Associate editor: T.C. Napier
Dynorphin and the pathophysiology of drug addiction

https://doi.org/10.1016/j.pharmthera.2007.06.011Get rights and content

Abstract

Drug addiction is a chronic relapsing disease in which drug administration becomes the primary stimulus that drives behavior regardless of the adverse consequence that may ensue. As drug use becomes more compulsive, motivation for natural rewards that normally drive behavior decreases. The discontinuation of drug use is associated with somatic signs of withdrawal, dysphoria, anxiety, and anhedonia. These consequences of drug use are thought to contribute to the maintenance of drug use and to the reinstatement of compulsive drug use that occurs during the early phase of abstinence. Even, however, after prolonged periods of abstinence, 80–90% of human addicts relapse to addiction, suggesting that repeated drug use produces enduring changes in brain circuits that subserve incentive motivation and stimulus–response (habit) learning. A major goal of addiction research is the identification of the neural mechanisms by which drugs of abuse produce these effects. This article will review data showing that the dynorphin/κ-opioid receptor (KOPr) system serves an essential function in opposing alterations in behavior and brain neurochemistry that occur as a consequence of repeated drug use and that aberrant activity of this system may not only contribute to the dysregulation of behavior that characterizes addiction but to individual differences in vulnerability to the pharmacological actions of cocaine and alcohol. We will provide evidence that the repeated administration of cocaine and alcohol up-regulates the dynorphin/KOPr system and that pharmacological treatments that target this system may prove effective in the treatment 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

References (222)

  • P. Di Ciano et al.

    Dissociable effects of antagonism of NMDA and AMPA/KA receptors in the nucleus accumbens core and shell on cocaine-seeking behavior

    Neuropsychopharmacology

    (2001)
  • P. Di Ciano et al.

    Neuropsychopharmacology of drug seeking: insights from studies with second-order schedules of drug reinforcement

    Eur J Pharmacol

    (2005)
  • W.M. Doyon et al.

    Kappa-opioid receptor modulation of accumbal dopamine concentration during operant ethanol self-administration

    Neuropharmacology

    (2006)
  • S.D. Glick et al.

    Archer S., Kappa opioid inhibition of morphine and cocaine self-administration in rats

    Brain Res

    (1995)
  • W. Gong et al.

    Conditioned place preference and locomotor activation produced by injection of psychostimulants into ventral pallidum

    Brain Res

    (1996)
  • W. Gong et al.

    6-Hydroxydopamine lesion of ventral pallidum blocks acquisition of place preference conditioning to cocaine

    Brain Res

    (1997)
  • A.M. Graybiel

    Neurotransmitters and neuromodulaters in the basal ganglia

    Trends Neurosci

    (1990)
  • A.M. Graybiel

    The basal ganglia: learning new tricks and loving it

    Curr Opin Neurobiol

    (2005)
  • H.J. Groenewegen et al.

    Organization of the output of the ventral striatopallidal system in the rat: ventral pallidal efferents

    Neuroscience

    (1993)
  • K. Gulya et al.

    Prodynorphin and vasopressin mRNA levels are differentially affected by chronic ethanol ingestion in the mouse

    Mol Brain Res

    (1993)
  • C.A. Heidbreder et al.

    The kappa-opioid receptor agonist U-69593 attenuates cocaine-induced behavioral sensitization in the rat

    Brain Res

    (1993)
  • M.H. Heijna et al.

    Opioid receptors and inhibition of dopamine-sensitive adenylate cyclase in slices of rat brain regions receiving a dense dopaminergic input

    Eur J Pharmacol

    (1992)
  • L. Heimer et al.

    The limbic lobe and its output channels: implications for emotional functions and adaptive behavior

    Neurosci Biobehav Rev

    (2006)
  • M.P. Hill et al.

    Modulation of glutamate release by a kappa-opioid receptor agonist in rodent and primate striatum

    Eur J Pharmacol

    (1995)
  • Y.L. Hurd

    Differential messenger RNA expression of prodynorphin and proenkephalin in the human brain

    Neuroscience

    (1996)
  • P. Hyytia

    Involvement of mu-opioid receptors in alcohol drinking by alcohol-preferring AA rats

    Pharmacol Biochem Behav

    (1993)
  • R.M. Jones et al.

