determine whether CDK5 activity plays a role in the escalation of ethanol self-administration triggered by dependence. METHODS. We tested the effect of systemically administered (S)-CR8, a non-selective CDK inhibitor, on operant responding for ethanol or saccharin, a highly palatable reinforcer, in adult male Wistar rats. Half of the rats were made ethanol-dependent via chronic intermittent ethanol inhalation (CIE). We then sought to identify a possible neuroanatomical locus for the behavioral effect of (S)-CR8 by quantifying protein levels of CDK5 and p35 in subregions of the extended amygdala and prefrontal cortex from ethanol-naïve, non-dependent, and dependent rats at the expected time of ethanol self-administration. We also analyzed the phosphorylation of four CDK5 substrates and of the CDK substrate consensus motif. RESULTS. (S)-CR8 dose-dependently reduced ethanol self-administration in dependent rats. It had no effect on water or saccharin self-administration, nor in non-dependent rats. The abundance of CDK5 or p35 was not altered in any of the brain regions analyzed. In the bed nucleus of the stria terminalis, CDK5 abundance was negatively correlated with intoxication levels during ethanol vapor exposure but there was no effect of dependence on the phosphorylation ratio of CDK5 substrates. In contrast, ethanol dependence increased the phosphorylation of low-molecular weight CDK substrates in the basolateral amygdala. CONCLUSIONS. The selective effect of (S)-CR8 on excessive ethanol intake has potential therapeutic value for the treatment of alcohol use disorders. Our data do not support the hypothesis that this effect would be mediated by the inhibition of upregulated CDK5 activity in the extended amygdala nor prefrontal cortex. However, increased activity of CDKs other than CDK5 in the basolateral amygdala may contribute to excessive ethanol consumption in alcohol dependence. Other (S)-CR8 targets may also be implicated.
Databáze: OpenAIRE
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