The α1 Antagonist Doxazosin Alters the Behavioral Effects of Cocaine in Rats.

Colin Haile,Yanli Hao,Thomas Newton,Patrick O'Malley,Therese Kosten

doi:10.3390/brainsci2040619

Abstract

Medications that target norepinephrine (NE) neurotransmission alter the behavioral effects of cocaine and may be beneficial for stimulant-use disorders. We showed previously that the short-acting, α1-adrenergic antagonist, prazosin, blocked drug-induced reinstatement of cocaine-seeking in rats and doxazosin (DOX), a longer-acting α1 antagonist blocked cocaine’s subjective effects in cocaine-dependent volunteers. To further characterize DOX as a possible pharmacotherapy for cocaine dependence, we assessed its impact on the development and expression of cocaine-induced locomotor sensitization in rats. Rats (n = 6–8) were administered saline, cocaine (COC, 10 mg/kg) or DOX (0.3 or 1.0 mg/kg) alone or in combination for 5 consecutive days (development). Following 10-days of drug withdrawal, all rats were administered COC and locomotor activity was again assessed (expression). COC increased locomotor activity across days indicative of sensitization. The high dose (1.0 mg/kg), but not the low dose (0.3 mg/kg) of DOX significantly decreased the development and expression of COC sensitization. DOX alone did not differ from saline. These results are consistent with studies showing that α1 receptors are essential for the development and expression of cocaine’s behavioral effects. Results also suggest that blockade of both the development and expression of locomotor sensitization may be important characteristics of possible pharmacotherapies for cocaine dependence in humans.

Highlights

Cocaine addiction is a chronic relapsing brain disease for which there are no FDA-approved treatments
The prevailing consensus is that cocaine’s powerful reinforcing effects in humans are mediated by its ability to increase central monoamines via transporter blockade within the mesocorticolimbic system [1,2]. This system consists of DAergic neurons in the ventral tegmentum (VTA) that project to the nucleus accumbens (NAc) and prefrontal cortex (PFC) among other areas
Not readily apparent from the figure, the DOX groups differed in baseline distances traveled on the habituation day (HAB) day before the start of the experiment

Summary

Introduction

Cocaine addiction is a chronic relapsing brain disease for which there are no FDA-approved treatments. The prevailing consensus is that cocaine’s powerful reinforcing effects in humans (e.g., euphoria, heightened alertness, increased energy levels) are mediated by its ability to increase central monoamines (dopamine, DA, norepinephrine, NE, and serotonin) via transporter blockade within the mesocorticolimbic system [1,2]. Neuroplastic changes secondary to chronic cocaine exposure result in augmented NAc DA and behavior termed sensitization that is hypothesized to relate to various aspects of dependency in humans [6,7,8]. Decades of preclinical and clinical drug development research focused on DA has not lead to a single medication with proven efficacy prompting the consideration of other possible therapeutic targets [9]

Objectives

Methods

Results

Conclusion