Associate editor: T.C. NapierDynorphin and the pathophysiology of drug addiction
Introduction
Dynorphin A 1–17 (DYN), the endogenous ligand for the κ-opioid receptor (KOPr) is distributed throughout the brain and spinal cord. Although a role of DYN in the modulation of pain has long been recognized, increasing evidence indicates that the DYN/KOPr system may be an effective target for the treatment of drug addiction. The KOPr subtype is enriched in brain circuits that control mood and motivation. Its activation modulates the activity of dopaminergic and glutamatergic neurons located therein. KOPr and DYN are located in brain regions that subserve stimulus-response (habit) learning and that have been implicated in the compulsive drug-seeking behavior that characterize drug addiction. Cocaine and other drugs of abuse increase prodynorphin (PDYN) gene expression in these same brain regions. Studies using pharmacological and gene targeting techniques have provided evidence that dysregulation of DYN/KOPr systems may not only contribute to the anhedonia and depressive symptomology associated with drug dependence but to the drug-craving and drug-seeking that frequently occurs in the withdrawn addict. A link between this opioid system and individual differences in vulnerability to drug and alcohol addiction has also been suggested. This chapter will review the mechanisms by which DYN/KOPr systems modulate neurotransmission within several brain regions comprising the limbic cortical-striatopallidal circuit, and the relevance of these effects to alterations in behavior and brain chemistry that occur following the repeated use of cocaine and alcohol.
Section snippets
Physiology and pharmacology of dynorphin/κ-opioid receptor systems
DYN is the major posttranslational product of the PDYN gene and the presumed endogenous ligand for the KOPr (Chavkin et al., 1982, Corbett et al., 1982). Although DYN binds with highest affinity to KOPr, it binds with high affinity to μ- opioid receptors (MOPr) and KOPr (Kosterlitz et al., 1989). Therefore, activation of multiple opioid receptor types may contribute to the effects of this peptide. Other posttranslational products of PDYN include the opioid peptide DYN B and biologically active
Neural substrates of drug and alcohol addiction
Drug addiction is a chronically relapsing disorder characterized by compulsion to seek and take drug(s) regardless of the adverse consequences that may ensue (American Psychiatric Association, 1994). Addicts typically exhibit decreased motivation for natural rewards (e.g., food, water, sex) that normally drive behavior. The abrupt cessation of drug use leads to the emergence of both affective (e.g., dysphoria, anxiety, anhedonia, somatic) and somatic withdrawal signs (Gawin, 1991, Koob and Le
Localization of dynorphin and κ-opioid receptor in the limbic cortical-striatopallidal system
DYN and KOPr are highly expressed in the prefrontal-cortico-striatal loop. PDYN expressing neurons are present throughout the neocortex with highest expression in the medial PFC and anterior cingulate (Alvarez-Bolado et al., 1990, Hurd, 1996). DYN content is low in comparison to other regions. However, immunoreactive cell bodies are found in layers II, III, V, and VI. Neurons in layer V are presumed to be corticofugal fibers that innervate the NAc and other subcortical regions.
KOPr protein and
Modulation of dopamine and glutamate transmission by κ-opioid receptor ligands
Microdialysis studies have shown that the systemic administration of selective KOPr agonists decreases DA overflow in the NAc (Di Chiara and Imperato, 1988, Chefer et al., 2005). The intra-NAc infusion of a selective KOPr agonist decreases DA levels in this region whereas intra-VTA infusion is without effect (Spanagel et al., 1992, Chefer et al., 2005, Margolis et al., 2006). Evidence that inhibition of mesoaccumbal DA transmission and the resulting decrease in D1 receptor activation underlies
Regulation of prodynorphin gene expression by dopamine and drugs of abuse
Manipulations that augment striatal DA transmission induce PDYN gene expression whereas depletion of striatal DA decreases DYN mRNA expression. Both effects have been attributed to the interaction of DA with D1 receptors located on DYN-containing medium spiny neurons (Gerfen et al., 1991). Studies examining the signal transduction pathways mediating PDYN gene regulation have identified 3 cAMP response elements (CRE) within the PDYN promoter. Studies in striatal cultures indicate that binding of
Behavioral effects κ-opioid receptor agonists relevant to addiction
Experimental animals will work to obtain electrical stimulation of the lateral hypothalamus, an effect attributed to the activation of reward circuits in the brain (Olds & Fobes, 1981). Acute administration of drugs of abuse decrease stimulation thresholds indicating that these agents activate the brain reward circuitry. Withdrawal from cocaine and other drugs of abuse is characterized by anhedonia, anxiety, and depressive-like symptomology. Withdrawal from various drugs of abuse increases the
Cocaine-antagonist-like effects of κ-opioid receptor agonists
The studies discussed above provide suggestive evidence that KOPr antagonists may be effective in attenuating alterations in behavior that occur during withdrawal from cocaine. A wealth of studies indicates that KOPr agonists can, when administered concurrently with cocaine, prevent cocaine-induced alterations in behavior and brain chemistry.
Acute pretreatment with KOPr agonists decreases the psychomotor stimulant and conditioned rewarding effects of cocaine in rats (Crawford et al., 1995).
Role of endogenous dynorphin/κ-opioid receptor systems in mediating vulnerability to cocaine
It has been suggested that repeated drug use increases the activity of DYN/KOPr systems and that this increase is a homeostatic mechanism that opposes alterations in behavior and brain function that occur as a consequence of drug use (Shippenberg et al., 1996, Shippenberg et al., 2001). Until recently, a direct test of this hypothesis was lacking. Studies, however, by Chefer et al. (2005) revealed that constitutive deletion of KOPr is associated with an enhancement of basal DA release and
Role of κ-opioid receptor systems in mediating the effects of ethanol
Evidence from both human and animals studies support the involvement of endogenous opioid systems in the effects of alcohol (Herz, 1997, Oswald and Wand, 2004). The opioid antagonist naltrexone is approved by the FDA for the treatment of alcoholism and reduces relapse to alcohol drinking in abstinent alcoholics (see O'Brien, 2005 for review). Recent studies have indicated an important role of the MOPr in alcohol drinking behavior (Hyytia, 1993, Roberts et al., 2000). However, information
Conclusions and therapeutic perspectives
Until recently, the development of effective therapies for the treatment of addiction has had as it primary focus the prevention or suppression of acute drug effects. However, recognition of the enduring alteration in brain function that occur as a consequence of repeated drug use has highlighted the potential importance of drug-induced neuroadaptions in maintaining compulsive drug-seeking behavior. Dysregulation of the DYN/KOPr system is one consequence of repeated drug use. Data from
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