Regional extracellular norepinephrine responses to amphetamine and cocaine and effects of clonidine pretreatment

doi:10.1016/0006-8993(94)91570-9

Brain Research

Volume 654, Issue 1, 15 August 1994, Pages 53-62

https://doi.org/10.1016/0006-8993(94)91570-9 Get rights and content

Abstract

Microdialysis in behaving animals was used to characterize the hippocampus (HP) and prefrontal cortex (PFC) norepinephrine (NE) responses to amphetamine (AMPH) and cocaine (COC). NE exhibited regionally similar dose- and time-dependent increases to each drug. However, peak NE concentrations were ∼ 2-fold greater at behaviorally similar doses of AMPH compared with COC. To examine the role of noradrenergic impulse flow in the mechanism(s) by which these stimulants enhance extracellular NE, groups of animals were pretreated with the α₂ autoreceptor agonist, clonidine (CLON), prior to stimulant administration. CLON (50 μg/kg) administration completely blocked the NE response to both 20 and 30 mg/kg COC. By contrast, CLON decreased the NE response to 0.5 mg/kg AMPH by 75%, but became progressively less effective on the response as the dose was increased to 1.75 and 5.0 mg/kg. CLON also had no effect on the caudate dopamine responses to either AMPH or COC, consistent with the presumed specificity of this drug for α₂ receptors and suggesting the absence of any significant pharmacokinetic interactions. These results indicate that COC acts as an uptake blocker at NE-containing neurons and suggest that AMPH increases extracellular NE through two consequences of its interaction with the neuronal transport carrier: (1) reuptake blockade which predominates at lower doses; (2) release which becomes more prevalent at higher doses. Behavioral analyses revealed effects of CLON which varied as a function of stimulant and dose.

References (93)

AbercrombieE.D. et al.
Microinjected clonidine inhibits noradrenergic neurons of the locus coeruleus in freely moving cats
Neurosci. Lett.
(1987)
AbercrombieE.D. et al.
Characterization of hippocampal norepinephrine release as measured by microdialysis perfusion: pharmacological and behavioral studies
Neuroscience
(1988)
AdamsL.M. et al.
Effects of locally infused pharmacological agents on spontaneous and sensory-evoked activity of locus coeruleus neurons
Brain Res. Bull.
(1988)
CallawayC.W. et al.
Reserpine enhances amphetamine stereotypies without increasing amphetamine-induced changes in striatal dialysate dopamine
Brain Res.
(1989)
CarboniE. et al.
Amphetamine, cocaine, phencyclidine and nomifensine increase extracellular dopamine concentrations preferentially in the nucleus accumbens of freely moving rats
Neuroscience
(1989)
CedarbaumJ.M. et al.
Catecholamine receptors on locus coeruleus neurons: pharmacological characterization
Eur. J. Pharmacol.
(1977)
ColeS.O.
Brain mechanisms of amphetamine-induced anorexia, locomotion, and stereotypy: a review
Neurosci. Biobehav. Rev.
(1978)
CuretO. et al.
Effect of desipramine and amphetamine on noradrenergic neurotransmission: electrophysiological studies in the rat brain
Eur. J. Pharmacol.
(1992)
CurtisA.L. et al.
Cocaine effects on brain noradrenergic neurons of anesthetized and unanesthetized rats
Neuropharmacology
(1993)
De LuciaR. et al.
On the mechanism of central stimulation action of fencamfamine
Genet. Pharmacol.
(1984)

GeyerM.A. et al.

Behavioral effects of xylamine-induced depletions of brain norepinephrine: interactions with amphetamine

Behav. Brain Res.

(1986)

JacksonH.C. et al.

α2-Adrenoceptor antagonists block the stimulant effects of cocaine in mice

Life Sci.

(1992)

KalénP. et al.

Basic characteristics of noradrenaline release in the hippocampus of intact and 6-hydroxydopamine-lesioned rats as studied by in vivo microdialysis

Brain Res.

(1988)

KuczenskiR. et al.

In vivo measures of monoamines during amphetamine-induced behaviors in rats

Prog. Neuro-Psychopharmacol. Biol. Psych. Suppl.

(1990)

LundbergJ. et al.

Ultrastructural localization of dopamine-B-hydroxylase in nerve terminals of the rat brain

Brain Res.

(1977)

LuttingerD. et al.

Alpha-2-adrenergic antagonists effect on amphetamine-induced behaviors

Pharmacol. Biochem. Behav.

(1986)

MaisonneuveI.M. et al.

Similar effects ofd-amphetamine and cocaine on extracellular dopamine levels in medial prefrontal cortex of rats

Brain Res.

(1990)

NicolaysenL.C. et al.

Effects of cocaine on release and uptake of dopamine in vivo: differentiation by mathematical modeling

Pharmacol. Biochem. Behav.

(1988)

PelayoF. et al.

Inhibition of neuronal uptake reduces the presynaptic effects of clonidine but not of alpha-methylnoradrenaline on the stimulation-evoked release of [3H]-noradrenaline from rat occipital cortex slices

Eur. J. Pharmacol.

(1980)

PhillipsJ.H.

Dynamic aspects of chromaffin granule structure

Neuroscience

(1982)

PittsD.K. et al.

Effects of cocaine on the electrical activity of single noradrenergic neurons from locus coeruleus

Life Sci.

(1986)

RaiteriM. et al.

d-Amphetamine as a releaser or reuptake inhibitor of biogenic amines in synaptosomes

Eur. J. Pharmacol.

(1975)

RaiteriM. et al.

d-Amphetamine and the release of 3H-norepinephrine from synaptosomes

Eur. J. Pharmacol.

(1974)

RamirezO.A. et al.

