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

doi:10.1016/S0306-4522(00)00417-6

Neuroscience

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

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

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

Abstract

Section snippets

Animals

Histology

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

Discussion

Conclusions

Subchronic cocaine treatment enhances cocaine-induced dopamine efflux, studied by in vivo intracerebral dialysis

Brain Res.

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

Proc. natn. Acad. Sci. USA

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

Analyt. Biochem.

Steady-state theory for quantitative microdialysis of solutes and water in vivo and in vitro

Life Sci.

Dopamine and norepinephrine innervated cells in the rat prefrontal cortex: pharmacological differentiation using microiontophoretic techniques

Life Sci.

In vivo assessment of dopamine uptake in rat medial prefrontal cortex: comparison with dorsal striatum and nucleus accumbens

J. Neurochem.

Modulation of cocaine-induced sensitization by kappa-opioid receptor agonists. Role of the nucleus accumbens and medial prefrontal cortex

Ann. N. Y. Acad. Sci.

Respective contributions of neuronal activity and presynaptic mechanisms in the control of the in vivo release of dopamine

J. neural Transm., Suppl.

Effect of tetrodotoxin and potassium infusion on microdialysis extraction fraction and extracellular dopamine in the nucleus accumbens

Neurosci. Lett.

Quantitative microdialysis of serotonin and norepinephrine: pharmacological influences on in vivo extraction fraction

J. Neurosci. Meth.

Rating the behavioral effects of amphetamine

Eur. J. Pharmac.

Inhibitory influence of the mesocortical dopaminergic system on spontaneous activity or excitatory response induced from the thalamic mediodorsal nucleus in the rat medial prefrontal cortex

Brain Res.

Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia

Neuroscience

Effects of cocaine on dopamine in subregions of the rat prefrontal cortex and their efferents to subterritories of the nucleus accumbens

Eur. J. Pharmac.

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

Brain Res.

U-69593 prevents cocaine sensitization by normalizing basal accumbens dopamine

NeuroReport

Role of extracellular dopamine in the initiation and long-term expression of behavioral sensitization to cocaine

J. Pharmac. exp. Ther.

Opioid receptor-mediated inhibition of dopamine and acetylcholine release from slices of rat nucleus accumbens, olfactory tubercle and frontal cortex

Eur. J. Pharmac.

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

Brain Res.

Quantitative microdialysis of neurotransmitters

J. Neurosci. Meth.

Neural substrate of sensitization to psychostimulants

Clin. Neuropharmac.

Effect of acute and daily cocaine treatment on extracellular dopamine in the nucleus accumbens

Synapse

Time course of extracellular dopamine and behavioral sensitization to cocaine. I. Dopamine axon terminals

J. Neurosci.

Time course of extracellular dopamine and behavioral sensitization to cocaine. II. Dopamine perikarya

J. Neurosci.

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

Brain Res. Rev.

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

Biol. Psychiat.

Both glutamate receptor antagonists and prefrontal cortex lesions prevent induction of cocaine sensitization and associated neuroadaptations

Synapse

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

Brain Res.

Tolerance-like attenuation to contingent and noncontingent cocaine-induced elevation of extracellular dopamine in the ventral striatum following 7 days of withdrawal from chronic treatment

Psychopharmacology, Berlin

Serotonin and dopamine sensitization in the nucleus accumbens, ventral tegmental area, and dorsal raphe nucleus following repeated cocaine administration

J. Neurochem.