Effects of the Alpha-1 Antagonist Prazosin on KOR Agonist-Induced Reinstatement of Alcohol Seeking.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
/ pharmacology
Adrenergic alpha-1 Receptor Antagonists
/ pharmacology
Alcoholism
/ drug therapy
Animals
Behavior, Animal
/ drug effects
Brain
/ drug effects
Central Nervous System Depressants
/ administration & dosage
Disease Models, Animal
Ethanol
/ administration & dosage
Gene Expression
/ drug effects
Genes, fos
/ drug effects
Male
Prazosin
/ pharmacology
Rats
Rats, Long-Evans
Receptors, Opioid, kappa
/ agonists
Stress, Psychological
/ drug therapy
Fos
alpha-1 adrenoceptor
kappa opioid
noradrenaline
stress
Journal
The international journal of neuropsychopharmacology
ISSN: 1469-5111
Titre abrégé: Int J Neuropsychopharmacol
Pays: England
ID NLM: 9815893
Informations de publication
Date de publication:
01 11 2019
01 11 2019
Historique:
received:
19
07
2019
revised:
20
08
2019
accepted:
16
09
2019
pubmed:
27
9
2019
medline:
13
5
2020
entrez:
27
9
2019
Statut:
ppublish
Résumé
Stress is associated with relapse to alcohol seeking during abstinence, but the processes underlying this relationship are poorly understood. Noradrenaline is a key transmitter in stress responses and in stress-induced drug seeking. The alpha-1 adrenoceptor antagonist prazosin has been investigated as a treatment for alcoholism and for chronic stress disorders that are frequently comorbid with alcoholism. In rats, we previously showed that prazosin blocks reinstatement of alcohol seeking induced by footshock and yohimbine stressors and reduces yohimbine-induced brain activation. The role of alpha-1 adrenoceptors in reinstatement induced by other stressors is not known. Our most recent work is on the role of kappa opioid receptors in stress-induced reinstatement of alcohol seeking and have reported that the selective kappa opioid receptor agonist U50,488 induces reinstatement and neuronal activation in stress- and relapse-related brain regions. Here we determine the involvement of alpha-1 receptors in reinstatement and brain activation induced by U50,488. We trained male Long-Evans rats to self-administer alcohol (12% w/v), extinguished alcohol-reinforced responding, and then determined the effects of prazosin (1 mg/kg) on U50,488 (2.5 mg/kg)-induced reinstatement and regional Fos expression. Prazosin blocked U50,488-induced reinstatement and decreased U50,488-induced Fos expression in the orbitofrontal cortex, nucleus accumbens core, ventral bed nucleus of the stria terminalis, central and basolateral amygdalar nuclei and ventral tegmental area. These findings suggest that prazosin may reduce U50,488-induced relapse by inhibiting activity in 1 or more of these brain areas.
Sections du résumé
BACKGROUND
Stress is associated with relapse to alcohol seeking during abstinence, but the processes underlying this relationship are poorly understood. Noradrenaline is a key transmitter in stress responses and in stress-induced drug seeking. The alpha-1 adrenoceptor antagonist prazosin has been investigated as a treatment for alcoholism and for chronic stress disorders that are frequently comorbid with alcoholism. In rats, we previously showed that prazosin blocks reinstatement of alcohol seeking induced by footshock and yohimbine stressors and reduces yohimbine-induced brain activation. The role of alpha-1 adrenoceptors in reinstatement induced by other stressors is not known. Our most recent work is on the role of kappa opioid receptors in stress-induced reinstatement of alcohol seeking and have reported that the selective kappa opioid receptor agonist U50,488 induces reinstatement and neuronal activation in stress- and relapse-related brain regions. Here we determine the involvement of alpha-1 receptors in reinstatement and brain activation induced by U50,488.
METHODS
We trained male Long-Evans rats to self-administer alcohol (12% w/v), extinguished alcohol-reinforced responding, and then determined the effects of prazosin (1 mg/kg) on U50,488 (2.5 mg/kg)-induced reinstatement and regional Fos expression.
RESULTS
Prazosin blocked U50,488-induced reinstatement and decreased U50,488-induced Fos expression in the orbitofrontal cortex, nucleus accumbens core, ventral bed nucleus of the stria terminalis, central and basolateral amygdalar nuclei and ventral tegmental area.
CONCLUSIONS
These findings suggest that prazosin may reduce U50,488-induced relapse by inhibiting activity in 1 or more of these brain areas.
Identifiants
pubmed: 31556948
pii: 5574396
doi: 10.1093/ijnp/pyz049
pmc: PMC6872965
doi:
Substances chimiques
Adrenergic alpha-1 Receptor Antagonists
0
Central Nervous System Depressants
0
Receptors, Opioid, kappa
0
Ethanol
3K9958V90M
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
67198-13-4
Prazosin
XM03YJ541D
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
724-734Subventions
Organisme : NIAAA NIH HHS
ID : R01 AA024341
Pays : United States
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of CINP.
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