Cocaine stimulates rat hypothalamic corticotropin-releasing hormone secretion in vitro

Abstract

Acute or chronic cocaine administration exerts multiple behavioral and physiologic effects including stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. Pharmacologically, cocaine shares major properties with at least 2 classes of pharmaceuticals. It is a local anesthetic and also a potent psychomotor stimulant. The psychomotor stimulant properties of cocaine are thought to be related to its ability to modify the metabolism and the activity of many neurotransmitter systems, such as acetylcholine (ACh), serotonin (5-HT), norepinephrine (NE), and dopamine (DA). We and others have shown that all these neurotransmitters are potent stimulants of hypothalamic corticotropin-releasing hormone (CRH) secretion. The present study was undertaken to examine whether cocaine stimulates hypothalamic CRH secretion and whether or not such an effect is mediated by any of the above neurotransmitters. To accomplish this task, we employed a rat hypothalamic organ culture system, in which CRH secretion form single explanted hypothalami was evaluated by specific radioimmunoassay (iCRH). Cocaine stimulated iCRH secretion in a dose-dependent fashion with peak of activity at 10 −8 M. Isolated or simultaneous pharmacologic blockade of cholinergic (atropine plus hexamethonium), serotonergic (ritanserin), α-adrenergic (phentolamine) and/or dopaminergic (compound SCH 23390) receptor subtypes failed to inhibit cocaine-induced iCRH secretion. On the other hand, cocaine-induced iCRH secretion was inhibited by GABA, a potent inhibitor of CRH secretion, dexamethasone, verapamil, a calcium channel blocker, tetrodotoxin, a sodium channel blocker, and carbamazepine, an antiepileptic and antidepressive agent. These data suggest that cocaine stimulates hypothalamic CRH secretion and that this effect may be related to the local anesthetic properties of cocaine rather than to increases of ACh, 5-HT, NE and/or DA. We speculate that cocaine activates the HPA axis in vivo by releasing hypothalamic CRH.