Cocaine-induced conditioned locomotion: Absence of associated increases in dopamine release

doi:10.1016/0306-4522(92)90406-R

Neuroscience

Volume 48, Issue 3, June 1992, Pages 621-629

https://doi.org/10.1016/0306-4522(92)90406-R Get rights and content

Abstract

The potent reinforcing effects of cocaine can readily become associated with salient environmental stimuli that acquire secondary reinforcing properties. This phenomenon is of considerable significance as intense craving can be evoked by stimuli previously associated with the effects of cocaine. It has been proposed that the reinforcing properties of these conditional stimuli are due to their ability to elicit neural events that are similar to those produced by the drug itself. Given the large body of evidence that implicates the mesolimbic dopaminergic projection in the unconditioned behavioural properties of cocaine, the present study used in vivo microdialysis to determine whether stimuli paired with cocaine elicit increases in interstitial dopamine in the nucleus accumbens that are similar to the unconditioned effects of this drug.

When administered acutely, cocaine (10 mg/kg, i.p.) produced a potent unconditioned increase in interstitial dopamine concentrations (300% of basal values) in the nucleus accumbens. The results from two separate experiments indicate that the administration of cocaine (10 mg/kg for seven days) in association with a specific environment produced significant locomotion in that environment. Compared to subjects that received saline in both settings, rats that received cocaine in their home cage (pseudoconditioned group) did not exhibit increased locomotion on the test day. Although repeated pairing of cocaine with a specific environment produced conditioned locomotion, there was no concomitant conditional increase in dopamine release. Specifically, the modest increase in dopamine (10–15% above basal values) observed after exposure to the conditional environment was equal in the conditioned and pseudoconditioned groups. Moreover, increases in the interstitial concentrations of the dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid were not significantly different between the conditioned and pseudoconditioned subjects.

These data do not support the hypothesis that stimuli paired with cocaine produce their behavioural effects by eliciting similar neurochemical effects as cocaine.

References (47)

BarrG.A. et al.
Classical conditioning, decay and extinction of cocaine-induced hyperactivity and stereotypy
Life Sci.
(1983)
BeningerR.J. et al.
Pimozide blocks the establishment but not expression of cocaine-produced environment-specific conditioning
Life Sci.
(1986)
CadorM. et al.
Involvement of the amygdala in stimulus-reward associations: interactions with the ventral striatum
Neuroscience
(1989)
CommissiongJ.W.
Monoamine metabolites: their relationship and lack of relationship to monoaminergic neuronal activity
Biochem. Pharmac.
(1985)
EverittB.J. et al.
The basolateral amygdala-ventral striatal system and conditioned place preference: further evidence of limbic-striatal interactions underlying reward-related processes
Neuroscience
(1991)
HeikkilaR.E. et al.
Studies on the distinction between uptake inhibition and release of [³H]dopamine in rat brain slices
Biochem. Pharmac.
(1975)
LynessW.H. et al.
Destruction of dopaminergic nerve terminals in nucleus accumbens: effects on d-amphetamine self-administration
Pharmac. Biochem. Behav.
(1979)
PfausJ.G. et al.
Sexual behavior enhances central dopamine transmission in the male rat
Brain Res.
(1990)
RobbinsT.W. et al.
Limbic-striatal interactions in reward-related process
Neurosci. Biobehav. Rev.
(1989)
RobertsD.C.S. et al.
On the role of ascending catecholaminergic systems in intravenous self-administration of cocaine
Pharmac. Biochem. Behav.
(1977)

Soares-da-SilvaP. et al.

A kinetic study of the rate of formation of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the brain of the rat: implications for the origin of DOPAC

Neuropharmacology

(1990)

WeissS.R.B. et al.

Context-dependent cocaine sensitization: differential effect of haloperidol on development versus expression

Pharmac. Biochem. Behav.

(1989)

WesterinkB.H.C.

Sequence and significance of dopamine metabolism in the rat brain

Neurochem. Int.

(1985)

BarrettJ.E. et al.

Neurochemical correlates of behavioural processes

Drug Dev. Res.

(1990)

BeningerR.J. et al.

Pimozide blocks the establishment but not expression of amphetamine-produced environment-specific conditioning

Science, Washington D.C.

(1983)

BrownE.E. et al.

Interstitial 3-methoxytyramine reflects striatal dopamine release: an in vivo microdialysis study

J. Neurochem.

(1991)

BrownE.E. et al.

Behavioral and neurochemical interactions between cocaine and buprenorphine: implications for the pharmacotherapy of cocaine abuse

J. Pharmac. exp. Ther.

(1991)

De WitH. et al.

Blockade of cocaine reinforcement in rats with the dopamine receptor blocker pimozide, but not with the noradrenergic blockers phentolamine and phenoxybenzamine

Can. J. Physiol.

(1977)

DelfsJ.M. et al.

Microinjections of cocaine into the nucleus accumbens elicits locomotor activation in the rat

J. Neurosci.

(1990)

Di ChiaraG. et al.

Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats

FibigerH.C. et al.

Role of catecholamine transmitters in brain reward systems: implications for the neurobiology of affect

FinlayJ.M. et al.

Fentanyl-induced conditional place preference: lack of associated conditional neurochemical events

Psychopharmacology

(1988)

GawinF.H.

Cocaine addiction: psychology and neurophysiology

Science, Washington D.C.

(1991)

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Cocaine-induced conditioned locomotion: Absence of associated increases in dopamine release

Abstract

Life Sci.

Life Sci.

Neuroscience

Biochem. Pharmac.

Neuroscience

Biochem. Pharmac.

Pharmac. Biochem. Behav.

Brain Res.

Neurosci. Biobehav. Rev.

Pharmac. Biochem. Behav.

Neuropharmacology

Pharmac. Biochem. Behav.

Neurochem. Int.

Neurochemical correlates of behavioural processes

Drug Dev. Res.

Pimozide blocks the establishment but not expression of amphetamine-produced environment-specific conditioning

Science, Washington D.C.

Interstitial 3-methoxytyramine reflects striatal dopamine release: an in vivo microdialysis study

J. Neurochem.

Behavioral and neurochemical interactions between cocaine and buprenorphine: implications for the pharmacotherapy of cocaine abuse

J. Pharmac. exp. Ther.

Blockade of cocaine reinforcement in rats with the dopamine receptor blocker pimozide, but not with the noradrenergic blockers phentolamine and phenoxybenzamine

Can. J. Physiol.

Microinjections of cocaine into the nucleus accumbens elicits locomotor activation in the rat

J. Neurosci.

Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats

Role of catecholamine transmitters in brain reward systems: implications for the neurobiology of affect

Fentanyl-induced conditional place preference: lack of associated conditional neurochemical events

Psychopharmacology

Cocaine addiction: psychology and neurophysiology

Science, Washington D.C.