Aminoglutethimide, a corticosteroid synthesis inhibitor, facilitates brain stimulation reward in food-restricted rats: an investigation of underlying mechanisms.
It was previously observed that the corticosteroid synthesis inhibitor, aminoglutethimide (AG), markedly facilitates lateral hypothalamide (AG), markedly facilitates lateral hypothalamic self-stimulation (LHSS) in food-restricted rats. This effect is not present 30 min after injection when plasma corticosterone levels are suppressed, but rather at 2 h when corticosterone has recovered from suppression. In experiment 1, it was confirmed that AG (50.0 mg/kg, s.c.) lowers the threshold for LHSS in food-restricted rats but not in control rats that have ad libitum access to food. This effect occurred independently of whether food restriction, by itself, lowered threshold. Experiment 2 examined whether the facilitation of LHSS coincides with biosynthetic rebound of corticosteroid precursors. While a pregnenolone surge was demonstrated by radioimmunoassay, dose-response testing with exogenous pregnenolone and progesterone (0.1, 1.0 and 10.0 mg/kg, s.c.) failed to confirm the prediction that one of these precursors facilitates reward. Therefore, a general test of the involvement of adrenocortical biosynthetic events was conducted in experiment 3 where rats were adrenalectomized (ADX) or sham-operated prior to food restriction. Surprisingly, ADX did not diminish the effect of AG. This finding raises the possibility of a CNS, rather than adrenal, site of action. AG is known to penetrate the blood-brain barrier and exert weak anticonvulsant effects. The facilitation of reward may result from central inhibitory effects of the drug and share a common basis with the enhanced reinforcing potency of other CNS depressants in food-restricted rats.
Abrahamsen
G C
GC
Millhauser Laboratories, Department of Psychiatry, New York University Medical Center, NY 10016, USA.
Kandawire
M J
MJ
Carr
K D
KD
D000305:Adrenal Cortex Hormones / Q000096:biosynthesis*; D000315:Adrenalectomy; D000616:Aminoglutethimide / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D003345:Corticosterone / Q000096:biosynthesis / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005508:Food Deprivation / Q000502:physiology*; D008297:Male; D011284:Pregnenolone / Q000096:biosynthesis / Q000097:blood; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward; D012653:Self Stimulation
D000305:Adrenal Cortex Hormones; D004791:Enzyme Inhibitors; D000616:Aminoglutethimide; D011284:Pregnenolone; D003345:Corticosterone