Locus coeruleus norepinephrine-containing neurons: effects of produced by acute and subchronic treatment with antipsychotic drugs and amphetamine

Brain Res.

(1986)

RossS.B. et al.

Inhibition of the uptake of triatiated catecholamines by anti-depressant and related agents

Eur. J. Pharmacol.

(1967)

RossettiZ.L. et al.

Brain dialysis provides evidence for D₂-dopamine receptors modulating noradrenaline release in the rat frontal cortex

Eur. J. Pharmacol.

(1989)

RossettiZ.L. et al.

Stress increases noradrenaline release in the rat frontal cortex: prevention by diazepam

Eur. J. Pharmacol.

(1990)

RutledgeC.O. et al.

Evidence for carrier-mediated efflux of norepinephrine displayed by amphetamine

RyanL.J. et al.

Amphetamine's effects on terminal excitability of noradrenergic locus coeruleus neurons are impulse-dependent at low but not high doses

Brain Res.

(1985)

SeyfriedC.A.

Dopamine uptake inhibiting versus dopamine releasing properties of fencamfamine: an in vitro study

Biochem. Pharmacol.

(1983)

SharpT. et al.

A direct comparison of amphetamine-induced behaviours and regional brain dopamine release in the rat using intracerebral dialysis

Brain Res.

(1987)

ShenoyA. et al.

Comparative regulation of potassium and amphetamine induced release of 3H-norepinephrine from rat brain via presynaptic mechanisms

Life Sci.

(1979)

StahleL. et al.

A comparison between three methods for estimation of extracellular concentrations of exogenous and endogenous compounds by microdialysis

J. Pharmacol. Methods

(1991)

SvenssonT.H. et al.

Inhibition of both noradrenergic and serotonegic neurons in brain by the alpha-adrenergic agonist clonidine

Brain Res.

(1975)

SwerdlowN.R. et al.

The neural substrates for the motor-activating properties of psychostimulants: a review of recent findings

Pharmacol. Biochem. Behav.

(1986)

Van VeldhuizenM.J.A. et al.

Microdialysis studies on cortical noradrenaline release: basic characteristics, significance of extracellular calcium and massive post-mortem increase

Neurosci. Lett.

(1990)

ZetterstromT. et al.

Effects of apomorphine on the in vivo release of dopamine and its metabolites, studied by brain dialysis

Eur. J. Pharmacol.

(1984)

AbercrombieE.D. et al.

Partial injury to central noradrenergic neurons: reduction of tissue norepinephrine content is greater than reduction of extracellular norepinephrine measured by microdialysis

J. Neurosci.

(1989)

ArcherT. et al.

Central noradrenaline depletion antagonizes aspects ofd-amphetamine-induced hyperactivity in the rat

Psychopharmacology

(1986)

AzzaroA.J. et al.

The importance of neuronal uptake of amines for amphetamine-induced release of 3H-norepinephrine from isolated brain tissue

J. Pharmacol. Exp. Ther.

(1974)

BenvenisteH. et al.

Determination of brain interstitial concentration by microdialysis

J. Neurochem.

(1989)

BonischH.

The transport of (+)-amphetamine by the neuronal noradrenaline carrier

Naunyn Schmiedeberg's Arch. Pharmacol.

(1984)

BonischH. et al.

The mechanism of action of indirectly acting sympathomimetic amines

BrodieB.B. et al.

A concept for a role of serotonin and norepinephrine as chemical mediators in the brain

Ann. N.Y. Acad. Sci.

(1957)

BunneyB.S. et al.

Dopaminergic neurons: effect of antipsychotic drugs and amphetamine on single cell activity

J. Pharmacol. Exp. Ther.

(1973)

ChurchW.H. et al.

Rapid sampling and determination of extracellular dopamine

Anal. Chem.

(1987)

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Regional extracellular norepinephrine responses to amphetamine and cocaine and effects of clonidine pretreatment

Abstract

Neurosci. Lett.

Neuroscience

Brain Res. Bull.

Brain Res.

Neuroscience

Eur. J. Pharmacol.

Neurosci. Biobehav. Rev.

Eur. J. Pharmacol.

Neuropharmacology

Genet. Pharmacol.

Behav. Brain Res.

Life Sci.

Brain Res.

Prog. Neuro-Psychopharmacol. Biol. Psych. Suppl.

Brain Res.

Pharmacol. Biochem. Behav.

Brain Res.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Neuroscience

Life Sci.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Brain Res.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Brain Res.

Biochem. Pharmacol.

Brain Res.

Life Sci.

J. Pharmacol. Methods

Brain Res.

Pharmacol. Biochem. Behav.

Neurosci. Lett.

Eur. J. Pharmacol.

Partial injury to central noradrenergic neurons: reduction of tissue norepinephrine content is greater than reduction of extracellular norepinephrine measured by microdialysis

J. Neurosci.

Central noradrenaline depletion antagonizes aspects ofd-amphetamine-induced hyperactivity in the rat

Psychopharmacology

The importance of neuronal uptake of amines for amphetamine-induced release of 3H-norepinephrine from isolated brain tissue

J. Pharmacol. Exp. Ther.

Determination of brain interstitial concentration by microdialysis

J. Neurochem.

The transport of (+)-amphetamine by the neuronal noradrenaline carrier

Naunyn Schmiedeberg's Arch. Pharmacol.

The mechanism of action of indirectly acting sympathomimetic amines

A concept for a role of serotonin and norepinephrine as chemical mediators in the brain

Ann. N.Y. Acad. Sci.

Dopaminergic neurons: effect of antipsychotic drugs and amphetamine on single cell activity

J. Pharmacol. Exp. Ther.

Rapid sampling and determination of extracellular dopamine

Anal. Chem.