Elsevier

Neuroscience

Volume 101, Issue 3, 15 November 2000, Pages 619-627
Neuroscience

Kappa-opioid receptor activation prevents alterations in mesocortical dopamine neurotransmission that occur during abstinence from cocaine

https://doi.org/10.1016/S0306-4522(00)00417-6Get rights and content

Abstract

In vivo microdialysis was used to characterize basal dopamine dynamics and cocaine-evoked dopamine levels in the medial prefrontal cortex of male Sprague–Dawley rats that had previously received once daily injections of cocaine (days 1–5; 20 mg/kg, i.p.) in combination with the selective kappa-opioid receptor agonist U-69593 (days 3–5; 0.32 mg/kg, s.c.) or its vehicle. The influence of these treatments on [3H]dopamine uptake in medial prefrontal cortex synaptosomes was also determined. Three days following the cessation of drug treatment, animals with prior history of cocaine administration exhibited enhanced psychomotor stimulation in response to a subsequent cocaine challenge. This effect was not apparent in animals that had previously received the cocaine treatment regimen in combination with the kappa-opioid receptor agonist U-69593. Cocaine challenge increased prefrontal dopamine levels in all pretreatment groups, but cocaine-pre-exposed animals had lower cocaine-evoked dopamine levels and higher basal in vivo extraction fraction, indicative of an increase in basal dopamine uptake relative to controls. Pretreatment with U-69593 prevented these effects of cocaine. Measurement of [3H]dopamine uptake in synaptosomes revealed a significant increase in uptake three days after the cessation of cocaine treatment. No increase in uptake was observed in animals that had received the cocaine treatment regimen in combination with U-69593.

These results demonstrate that the early phase of abstinence from cocaine is associated with marked alterations in medial prefrontal cortex dopamine neurotransmission and that these neuroadaptations are prevented by the activation of kappa-opioid receptors. Furthermore, they raise the possibility that mesocortical dopamine neurons may be an important neural substrate upon which kappa-opioid agonists act to prevent the development of cocaine-induced behavioral sensitization.

Section snippets

Animals

Male Sprague–Dawley rats (Charles River Laboratories) weighing 250–350 g were housed in groups of three per cage for at least one week before use. They were maintained in a temperature- and humidity-controlled environment under an artificial 12 h/12 h light–dark cycle with laboratory rat chow and water available ad libitum. Animals used in this study were maintained in facilities accredited by the American Association for the Accreditation of Laboratory Animal Care (AAALAC), and all experiments

Histology

The placement of the microdialysis probes in the mPFC is illustrated in Fig. 1. The active 2 mm portion of each probe is shown. All probe placements with more than 25% of the dialysis membrane located outside the mPFC were excluded from the data analysis and are not shown here. On average, histological analysis confirmed correct placement of the microdialysis probes in 95% of the animals. There was no systematic group difference in histological placement of the microdialysis probes.

Influence of U-69593 pretreatment in combination with saline or cocaine upon cocaine-evoked locomotor activity

Discussion

This study demonstrates that the early phase of abstinence from cocaine is associated with an elevation of basal DA uptake in the mPFC and a blunted response of mesocortical DA neurons to a subsequent cocaine challenge. The co-administration of the selective kappa-opioid receptor agonist U-69593 with cocaine prevents these changes in prefrontal DA neurotransmission, and it is effective in preventing the sensitized behavioral response to cocaine that develops as a consequence of repeated drug

Conclusions

The present study demonstrates that basal and cocaine-evoked mPFC DA dynamics are altered during the early phase of abstinence from cocaine. The systemic administration of a selective kappa-opioid agonist prevents these changes in DA neurotransmission and the development of sensitization to the psychomotor stimulant effects of cocaine. Given the role of the mPFC in the regulation of the induction of behavioral sensitization, we hypothesize that the normalization of DA neurotransmission in the

References (62)

  • Y.L Hurd et al.

    Cocaine reinforcement and extracellular dopamine overflow in rat nucleus accumbens: an in vivo microdialysis study

    Brain Res.

    (1989)
  • J.B.J Justice

    Quantitative microdialysis of neurotransmitters

    J. Neurosci. Meth.

    (1993)
  • P.W Kalivas et al.

    Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity

    Brain Res. Rev.

    (1991)
  • Y Kazahaya et al.

    Subchronic methamphetamine treatment enhances methamphetamine- or cocaine-induced dopamine efflux in vivo

    Biol. Psychiat.

    (1989)
  • S.M Meiergerd et al.

    Repeated cocaine and stress increase dopamine clearance in the rat medial prefrontal cortex

    Brain Res.

    (1997)
  • L.H Parsons et al.

    The in vivo microdialysis recovery of dopamine is altered independently of basal level by 6-hydroxydopamine lesions to the nucleus accumbens

    J. Neurosci. Meth.

    (1991)
  • S.L Patrick et al.

    Concomitant sensitization of amphetamine-induced behavioral stimulation and in vivo dopamine release from rat caudate nucleus

    Brain Res.

    (1991)
  • S Retaux et al.

    Opposing effects of dopamine D2 receptor stimulation on the spontaneous and the electrically evoked release of [3H]GABA on rat prefrontal cortex slices

    Neuroscience

    (1991)
  • S Retaux et al.

    Synergism between D1 and D2 dopamine receptors in the inhibition of the evoked release of [3H]GABA in the rat prefrontal cortex

    Neuroscience

    (1991)
  • T.E Robinson et al.

    Behavioral sensitization is accompanied by an enhancement in amphetamine-stimulated dopamine release from striatal tissue in vitro

    Eur. J. Pharmac.

    (1982)
  • T.E Robinson et al.

    Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis

    Brain Res.

    (1986)
  • D.S Segal et al.

    In vivo microdialysis reveals a diminished amphetamine-induced DA response corresponding to behavioral sensitization produced by repeated amphetamine pretreatment

    Brain Res.

    (1992)
  • D.S Segal et al.

    Repeated cocaine administration induces behavioral sensitization and corresponding decreased extracellular dopamine responses in caudate and accumbens

    Brain Res.

    (1992)
  • A.D Smith et al.

    The effect of inhibition of synthesis, release, metabolism and uptake on the microdialysis extraction fraction of dopamine

    J. Neurosci. Meth.

    (1994)
  • B.A Sorg et al.

    Effects of cocaine and footshock stress on extracellular dopamine levels in the medial prefrontal cortex

    Neuroscience

    (1993)
  • B.A Sorg et al.

    Mechanisms of cocaine-induced sensitization

    Prog. Neuropsychopharmac. biol. Psychiat.

    (1992)
  • M.F Suaud-Chagny et al.

    Relationship between dopamine release in the rat nucleus accumbens and the discharge activity of dopaminergic neurons during local in vivo application of amino acids in the ventral tegmental area

    Neuroscience

    (1992)
  • T.M Tzschentke et al.

    The development of cocaine-induced behavioral sensitization is affected by discrete quinolinic acid lesions of the prelimbic medial prefrontal cortex

    Brain Res.

    (1998)
  • M.E Wolf et al.

    Effects of lesions of prefrontal cortex, amygdala, or fornix on behavioral sensitization to amphetamine: comparison with N-methyl-d-aspartate antagonists

    Neuroscience

    (1995)
  • U Arvidsson et al.

    The kappa-opioid receptor is primarily postsynaptic: combined immunohistochemical localization of the receptor and endogenous opioids

    Proc. natn. Acad. Sci. USA

    (1995)
  • H Bradford

    A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein–dye binding

    Analyt. Biochem.

    (1976)
  • Cited by (0)

    View full text