The role of noradrenaline and 5-hydroxytryptamine in yohimbine-induced increases in alcohol-seeking in rats.
OBJECTIVE
We previously showed that systemic administration of the prototypical alpha-2 noradrenaline (NA) receptor antagonist yohimbine increases alcohol self-administration and reinstatement. Yohimbine also acts as an agonist of 5-hydroxytryptamine (5-HT) 5-HT1A receptors, which have been shown to be involved in alcohol seeking. Here, we determined the contributions of the alpha-2 and 5-HT1A properties of yohimbine to its effects on alcohol seeking.


METHODS
The effects of lesions of the dorsal or ventral NA bundles with 6-OHDA on yohimbine-induced alcohol self-administration were first determined in male Wistar rats trained to self-administer alcohol (12% w/v, 0.19 ml per alcohol delivery), and then on reinstatement induced by yohimbine after extinction of the operant response. It was then determined whether the selective alpha-2 antagonist RS-79948 (0.1, 0.2, 0.4 mg/kg) would mimic the effects of yohimbine on self-administration and reinstatement. The effects of the alpha-2 receptor agonist clonidine, or the 5-HT1A antagonist WAY 100,635 were then determined on yohimbine-induced self-administration and reinstatement.


RESULTS
Lesions of the NA systems did not affect yohimbine-induced alcohol self-administration or reinstatement, and RS-79948 did not mimic the effects of yohimbine. Clonidine did not significantly affect increased alcohol self-administration induced by yohimbine, but did attenuate its effects on reinstatement. Blockade of 5-HT1A receptors reduced both yohimbine-induced self-administration and reinstatement.


CONCLUSIONS
These results suggest that alpha-2 antagonist properties of yohimbine may play a role in the reinstatement of alcohol-seeking, but not self-administration. On the other hand, yohimbine's actions on 5-HT1A receptors contribute to its effects on both alcohol self-administration and reinstatement.
Dzung Lê
Anh
A
Neuroscience Department, Centre for Addiction and Mental Health, Toronto, Canada. anh_le@camh.net
Funk
Douglas
D
Harding
Stephen
S
Juzytsch
Walter
W
Fletcher
Paul J
PJ
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000428:Alcohol Drinking / Q000523:psychology*; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009287:Naphthyridines / Q000494:pharmacology; D009638:Norepinephrine / Q000502:physiology*; D016627:Oxidopamine; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D012008:Recurrence; D012646:Self Administration; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013268:Stimulation, Chemical; D013563:Sympathectomy, Chemical; D013565:Sympatholytics; D015016:Yohimbine / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D015306:Biogenic Monoamines; D007546:Isoquinolines; D009287:Naphthyridines; D010879:Piperazines; D011725:Pyridines; C104875:RS 79948-197; D012702:Serotonin Antagonists; D013565:Sympatholytics; D015016:Yohimbine; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D016627:Oxidopamine; D003000:Clonidine; D009638:Norepinephrine