Effects of Cocaine in Rats Exposed to Heroin

Abstract

We investigated whether chronic exposure to heroin alters responses to cocaine in ways that might explain the use of cocaine by opioid addicts. To this end, the effects of cocaine (5 and 20 mg/kg) were assessed on locomotor activity of rats chronically exposed to heroin (0.0, 3.5, 7.0, and 14.0 mg/kg/day, over 14 days, via osmotic mini-pumps), or withdrawn from heroin (1 day, acute withdrawal, and 14 days, protracted withdrawal). Chronic heroin exposure, in itself, dose dependently increased locomotion and acute cocaine administration further elevated locomotor activity in a dose-dependent and additive manner. During acute withdrawal, there was a dosedependent decrease in locomotion that was reversed by cocaine in a dose-dependent manner. During protracted withdrawal, spontaneous locomotion normalized, but rats previously exposed to heroin displayed cross-sensitization to cocaine as indicated by small, but significant, enhanced locomotor response to 5 mg/kg of cocaine, and enhanced intravenous self-administration of low doses of cocaine (0.13 mg/kg/infusion). In a separate study, we measured extracellular dopamine (DA) in the nucleus accumbens (Acb) using in vivo microdialysis before and after acute withdrawal from heroin. During chronic exposure to heroin, basal extracellular DA was elevated dose dependently, whereas in acute withdrawal, levels were not different from those in vehicle-treated rats. In response to cocaine, however, DA activity in the Acb was significantly lower in rats withdrawn from the highest dose of heroin.

No Effect of Morphine on Ventral Tegmental Dopamine Neurons during Withdrawal

“…pulse activity during morphine dependence. These data are consistent with a recent microdialysis study showing that continuous exposure to heroin elevates the basal level of DA in the nucleus accumbens (Leri et al, 2003). Notably, this change in tonic activity of VTA DA neurons during dependence coexisted with tolerance to the phasic excitatory effect of morphine.…”

“…These data are consistent with a recent microdialysis study showing that during acute withdrawal, basal extracellular DA levels in the nucleus accumbens were not different from those in vehicle-treated rats (Leri et al, 2003). Our data, however, contrast with the results of Diana et al (1999), who found a lasting reduction in VTA DA activity after morphine withdrawal and an augmented magnitude of the response of these neurons to morphine after 14 d of withdrawal.…”

“…Thus, adaptive changes at the level of the DAT could produce the long-lasting changes in morphine-induced mesolimbic dopamine release observed (Spanagel et al, 1993) without altering the activity of VTA DA neurons (Budygin et al, 2004). This hypothesis is indirectly supported by studies showing that a history of opiate dependence can enhance the reinforcing effects of cocaine in a conditioned place preference (Lett, 1989;Leri et al, 2003).…”

Methadone Maintenance Reduces Heroin- and Cocaine-Induced Relapse without Affecting Stress-Induced Relapse in a Rodent Model of Poly-Drug Use

“…In our laboratory, we have examined pharmacological interactions between chronic heroin exposure (via minipump) and acute injections of cocaine (Leri et al, 2003). In both the heroin study and the present study with methadone, we have consistently observed that chronic exposure to opiate drugs elevates locomotor activity in a dose-dependent manner and that the stimulatory effects of cocaine summate with those of the opiate drugs.…”

“…The dose chosen for the cocaine challenge was 5 mg/kg (i.p. ), and the decision was based on previous studies indicating that, at this dose, cocaine induces significant elevations in locomotor activity in rats chronically exposed to heroin (Leri et al, 2003).…”