Sensitization of neuronal response to cocaine during withdrawal following chronic treatment.

The neural basis of sensitization was examined by assessing the expression of zif/268 mRNA in cortical and striatal neurons following cocaine challenge (30 mg kg-1, i.p.) after 2 weeks of daily treatment with cocaine or saline vehicle. Acute cocaine challenge induced zif/268 mRNA expression in neurons of the caudate putamen (CP), nucleus accumbens (NAc) shell and prelimbic cortex. Chronic cocaine treatment attenuated zif/268 mRNA expression in these regions, although zif/268 mRNA response in CP neurons recovered after 7 days of withdrawal. In contrast, cocaine challenge during withdrawal augmented zif/268 response in neurons of the infralimbic cortex and olfactory tubercle. Sensitized activity in these regions could serve to amplify mesolimbic dopamine and NAc responses, and might provide a critical stimulus to drug craving.

Pretreatment with a dopamine D1-receptor antagonist prevents metabolic activation by cocaine.

The pharmacological mechanism underlying metabolic activation of the rat extrapyramidal system by acute cocaine was examined using the quantitative 2-deoxyglucose autoradiographic method. Pretreatment with a selective dopamine D1-like receptor antagonist, SCH 23390, prevented cocaine-induced metabolic activation in the entopeduncular nucleus and substantia nigra pars reticulata in a dose-dependent manner. These results suggest that activity in striatonigral circuits is induced by stimulation of D1-like receptors by dopamine in the presence of acute cocaine.

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

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.

Cocaine-induced sensitization of metabolic activity in extrapyramidal circuits involves prior dopamine D1-like receptor stimulation.

Chronic cocaine treatment leads to the development of behavioral sensitization in experimental animals. The neural circuitry underlying sensitization was studied using the quantitative 2-deoxyglucose technique, with a modification of a rapid procedure that produces locomotor and neurochemical sensitization. Acute cocaine treatment, administered by i.p. injection, increased the regional cerebral metabolic rate for glucose (rCMRglc) in various extrapyramidal regions, compared with saline vehicle treatment, as previously reported. Repeated cocaine treatment further increased rCMRglc in the entopeduncular nucleus and the substantia nigra pars reticulata, producing a sensitized metabolic response only in regions innervated by direct striatonigral neurons. Repeated cocaine treatment also increased rCMRglc in the nucleus accumbens, hippocampus, dentate gyrus and laterodorsal thalamus, as well as sensory and motor cortices, compared with saline vehicle treatment. The pharmacology underlying this sensitized metabolic response to cocaine was investigated by administering either dopamine D1- or D2-like receptor agonists on the first treatment day, followed by cocaine on the final day. Prior treatment with quinpirole (0.2 mg/kg, i.p.), a D2-like receptor agonist, produced metabolic responses that were significantly lower than those produced by repeated cocaine treatment in the entopeduncular nucleus and substantia nigra pars reticulata, similar to those of acute cocaine treatment. In contrast, prior treatment with SKF 38393 (2.0 mg/kg, l.p.), a partial D1-like receptor agonist, increased rCMRglc in the entopeduncular nucleus and substantia nigra pars reticulata, although not as much as did repeated cocaine treatment. These data suggest that the development of metabolic sensitization in striatonigral circuits involves prior D1-like receptor activation.