Gradual tolerance of metabolic activity is produced in mesolimbic regions by chronic cocaine treatment, while subsequent cocaine challenge activates extrapyramidal regions of rat brain

Abstract

Acute administration of cocaine is known to enhance extracellular dopamine levels in the striatum and to activate immediate-early gene expression in striatal neurons. Regional cerebral metabolic rate for glucose (rCMRglc) reportedly increases in extrapyramidal and mesolimbic brain regions in response to acute cocaine treatment. However, chronic administration attenuates the cocaine-induced enhancement of regional dopamine response and the induction of immediate-early gene expression in these regions. Chronic treatment also produces tolerance to cocaine's reinforcing effects. Thus, differential responses to cocaine occur with increasing length of treatment. Therefore, we examined the time course of effects of repeated daily cocaine treatment on rCMRglc in rat brain. Acute administration of 10 mg/kg cocaine slightly increased rCMRglc in mesolimbic and extrapyramidal regions. However, no significant effects were observed until more than 7 d of treatment, whereupon rCMRglc was reduced compared to saline treatment in the infralimbic portion of the medial prefrontal cortex, nucleus accumbens, olfactory tubercle, habenula, amygdala, and a few other brain regions. In contrast, after 13 d of 10 mg/kg cocaine treatment, challenge with 30 mg/kg cocaine increased rCMRglc in the striatum, globus pallidus, entopeduncular nucleus, subthalamus, substantia nigra pars reticulata, and a few other regions without affecting limbic or mesolimbic regions. Thus, repeated daily treatment with a low dose of cocaine gradually decreased metabolic activity particularly in mesolimbic regions. Subsequent treatment with a higher dose produced metabolic activation mostly in extrapyramidal regions. This effect of chronic treatment could represent tolerance to the initial metabolic response, which can be replicated thereafter but only by increasing the drug dose. These results suggest that tolerance to the metabolic effects of cocaine in selective mesolimbic circuits may contribute to the development of behavioral dependence with repeated exposure.

Psychostimulant-Induced Neuroadaptations in Nucleus Accumbens AMPA Receptor Transmission

“…This line of work, which has since led to clinical trials assessing the effect of N-acetylcysteine on cocaine craving in humans Mardikian et al 2007), was among the first to indicate that repeated cocaine resulted in changes in accumbens glutamatergic transmission that influenced drug-seeking behavior . In addition to the microdialysis studies mentioned above, which showed changes in nonsynaptic glutamate pools, other results suggested decreased activity of glutamatergic afferents to the nucleus accumbens during cocaine withdrawal (Hammer and Cooke 1994;Goldstein and Volkow 2002;Sun and Rebec 2006;Porrino et al 2007). In addition, electrophysiological studies showed that repeated cocaine exposure decreased the intrinsic excitability of accumbens neurons by altering voltage-gated conductances (Zhang et al 1998(Zhang et al , 2002Hu et al 2004Hu et al , 2005Dong et al 2006;Ishikawa et al 2009;Kourrich and Thomas 2009;Mu et al 2010).…”

Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse

“…10 By effecting downstream events, even short-lived changes in expression patterns may lead to more enduring modifications, and thereby provide the neurobiological substrates for sensitization, tolerance, craving, and addiction. 3,11 While cocaine has a distinct effect in different anatomical regions, [12][13][14] it appears to rely heavily on the prefrontal cortex (PFC) both for the induction and long-term sensitization to cocaine. 1,15,16 Imaging studies have demonstrated altered neuronal activity in the PFC of cocaine abusers responding to cocaine or cocaine-related cues.…”

Patterns of functional activity associated with cocaine self-administration in the rat change over time

“…Acute cocaine administration to rats produces widespread elevations in cerebral metabolism throughout the mesolimbic and extrapyramidal brain systems (Porrino 1993;Porrino et al 1988; Thomas et al 1996;Zocchi et al 2001). On the other hand, with repeated cocaine administration, both reductions (Hammer and Cooke 1994) and elevations (Thomas et al 1996) in rates of glucose utilization have been observed in some of the same mesolimbic regions, including the nucleus accumbens (NAcc). These findings suggest the importance of the duration of cocaine treatment as a critical variable in determining the circuits activated by cocaine administration.…”