Effects of ICV administration of the alpha1A-adrenoceptor antagonist 5-methylurapidil on concurrent measures of eating and locomotion after cocaine in the rat

Abstract

Psychostimulants including amphetamine and cocaine induce locomotion and stereotypy and suppress eating. Although the capacity of cocaine to alter locomotion is usually viewed as related to dopamine neurotransmission, recent studies suggest that norepinephrine, acting through alpha1-adrenergic receptors (alpha1-ARs) can facilitate cocaine-stimulated locomotion. Of the three alpha1-AR subtypes (alpha(1A), alpha(1B), and alpha(1D)) identified to date, inactivation of the alpha(1B)-AR subtype diminishes cocaine-stimulated locomotion, whereas the impact of inactivation of the alpha(1A)-AR subtype on either eating or locomotion is unknown. In the present study, we assessed the relative impact of ICV administration of the alpha(1B)-AR antagonist 5-methylurapidil (5-MU) on cocaine-stimulated hyperlocomotion and hypophagia, using a concurrent method [Wellman, P.J., Ho, D.H., Davis, K.W., 2005. Concurrent measures of feeding and locomotion in rats. Physiology of Behavior 84 (5), 769-774.]. Rats were infused ICV with one of 3 doses of 5-MU (0, 3, or 30 nmol) and then injected (i.p.) with 0, 2.5, 5.0, 10.0, or 20.0 mg/kg cocaine HCl on each of five tests. Rats always received the same 5-MU dose, but a different cocaine dose on each trial. Feeding and locomotion were assessed concurrently during a 45-min postinjection period. Significant suppression of eating was noted at 2.5 mg/kg cocaine, a dose that does not alter forward locomotion in the rat. Administration of 5-MU did not alter locomotion in rats treated with saline, but did significantly increase baseline food intake. Neither cocaine-induced hypophagia nor hyperlocomotion was altered by ICV administration of 5-MU. These results suggest that the capacity of alpha1-AR agonists (e.g. phenylpropanolamine) to suppress eating may be related to activation of the alpha(1A)-AR subtype, whereas cocaine does not act through the alpha(1A)-AR subtype to suppress eating nor does this subtype modulate cocaine-induced hyperlocomotion.

The expression of MC4Rs in D1R neurons regulates food intake and locomotor sensitization to cocaine

“…Because recent studies have shown that MC4R signaling in the NAc is required for certain behavioral responses to cocaine- (Hsu et al 2005) and stress-induced anhedonia, hypophagia and body weight loss (Lim et al 2012), we speculated that MC4R signaling in D1R neurons might suppress food intake under specific conditions. To test this hypothesis, we determined the effect of cocaine, which potently suppresses appetite (Clifford et al 2007;Wellman et al 2002), on food intake in our mouse models. An acute IP injection of cocaine (15 mg/kg) induced a significant suppression of food intake in the control and MC4R/D1R groups Genes, Brain and Behavior (2013) after 4 h (one-way ANOVA followed by Tukey's post hoc analysis, F 2,23 = 5.925, P = 0.0084, Fig.…”

Adrenaline Rush: The Role of Adrenergic Receptors in Stimulant-Induced Behaviors

“…However, spontaneous wheel running and novelty-induced rearing were also reduced in these animals, indicating a nonspecific effect on motor activity (Sadalge et al, 2003). Intracerebroventricular administration of the a1a receptor antagonist, 5-methylurapidil, failed to suppress cocaine hyperlocomotion (Clifford et al, 2007). The location of the a1ARs regulating stimulant-induced activity appears to be the prefrontal cortex (PFC; Blanc et al, 1994;Darracq et al, 1998) and nucleus accumbens shell (Mitrano et al, 2012), because local infusions of a1AR antagonists into these regions reduced cocaine and/or amphetamineinduced locomotion.…”

Heterogeneity of Reward Mechanisms

“…5-HT1B and 5-HT2C mediate satiety, while 5-HT6 antagonists reduce food intake [161]. Cocaine was found to suppress eating; this was not affected by a NE antagonist, which by itself, stimulated eating [162]. The specificity of food reward is indicated by such findings as a glutamate antagonist reduces amphetamine but not food reward [163].…”