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Sensitization to the Behavioral Effects of Cocaine: Modulation by Dynorphin and κ-Opioid Receptor Agonists

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Abstract

Several lines of evidence suggest an involvement of the mesolimbic dopamine (DA) system in the mediation of psychostimulant-induced sensitization. It is also apparent that endogenous opioid peptide systems can modulate the activity of this same DA system. Psychostimulant-induced alterations in opioid peptide gene expression have also been reported. In this review, evidence will be presented that demonstrates that the administration of κ-opioid agonists can prevent the initiation of behavioral sensitization to cocaine and that such treatment is also effective in preventing alterations in mesolimbic DA neurotransmission that occur as a consequence of repeated cocaine administration. The putative role of opioid–DA interactions in the modulation of psychostimulant-induced sensitization will also be discussed.

Section snippets

Modulation of mesolimbic dopamine neurotransmission by κ-opioid receptor ligands

Evidence indicating interactions between mesolimbic DA neurons and neurons containing the opioid peptide dynorphin, the postulated endogenous ligand for the κ-opioid receptor [3], has been derived from both anatomical and neurochemical studies. A moderate density of κ-opioid receptors is found in the ventral tegmental area and the core of the nucleus accumbens, whereas a high density of κ-opioid receptors is found in the dorsomedial shell of the NAC 33, 39. Nerve terminals containing dynorphin

Influence of κ-opioid receptor agonists upon the development of sensitization to cocaine: behavioral studies

In view of the interactions between DA and κ-opioid receptor systems, our laboratory has sought to determine whether pharmacological manipulations of these systems can modify psychostimulant-induced behavioral sensitization. Recent studies examining the interaction of κ-opioid receptor agonists with cocaine suggest that this is the case. Heidbreder et al. 12, 13evaluated the locomotor stimulatory effects of cocaine in animals that had received once-daily injections of cocaine (10.0–30.0

Influence of κ-opioid receptor agonists upon cocaine-induced alterations in extracellular dopamine

Two microdialysis studies 5, 32have examined the influence of κ-agonist administration upon the response of mesolimbic DA neurons to an acute cocaine challenge. Both studies have found that administration of the κ-opioid receptor U50488 ca. 20 min prior to an acute cocaine challenge significantly inhibits cocaine-induced DA overflow. Indeed, such findings are not unexpected in view of the inhibitory effects of κ-opioid receptor agonists on basal DA release [10]. Interestingly, however, the

Influence of repeated cocaine administration upon endogenous opioid peptide systems

DA neurons have been shown to regulate dynorphin gene expression in the mammalian central nervous system. Stimulation of DA receptors by the D1–D2 dopamine receptor agonist apomorphine increases dynorphin immunoreactivity and prodynorphin mRNA in both the striatum and the NAC 30, 31. In contrast, the chronic blockade of D1 DA receptors decreases prodynorphin gene expression and tissue levels of dynorphin 7, 35, 36.

Pronounced changes in dynorphin gene expression are also observed in response to

Conclusions

Several studies have shown that κ-opioid receptor agonists can prevent the development of behavioral sensitization to cocaine as well as those changes in mesolimbic DA neurotransmission that occur in response to repeated administration of this agent. It is also apparent that repeated administration of cocaine and other psychostimulants can profoundly affect the activity of endogenous κ-opioid systems. κ-Opioid receptors within the NAC are increased 19, 57, prodynorphin gene expression is

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