Bean animal overflow box measerements4/24/2024 ![]() Subsequent studies examining self-administration of lower dose combinations, as well as experimenter-administered speedball combinations, have reported similar synergistic elevations ( Hemby et al., 1999 Smith et al., 2006 Zernig et al., 1997). Interestingly, we have demonstrated that intravenous speedball self-administration resulted in synergistic elevations in NAc e (~1000% of baseline) compared with cocaine (400%) or heroin alone (no change) ( Hemby et al., 1999). Previous studies have shown that extracellular DA concentrations ( e) in the NAc are significantly elevated (300–400% baseline) during cocaine self-administration ( Hemby et al., 1997 Pettit and Justice, 1989 Wise et al., 1995b) and moderately increased (120–150% baseline) by heroin self-administration ( Leri et al., 2003b Wise et al., 1995a) in rats as measured by in vivo microdialysis (but see ( Hemby et al., 1999 Hemby et al., 1995 Smith et al., 2006) where heroin self-administration did not significantly alter NAc e). In general, drugs of abuse activate this pathway and stimulate DA neurotransmission in the nucleus accumbens (NAc) in humans, nonhuman primates and rodents ( Lyons et al., 1996 Porrino, 1993 Volkow et al., 1997), which is an effect associated with the abuse liability of such substances. ![]() The mesolimbic dopamine (DA) system is recognized as a critical substrate for the reinforcing effects of drugs of abuse. The potentiated euphorigenic effects in humans and the corresponding enhancement of reinforcing effects in animal models may be based on an augmented neurochemical response in brain pathways underlying reinforcement processes. The hypothesis of enhanced euphorigenic effects in humans is paralleled in preclinical studies, which demonstrate that cocaine and heroin potentiate the reinforcing effects of one another in the self-administration paradigm ( Mattox et al., 1997 Rowlett and Woolverton, 1997) however, the specific biological contributors which mediate the amplified reinforcing effects of speedball have not been confirmed. Several hypotheses have been proposed to explain the combined use of cocaine and heroin in humans, including an enhancement of the positive effects of either drug, reduction in the magnitude or duration of undesired side effects, induction of euphoria beyond what either drug alone provides, or independent, non-additive effects even though the drugs are administered concurrently ( Foltin and Fischman, 1992 Hemby et al., 1996 Kosten et al., 1987). Specifically, the likelihood of positive treatment outcomes for opiate addicts decreases severely when high amounts of cocaine are co-abused ( Downey et al., 2000). Negative health and social consequences of such combinations are severe, particularly when cocaine is used intravenously ( Schutz et al., 1994). The prevalence of cocaine use among heroin addicts ranges from 30% to 80% ( Leri et al., 2003a Schutz et al., 1994). The co-use of cocaine and opiates, termed speedball ( Leri et al., 2003a), has been on the rise since the 1970s and represents a growing subpopulation of drug abusers ( Craddock et al., 1997 Greberman and Wada, 1994 Kosten et al., 1987). These data, combined with published microdialysis and electrophysiological results, indicate that the combination of cocaine-induced competitive inhibition of DAT and the increase in the DA release elicited by heroin is responsible for the synergistic increase in ( e) induced by speedball. Neither drug induced substantial changes in the maximal reuptake rate ( V max). ![]() ![]() However, DA transporter (DAT) apparent affinity ( K m) values were similarly elevated following cocaine and speedball administration, but unaffected by heroin. DA efflux was significantly greater following cocaine compared to speedball. Evoked DA efflux was increased following both cocaine and speedball delivery, whereas heroin did not significantly change evoked DA release from baseline. These parameters were extracted from accumbal DA overflow induced by electrical stimulation of the ventral tegmental area. To further delineate the mechanism of this neurochemical synergism, in vivo fast-scan cyclic voltammetry (FSCV) was used to compare NAc DA release and reuptake kinetic parameters following acute administration of cocaine, heroin and speedball in drug-naïve rats. Cocaine/heroin combinations (speedball) induce a synergistic elevation in extracellular dopamine concentrations ( e) in the nucleus accumbens (NAc) that can explain the increased abuse liability of speedball. ![]()
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