    5′-Guanidinonaltrindole, a highly selective and potent kappa-opioid receptor antagonist

    Eur J Pharmacol

    (2000)
  • P.W. Kalivas et al.

    Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmission

    Neuron

    (2005)
  • M.A. Klitenick et al.

    Topography and functional role of dopaminergic projections from the ventral mesencephalic tegmentum to the ventral pallidum

    Neuroscience

    (1992)
  • A.V. Kuzmin et al.

    Kappa-opioid receptor agonist U50, 488H modulates cocaine and morphine self-administration in drug-naïve rats and mice

    Eur J Pharmacol

    (1997)
  • R.A. Lahti et al.

    [3H]U-69593 a highly selective ligand for the opioid kappa receptor

    Eur J Pharmacol

    (1985)
  • S. Lindholm et al.

    Repeated ethanol administration induces short- and long-term changes in enkephalin and dynorphin tissue concentrations in rat brain

    Alcohol

    (2000)
  • S. Lindholm et al.

    The selective kappa-opioid receptor agonist U50, 488H attenuates voluntary ethanol intake in the rat

    Behav Brain Res

    (2001)
  • L.Y. Liu-Chen

    Agonist-induced regulation and trafficking of kappa opioid receptors

    Life Sci

    (2004)
  • Y.P. Maneuf et al.

    Functional implications of kappa opioid receptor-mediated modulation of glutamate transmission in the output regions of the basal ganglia in rodent and primate models of Parkinson's disease

    Brain Res

    (1995)
  • A. Mansour et al.

    Immunohistochemical localization of the cloned kappa 1 receptor in the rat CNS and pituitary

    Neuroscience

    (1996)
  • G. Alvarez-Bolado et al.

    Expression of the prodynorphin gene in the developing and adult cerebral cortex of the rat: an in situ hybridization study

    J Comp Neurol

    (1990)
  • American Psychiatric Association.

    Diagnostic and statistical manual of mental disorders

    (1994)
  • R. Bals-Kubik et al.

    Evidence that the aversive effects of opioid antagonists and kappa-agonists are centrally mediated

    Psychopharmacology

    (1989)
  • R. Bals-Kubik et al.

    Neuroanatomical sites mediating the motivational effects of opioids as mapped by the conditioned place preference paradigm in rats

    J Pharmacol Exp Ther

    (1993)
  • D.A. Baker et al.

    Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse

    Nat Neurosci

    (2003)
  • A.M. Barr et al.

    A “crash” course on psychostimulant withdrawal as a model of depression

    Trends Pharmacol Sci

    (2002)
  • P.M. Beardsley et al.

    Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by foot shock stressors vs. cocaine primes and its antidepressant-like effects in rats

    Psychopharmacology

    (2005)
  • H.W. Berendse et al.

    Topographical organization and relationship with ventral striatal compartments of prefrontal corticostriatal projections in the rat

    J Comp Neurol

    (1992)
  • R.G. Bhushan et al.

    A bivalent ligand (KDN-21) reveals spinal delta and kappa opioid receptors are organized as heterodimers that give rise to delta(1) and kappa(2) phenotypes. Selective targeting of delta-kappa heterodimers

    J Med Chem

    (2004)
  • C.L. Brandon et al.

    Repeated methylphenidate treatment in adolescent rats alters gene regulation in the striatum

    Eur J Neurosci

    (2003)
  • J.H. Broadbear et al.

    Differential effects of systemically administered nor-binaltorphimine (nor-BNI) on kappa-opioid agonists in the mouse writhing assay

    Psychopharmacology (Berl)

    (1994)
  • M.S. Brodie et al.

    Ethanol directly excites dopaminergic ventral tegmental area reward neurons

    Alcohol Clin Exp Res

    (1999)
  • N. Capriles et al.

    A role for the prefrontal cortex in stress- and cocaine-induced reinstatement of cocaine seeking in rats

    Psychopharmacology

    (2003)
  • W.A. Carlezon et al.

    Regulation of cocaine reward by CREB

    Science

    (1998)
  • Cited by (303)

    View all citing articles on Scopus
    View full text