Opposite effects of midazolam and β-carboline-3-carboxylate ethyl ester on the release of dopamine from rat nucleus accumbens measured by in vivo mudialysis

doi:10.1016/0014-2999(94)90301-8

European Journal of Pharmacology

Volume 261, Issues 1–2, 11 August 1994, Pages 65-71

https://doi.org/10.1016/0014-2999(94)90301-8 Get rights and content

Abstract

This report describes the effects of midazolam and β-carboline-3-carboxylate ethyl ester (β-CCE) on extracellular concentrations of dopamine in the nucleus accumbens of freely moving rats measured by in vivo mudialysis. The two compounds had opposite effects, midazolam (0.075 and 0.15 mg/kg i.v.) dose dependently decreasing, and β-CCE (3 and 10 mg/kg i.p.) dose dependently increasing, dialysate concentrations of dopamine. Flumazenil (6 μg/kg i.v.) did not affect the efflux of dopamine but it prevented the effects of both midazolam and β-CCE on dopamine efflux. N⁶-Cyclohexyladenosine (0.1, and 1 mg/kg i.p.), a seletive adenosine A₁ agonist, dose dependently increased the efflux of dopamine. This effect was blocked by 8-cyclopentyl-1,3-dipropylxanthine (25 mg/kg i.p.), a selective adenosine A₁ receptor antagonist, a dose which given alone did not affect dopamine efflux; responses to midazolam were not affected. 3,7-Dimethyl-1-propargylxanthine (1 and 3 mg/kg i.p.), a selective adenosine A₂ receptor antagonist, did not mimic the effects of β-CCE. The results suggest that midazolam and β-CCE modulate dopamine release in the nucleus accumbens by an action at the benzodiazepine binding site associated with the GABA_A receptor complex.

References (43)

H. Benveniste et al.
mudialysis - theory and application
Prog. Neurobiol.
(1990)
N. Brose et al.
Dopamine in the basal ganglia and benzodiazepine-induced sedation
Neuropharmacology
(1988)
M.D. D'Angio et al.
Tail-pinch stress increases extracellular DOPAC levels (as measured by in vivo voltammetry) in rat nucleus accumbens but not frontal cortex: antagonism by diazepam and zolpidem
Brain Res.
(1987)
F. Fadda et al.
Stress-induced increase in 3,4-dihydroxyphenyl-acetic acid (DOPAC) levels in the cerebral cortex and in nucleus accumbens: reversal by diazepam
Life Sci.
(1978)
S.E. File et al.
The anxiogenic action of benzodiazepine antagonists
Neuropharmacology
(1982)
R.J. Gruen et al.
Tonic inhibition of striatal dopamine transmission: effects of benzodiazepine and GABA_A receptor antagonists on extracellular dopamine levels
Brain Res.
(1992)
M. Hawkins et al.
Chronic administration of diazepam downregulates adenosine receptors in the rat brain
Pharmacol. Biochem. Behav.
(1988)
R. Invernizzi et al.
Release of dopamine is reduced by diazepam more in the nucleus accumbens that in the caudate nucleus of conscious rats
Neuropharmacology
(1991)
A.M. Knorr et al.
The anxiogenic β-carboline FG-7142 increases in vivo and in vivo tyrosine hydroxylation in the prefrontal cortex
Brain Res.
(1989)
N. Lindefors et al.
Intracerebral mudialysis. I. Experimental studies of diffusion kinetics
J. Pharmacol. Meth.
(1989)

P.F. Morgan et al.

Benzodiazepine inhibition of adenosine uptake is not prevented by benzodiazepine antagonists

Eur. J. Pharmacol.

(1983)

P.F. Morgan et al.

Inhibition of adenosine accumulation by a CNS benzodiazepine antagonist (Ro 15-1788) and a peripheral benzodiazepine receptor ligandd (Ro 05-4864)

Neurosci. Lett.

(1983)

E. Ongini et al.

Intrinsic and antagonistic effects of beta-carboline FG-7142 on behavioral and EEG actions of benzodiazepines and pentobarbital in cats

Eur. J. Pharmacol.

(1983)

E. Petersen et al.

Proconflict effect of benzodiazepine inverse agonists and other inhibitors of GABA function

Eur. J. Pharmacol.

(1984)

J.W. Phillis et al.

Benzodiazepine interaction with adenosine systems explains some anomalies in GABA hypothesis

Trends Pharmacol. Sci.

(1988)

J.W. Phillis et al.

