Elsevier

Brain Research

Volume 798, Issues 1–2, 6 July 1998, Pages 156-165
Brain Research

Research report
Nucleus accumbens dopamine release modulation by mesolimbic GABAA receptors—an in vivo electrochemical study

https://doi.org/10.1016/S0006-8993(98)00406-5Get rights and content

Abstract

The role of GABA receptors in regulating the mesolimbic dopamine (DA) system and drug reinforced behaviors has not been well characterized. Using fast-cyclic voltammetry, the effects of specific GABA receptor modulation on DA release in the nucleus accumbens (NAcc) and heroin self-administration (SA) behavior was investigated. The GABAA agonist muscimol, administered either intravenously or directly into the ventral tegmental area (VTA), significantly increased DA release in the NAcc in 7 of the 10 rats tested. DA release decreased in the remaining three rats; both effects were blocked by pretreatment with the GABAA receptor antagonist bicuculline. In contrast, the GABAB agonist baclofen decreased, while 2-OH-saclofen (a GABAB antagonist) increased DA release in the NAcc. However, when VTA GABAB receptors were previously activated or inactivated by microinjections of baclofen or 2-OH-saclofen, systemic injections of muscimol caused an inhibition of NAcc DA release. These results suggest that GABAA receptors may be co-localized on both DA neurons and non-DA (GABAergic) interneurons in the VTA, with the effects of GABAA determined by the net effect of both direct inhibition and indirect disinhibition of DA neurons. Finally, although a DA releaser, muscimol was neither self-administered in drug naive rats, nor did it substitute for heroin in rats previously trained to self-administer heroin, suggesting that GABAA receptors appear to play a complex role in mediating drug reinforcement, depending upon the dynamic functional state of GABAA receptors on both tegmental DA and non-DA neurons.

Introduction

γ-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the adult mammalian central nervous system, acts upon at least two pharmacologically distinct receptor subtypes, i.e., GABAA and GABAB receptors. GABAB receptor activation leads to a reduction in DA neuronal excitability by inhibiting presynaptic Ca2+ conductance or activating postsynaptic K+ conductance 23, 30, 32, 37.

Paradoxically, activation of GABAA receptors often appears to excite DA neurons. For example, previous electrophysiological studies have demonstrated that intravenous or microiontophoretic administration of GABAA agonists significantly increase DA neuronal firing and/or suppresses non-DA neuronal activity in the mesolimbic DA system 29, 47. Similar excitatory effects have also been observed electrophysiologically in the substantia nigra 10, 11, 24, 46. In an attempt to explain this dichotomy, a disinhibitory hypothesis has been proposed suggesting that GABA's excitatory modulation of DA neurons may be the result of its action upon reticular inhibitory interneurons [10]. In further support of this hypothesis, two types of neurons have been electrophysiologically identified in the VTA [17], with GABAA receptors located mainly on non-DA interneurons intrinsic to the VTA [5]. In contrast to these disinhibitory effects, intracellular recordings demonstrate that GABAA agonists may directly hyperpolarize VTA and nigrostriatal DA neurons 17, 23, 30, 32, 37. These data suggest that GABAA receptors may also directly inhibit DA projection neurons.

Adding to the paradox, results from microdialysis studies are conflicting. For example, Kalivas' group has reported increased DA release in the NAcc following muscimol microinjections into the VTA 18, 20. However, a muscimol-induced dose-dependent decrease in DA has been observed in the same area [48]. Similar inhibitory effects of GABAA agonists on DA neurons have also been reported in the striatum 33, 39, 43, prefrontal cortex [36], and tuberoinfundibular region of the hypothalamus [44].

Behavioral studies have demonstrated that activation of GABAA receptors in the VTA facilitate general locomotor behaviors 18, 28, 31, 42, 49, modulate or maintain ethanol oral [2], and intravenous (i.v.) self-administration [14]and ethanol preference during withdrawal [7], as well as decrease brain self-stimulation reward threshold [53]. Together, these data suggest that activation of GABAA receptors in the mesolimbic DA system modulates drug reinforced behaviors. It is noteworthy that GABAA antagonists can be directly self-administered into the VTA in rats [15]and mice [6], and also increase DA release in the NAcc [16].

