Effects of Flupenthixol and Quadazocine on Self-Administration of Speedball Combinations of Cocaine and Heroin by Rhesus Monkeys

Abstract

The simultaneous i.v. administration of heroin and cocaine, called "speedball," is often reported clinically, and identification of effective pharmacotherapies for polydrug abuse is a continuing challenge. This study compared the effects of treatment using combinations of dopamine and opioid antagonists with each antagonist alone onIt is increasingly recognized that drug abusers tend to use multiple drugs rather than a single drug (NIDA, 1998). Polydrug abuse often involves the concurrent abuse of cocaine and heroin, and both cocaine and continued opiate abuse have been reported in methadonemaintained patients (Condelli et al. 1991;Kosten et al. 1989b;Schottenfeld et al. 1993Schottenfeld et al. , 1997. One common form of polydrug abuse is called the speedball, which usually refers to the simultaneous intravenous administration of cocaine and heroin (NIDA, 1998;Schütz et al. 1994). Currently approved pharmacotherapies for opiate abuse have been only moderately effective in reducing polydrug abuse, and there is no consistently effective pharmacotherapy for either abuse of cocaine alone or combinations of cocaine and heroin "speedball" .Preclinical evaluation of medications for reducing Received December 10, 1998; revised March 8, 1999; accepted April 19, 1999. 576 N.K. Mello and S.S. Negus N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 21 , NO . 4 polydrug abuse has been greatly facilitated by the development of animal models of speedball self-administration (Hemby et al. 1996(Hemby et al. , 1999Mello and Negus 1998;Rowlett and Woolverton 1997) and speedball discrimination (Negus et al. 1998a). Combinations of cocaine and heroin produce robust reinforcing and discriminative stimulus effects in these animal models, and cocaine and heroin may enhance each other's reinforcing and discriminative stimulus effects under some conditions (Negus et al. 1998a;Rowlett and Woolverton 1997).Similarly, neurochemical evidence suggests that selfadministration of cocaine and heroin in combination has synergistic effects on extracellular dopamine release at the nucleus accumbens in rats (Hemby et al. 1999). Dopamine levels measured by microdialysis remained at baseline levels during heroin self-administration, increased by 400% during cocaine self-administration, and increased by 1000% during speedball selfadministration, even though cocaine levels measured in dialysate samples were equivalent during cocaine and speedball self-administration (Hemby et al. 1999). Interestingly, however, the synergistic increases in dopamine levels during speedball self-administration were not accompanied by differences in operant responding maintained by cocaine and heroin alone and in combination (Hemby et al. 1999). Moreover, several other studies found that co-administration of cocaine and opioids produced discrimination stimulus and reinforcing effects that were additive or less than additive and resembled the effects of cocaine or heroin alone Negus et al. 1998b;Lamas et al. 1998;Rowlett and Spealman 1998).Taken together, these findings are cons...

Effects of d-Amphetamine and Buprenorphine Combinations on Speedball (Cocaine+Heroin) Self-Administration by Rhesus Monkeys

“…Results of the present study support the hypothesis that a combination of medications that target both the cocaine and the heroin component of the speedball might reduce self-administration more effectively than only one of the same medications alone (Hemby et al, 1996;Mello and Negus, 1999). These findings are also consistent with our previous reports that combinations of the dopamine antagonist flupenthixol and the opioid antagonist quadazocine, as well as combinations of the dopamine reuptake inhibitor indatraline and the partial mu opioid agonist buprenorphine, significantly reduced speedball self-administration by rhesus monkeys, whereas the same doses of each medication alone had no significant effect (Mello andNegus, 1999, 2001).…”

“…We found that a combination of the dopamine antagonist flupenthixol and the opioid antagonist quadazocine was more effective in reducing both speedball self-administration and speedball discrimination than either antagonist alone Mello and Negus, 1999). In addition, chronic treatment with a combination of the dopamine reuptake inhibitor indatraline and the partial mu opioid agonist buprenorphine significantly reduced speedball self-administration in comparison to saline treatment, whereas the same doses of each medication alone had no significant effect on speedball-maintained responding (Mello and Negus, 2001).…”

Modulation of Heroin and Cocaine Self-Administration by Dopamine D1- and D2-Like Receptor Agonists in Rhesus Monkeys

“…Hemby et al (1996), for example, showed that the DA D2-like antagonist eticlopride reversed cocaine-induced alterations in heroin self-administration in rats. In addition, Mello and Negus (1999) observed attenuation of speedball self-administration by the nonselective DA antagonist flupenthixol when combined with relatively low, ineffective doses of an opioid antagonist. Using a different approach, the present study aimed to evaluate the capacity of agonists with selectivity for D1-like and D2-like receptor subtypes to alter the self-administration of heroin.…”

Repeated Lofexidine Treatment Attenuates Stress-Induced, But not Drug Cues-Induced Reinstatement of a Heroin-Cocaine Mixture (Speedball) Seeking in Rats

“…Drug cues are thought to reinstate drug seeking by inducing a "drug-like" state, similar to that induced by the self-administered drug . As mentioned, activation of both opioid and DA receptors is involved in the reinforcing effects of speedball (Hemby et al 1996;Mello and Negus 1999). Furthermore, during speedball self-administration, DA levels in the NAc are dramatically elevated (Hemby et al 1999).…”

“…Preclinical studies reported that speedball is readily self-administered in rats (Duvauchelle et al 1998;Hemby et al 1996) and monkeys (Mello et al 1995;Rowlett et al 1999). It was also found that while opioid and dopamine (DA) receptor antagonists have some effects on speedball self-administration (Hemby et al 1996;Negus and Mello 1998;Rowlett et al 1999), a more effective way to attenuate speedballmaintained behavior is to block both opioid and DA receptors (Mello and Negus 1999). These data indicate that both receptor types are involved in the maintenance of speedball self-administration behavior and are in concordance with previous studies on the pharma-cology of heroin and cocaine reinforcement (Ettenberg et al 1982).…”