Inhibition of adenosine uptake into rat brain synaptosomes by prostaglandins, benzodiazepines and other centrally active compounds

Gen. Pharmacol.

(1983)

M.S. Reid et al.

Differential modulation of striatal dopamine release by intranigral injection of gamma-aminobutyric acid (GABA), dynorphin A and substance P

Eur. J. Pharmacol.

(1988)

M. Santiago et al.

The role of GABA receptors in the control of nigrostriatal dopaminergic neurons: dual probe mudialysis study in awake rats

Eur. J. Pharmacol.

(1992)

T.W. Seale et al.

3.7-Dimethyl-1-propargylxanthine: a potent and selective in vivo antagonist of adenosine analogues

Life Sci.

(1988)

E.F. Sperber et al.

Intranigral GABAergic drugs effects on striatal dopamine activity

Pharmacol. Biochem. Behav.

(1989)

K. Takada et al.

Discriminative and aversive properties of beta-carboline-3-carboxylic acid ethyl ester, a benzodiazepine receptor inverse agonist, in rhesus monkeys

Life Sci.

(1986)

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Indeed, subcutaneous acute or chronic (twice a day for 14 days) injections of midazolam decreased extracellular DA concentrations in the nucleus accumbens (NAc) (as measured 40 min after the injection). Similar results were obtained in rats when midazolam [52] or flurazepam [53] was locally injected into the NAc. However, in this latter case, because the drug is restricted to the NAc, GABAARs of VTA cells are not potentiated, which could explain this result.
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While on the surface this finding might appear to invalidate our working hypothesis, electrophysiological evidence suggests that co-activation of D1 and D2 receptors on NAc neurons can, under some conditions, cause a reduction in their membrane excitability that is not seen in response to either agonist alone (O'Donnell and Grace, 1996). In addition, more work is needed to study the behavioral effects of intra-NAc microinfusions of GABA agonists; historically, this work has been hindered by poor solubility of benzodiazepines – which are known to be addictive (Griffiths and Ator, 1980) despite their tendency to decrease dopamine function in the NAc (Wood, 1982; Finlay et al., 1992: Murai et al., 1994) – and the relatively small number of researchers who use brain microinjection procedures together with models of reward. Still other ways of testing our hypothesis would be to study the effects of manipulations in brain areas downstream of D2 receptor-containing MSNs.
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Pentobarbital is reported to inhibit ketamine-induced dopamine (DA) release in the rat nucleus accumbens. The accumbens is a part of the limbic dopaminergic system in the brain, and the dopaminergic neural activity of other components may also be sensitive to pentobarbital. We investigated the effect of pentobarbital administration on DA release in the striatum known as DA-rich basal ganglia, and the interaction between pentobarbital and l-DOPA, using in vivo microdialysis techniques. Male SD rats were implanted microdialysis probe into the right striatum. The probe was perfused with modified Ringer's solution and dialysate was directly injected to an HPLC. Every group of rats was consisted of six to seven animals. In the first experiment, rats were given saline, 25 and 50 mg kg⁻¹ pentobarbital. The second, each rat was given a local administration of 2 and 5 μg ml⁻¹ of l-DOPA with perfusate. Finally, other sets of rats were given 5 μg ml⁻¹ of l-DOPA and 25, 50, or 100 mg kg⁻¹ pentobarbital. Pentobarbital anaesthesia decreased the extracellular concentration of DA, and local administration of l-DOPA significantly increased DA concentration. Pretreatment with pentobarbital diminished the l-DOPA-induced DA increase. The results of the present investigation demonstrate that administration of pentobarbital might inhibit dopaminergic neural activity not only in the nucleus accumbens but also in the rat striatum. Pentobarbital anaesthesia antagonizes DA increase induced by l-DOPA and suggests the inhibition of metabolism of l-DOPA. The results of some animal experiments on dopaminergic activity under pentobarbital anaesthesia should be reconsidered.

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Opposite effects of midazolam and β-carboline-3-carboxylate ethyl ester on the release of dopamine from rat nucleus accumbens measured by in vivo mudialysis

Abstract

Prog. Neurobiol.

Neuropharmacology

Brain Res.

Life Sci.

Neuropharmacology

Brain Res.

Pharmacol. Biochem. Behav.

Neuropharmacology

Brain Res.

J. Pharmacol. Meth.

Eur. J. Pharmacol.

Neurosci. Lett.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Trends Pharmacol. Sci.

Gen. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Life Sci.

Pharmacol. Biochem. Behav.

Life Sci.