Effects of Bremazocine on Self-Administration of Smoked Cocaine Base and Orally Delivered Ethanol, Phencyclidine, Saccharin, and Food in Rhesus Monkeys: A Behavioral Economic Analysis

Abstract

There is increasing evidence that -opioid receptor agonists modulate cocaine-maintained behavior, and limited findings implicate the involvement of -opioid receptors in ethanol-maintained behaviors. The purpose of the present study was to investigate the effects of bremazocine, a -opioid agonist, on the self-administration of smoked cocaine base and oral ethanol in rhesus monkeys (Macaca mulatta). To determine the selectivity of bremazocine, the effects of bremazocine pretreatment on the oral selfadministration of phencyclidine (PCP), saccharin, and food were also examined. Adult male rhesus monkeys were trained to selfadminister oral ethanol, PCP, saccharin (n ϭ 8), food (n ϭ 6), or smoked cocaine base (n ϭ 6) and water during daily sessions. Bremazocine (0.00032-, 0.001-, and 0.0025-mg/kg i.m.) injections were given 15 min before session. The 4 days of stable behavior before pretreatment served as baseline. Demand curves (consumption ϫ fixed ratio; FR) were obtained for smoked cocaine base, ethanol, and PCP by varying the cost (FR) of drug deliveries and measuring consumption (deliveries). Bremazocine (0.001 mg/ kg) was administered at each FR value in nonsystematic order. Results indicate that bremazocine dose dependently reduced cocaine, ethanol, PCP, and saccharin intake. Food intake was affected less by bremazocine than the other substances in five of the six monkeys. Generally, bremazocine treatment reduced the demand for cocaine, ethanol, and PCP as well as other measures of response strength. These results extend the findings that -agonists reduce the self-administration of drug and nondrug reinforcers to smoked cocaine base and oral ethanol, PCP, and saccharin in rhesus monkeys.Cocaine and alcohol abuse are well recognized psychiatric disorders with high rates of recidivism. Currently, there are few effective pharmacotherapies for the treatment of these disorders. However, recently -opioid receptor agonists have shown potential for the treatment of cocaine abuse, and limited evidence suggests that -agonists modulate ethanolmaintained behaviors (Nestby et al., 1999). It is increasingly evident that the mesolimbic dopamine system plays a role in mediating the reinforcing effects of psychostimulant drugs. It is well known that within this system, -and ␦-agonists stimulate and -agonists suppress dopaminergic neurotransmission (Herz, 1998), and it is likely that these opposing effects of -or ␦-and -opioid receptors within this system modulate drug-maintained behaviors. For example, the -opioid agonists U50488 and bremazocine reduced dopamine transmission in the mesolimbic dopamine system; whereas, -agonists stimulated dopamine transmission (Di Chiara and Imperato, 1988).It is generally accepted that -opioid receptors are involved in the neurobiological and behavioral effects of cocaine.-Agonists suppressed the increase in basal dopamine dialysate levels occurring during abstinence from cocaine (Heidbreder and Shippenberg, 1994;Chefer et al., 2000). The -agonist U69593 decreased basal rates of dopami...

The Motivation to Self-Administer is Increased After a History of Spiking Brain Levels of Cocaine

“…Appetitive behavior is assessed later in the session by determining the lowest unit dose (ie, highest unit price) that maintains consumption. Typically in self-administration studies, price is manipulated by holding a drug dose constant and increasing the response requirement (Cosgrove and Carroll, 2002;Wade-Galuska et al, 2007); however, fixing the response requirement and decreasing the available unit dose accomplishes the same thing (Bickel et al, 1990). Here, the decreasing series of unit doses resulted in an ascending series of unit prices (2.4, 4.2, 7.5, 13, 24, 40, 77, 133, 244, 416, and 750 responses/mg).…”

Effects of the kappa opioid agonist U50,488 and the kappa opioid antagonist nor-binaltorphimine on choice between cocaine and food in rhesus monkeys

“…Interactions between kappa agonists and cocaine have also been evaluated in drug self-administration procedures, and kappa agonists usually decreased rates of cocaine selfadministration in both rats (Glick et al 1995;Schenk et al 1999) and rhesus monkeys (Bowen et al 2003;Cosgrove and Carroll 2002;Mello and Negus 1998;Negus et al 1997). However, the principal dependent measure in these procedures has been the rate of self-administration measured as either responses or injections per unit time, and it is well established that kappa agonists alter response rates maintained by non-drug reinforcers (Bergman and Warren 1989;Dykstra et al 1987;Negus et al 1993).…”

k Opioids as potential treatments for stimulant dependence

“…76 This work also indicates that k agonists attenuate self-administration of drug and nondrug reinforcers to smoked cocaine base, oral ethanol, PCP, and saccharin in rhesus monkeys. Furthermore, bremazocine reduces unrestricted free-choice ethanol self-administration in rats without affecting sucrose consumption.…”