Cocaine-induced hypophagia and hyperlocomotion in rats are attenuated by prazosin

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Abstract

The present studies examined the effects of antagonizing α1-adrenoceptors via systemic administration of prazosin on the behavioral actions of cocaine in rats, including induction of locomotion and suppression of eating. In Experiment 1, locomotor activity was monitored in automated chambers for 80 min in adult male rats pretreated with the α1-adrenoceptor antagonist prazosin (0, 0.5, or 2 mg/kg, i.p.) and then treated (i.p.) with either 0, 10, 20, or 40 mg/kg cocaine hydrochloride. Cocaine dose-dependently increased total distance traveled and the number of stereotypy counts, and significantly decreased rest time. Each dose of prazosin produced a significant attenuation of the locomotor effects of a limited range of cocaine doses (i.e. 10 and/or 20 mg/kg cocaine, but not 40 mg/kg cocaine). Prazosin alone did not alter any measure of locomotion. In Experiment 2, eating and drinking were monitored for 60 min in male rats pretreated with prazosin (0, 1, and 2 mg/kg, i.p.) and then treated with 0, 10, 20, or 40 mg/kg (i.p.) cocaine. Rats pretreated with vehicle exhibited a dose-dependent suppression of eating, but not drinking, to cocaine. The impact of prazosin on cocaine-induced hypophagia paralleled that noted for locomotion in that administration of prazosin significantly attenuated the hypophagic action of 20 mg/kg cocaine, but not that of 40 mg/kg cocaine. These findings confirm earlier studies noting a partial role for α1-adrenoceptors in the locomotor stimulant actions of cocaine and extend those findings to the feeding-inhibitory actions of cocaine.

Introduction

Inactivation by cocaine of neuronal membrane transporter proteins increases extracellular levels of dopamine, norepinephrine, and serotonin (Rothman et al., 2001), which may act in multiple brain regions via multiple pathways to influence behavioral activation (Woolverton and Kleven, 1988). Pharmacological antagonism of dopamine receptors, for example, attenuates the locomotor activating effects of cocaine Baker et al., 1996, Bhattacharyya et al., 1979, whereas inactivation of the α1-adrenoceptor subtype, using the antagonist prazosin, has yielded mixed results. Thiebot et al. (1981) reported no significant alteration of cocaine-induced locomotion by prazosin, while other studies report that prazosin significantly attenuates the stimulatory actions of cocaine on locomotor activation Drouin et al., 2002a, Snoddy and Tessel, 1985, Tessel and Barrett, 1986. These studies vary widely in procedural details, which may contribute to the different outcomes. The former study employed single doses of cocaine (4 mg/kg) and prazosin (0.25 mg/kg) in mice, while the latter studies commonly used a single dose of cocaine and/or prazosin in rats (Drouin et al., 2002a) and a global measure of locomotion (e.g. Berthold et al., 1992, Drouin et al., 2002a). Confirmation of an attenuation of cocaine activity by prazosin would suggest that norepinephrine, acting via noradrenergic receptors, may contribute to the behavioral actions of cocaine.

Drugs that increase extracellular norepinephrine via blockade of reuptake can inhibit eating Jackson et al., 1997a, Jackson et al., 1997b, Gehlert et al., 1998, whereas overeating accompanies the loss of brain norepinephrine innervation produced by ablation of the ascending ventral noradrenergic bundles (Ahlskog, 1974). Sympathomimetic drugs such as phenylpropanolamine, ephedrine, or cirazoline are known to directly or indirectly activate α1-adrenoceptors and these drugs are known to inhibit eating in the rat Fox et al., 1985, Minneman et al., 1983, Wellman et al., 1993. Moreover, prazosin administration attenuates the hypophagia in rats induced by a series of sympathomimetic drugs including amphetamine, ephedrine, phenylpropanolamine, aminorex, and phentermine Jackson et al., 1997a, Mitchell et al., 1998, Wellman et al., 1993, Wellman et al., 2003. The capacity of cocaine to inhibit eating in the rat is attenuated by pharmacological antagonism of dopamine receptors Cooper and van der Hoek, 1993, Heffner et al., 1977, Rapoza and Woolverton, 1991, but the hypophagic action of cocaine is not completely mimicked by dopamine receptor subtype agonists Cooper et al., 1990, Rusk and Cooper, 1989. These results suggest that cocaine may act in part on non-dopaminergic substrates to inhibit eating in the rat.

The intent of the present experiments was therefore to further examine the impact of antagonism of α1-adrenoceptors using prazosin on the behavioral effects of cocaine in rats. Experiment 1 considered the impact of 0.5 and 2.0 mg/kg prazosin on multiple measures of locomotion (e.g. total distance traveled, stereotypy counts, rest time) in rats treated with a full range of cocaine doses (0, 10, 20, or 40 mg/kg). Experiment 2 considered whether prazosin (0, 1, and 2 mg/kg) produced a similar attenuation of the hypophagic action of cocaine (0, 10, 20, or 40 mg/kg) in rats.

Section snippets

Animals

Eighty-four Sprague–Dawley albino rats (Harlan Industries, Houston, TX) weighing 265–310 g at the start of the experiment were housed individually in hanging wire rodent cages in a colony room maintained at 21.0±1 °C under a 12:12 h illumination schedule (lights on at 0800 h).

Drugs

A vehicle solution was prepared using sterile distilled water and 0.9% (w/v) sodium chloride. Solutions of cocaine hydrochloride (10, 20, or 40 mg/ml) and prazosin hydrochloride (0.5 or 2 mg/ml) were prepared in sterile

Total distance traveled scores

In this study, the rats were adapted to the activity chambers for 2 days prior to an assessment of the impact of prazosin and cocaine on locomotion. On the third day, rats pretreated with vehicle at time=−2 and then treated with vehicle at time=0 (Fig. 2A) exhibited a decline in total distance traveled scores over the test session. In contrast, administration of cocaine at doses of 10, 20, and 40 mg/kg in the 0 mg/kg prazosin groups produced dose-dependent increases in total distance traveled

Discussion

The present studies confirm that administration of the α1-adrenoceptor antagonist prazosin significantly attenuated the behavioral actions of cocaine on locomotion and extended this effect of prazosin to the capacity of cocaine to inhibit eating in the rat. The results of Experiment 1 thus confirm earlier studies in which administration of prazosin significantly attenuated the locomotor stimulatory actions of cocaine Berthold et al., 1992, Drouin et al., 2002a, Snoddy and Tessel, 1985. The

Acknowledgements

This research was supported in part by funds provided by a grant from the Tobacco Health Initiative to LLB, PJW, and ACB, and from NIDA to JRN. The experiments reported herein were approved by the Texas A&M University Laboratory Animal Care Committee.

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