To further clarify the actions and the mechanisms of GABAA agonists within the mesolimbic DA system and their `paradoxical' reinforcing properties, the high temporal and spatial resolution of fast-cyclic voltammetry was used to measure the effects of GABA-mimetic drugs on DA release in the NAcc in freely behaving rats. The reinforcing effect of a GABAA agonist was assessed using drug self-administration (SA). These experiments sought to answer three primary questions: first, can GABAA agonists activate DA neurons in the VTA, and if so, by what receptor mechanism(s); second, are GABAA receptors also located directly on mesolimbic DA neurons in addition to their principal location on GABAergic interneurons; and third, can GABAA agonists be self-administered in drug naive rats or substitute for heroin in opiate experienced animals. Our working hypothesis was that GABAA agonists would induce DA release via a disinhibitory mechanism by reversing the effects of tonic GABAB receptor activation on GABAergic interneurons. Thus, if GABAA receptors co-exist on DA neurons, prior activation or blockade of GABAB receptors should not only block a GABAA agonist-induced increase in NAcc DA release, but also unmask the inhibitory effect of the GABAA agonist. Our data support this hypothesis. Furthermore, much as heroin SA has been shown to increase mesolimbic DA release [51], GABAA agonists should also be self-administered as a consequence of activating the mesolimbic system. While we did not observe i.v. SA of a GABAA agonist, these GABA may play an important modulatory role in regulating the mesolimbic system in drug abuse.

Section snippets

Surgical preparation

Nineteen male Long–Evans rats (Sasco, Madison, WI) weighing 300–450 g at the time of surgery, were individually housed and maintained on a 12:12 h light/dark cycle with free access to food and water (lights on from 2000 to 0800 h). Under sodium pentobarbital anaesthesia (60 mg/kg i.p.), all rats were implanted with a chronic silastic jugular catheter which was passed subcutaneously to terminate on the head assembly. Rats were divided into two groups, one for SA alone (n=9), the other for

Effects of GABAA agonists on DA release in the NAcc

Intravenous injections of the GABAA agonist muscimol (0.1 mg/kg) significantly increased DA release in the NAcc in 7 of the 10 rats tested, with a peak mean amplitude of 0.52±0.07 μM. A DA signal decrease was observed in the remaining three rats (Fig. 1A). Muscimol-induced only slight to moderate general locomotor behavior in all 10 rats (data not shown). The DA signal began to change within 1 min after drug injection, although the earliest significant changes (>0.2 μM, p<0.05) occurred with a

GABAB receptor-mediated disinhibition

Results from this experiment demonstrate that microinjections of the GABAB receptor agonist baclofen into the VTA significantly decrease, while the GABAB receptor antagonist 2-OH-saclofen increase DA release in the nucleus accumbens. Systemic 2-OH-saclofen pretreatment blocked the VTA baclofen-induced inhibition, suggesting that GABAB receptors tonically modulate DA neuronal activity in the VTA by acting directly upon these projection neurons. These results are consistent with those of previous

Acknowledgements

The study was supported in part by USPHS grants DA09465 to E.A.S. and a NIDA/INVEST Fellowship (N01DA-3-0002) to Z.X. Xi.

References (53)

  • A Martz et al.

    Behavioral evidence for the involvement if gamma-aminobutyric acid in the actions of ethanol

    Eur. J. Pharmacol.

    (1983)
  • R.M McKernan et al.

    Which GABAA-receptor subtypes really occur in the brain?

    TINS

    (1996)
  • P.J Mudar et al.

    Methadone, pentobarbital, pimozide, and ethanol-intake

    Alcohol

    (1986)
  • H.R Olpe et al.

    The action of baclofen on neurons of the substantia nigra and ventral tegmental area

    Brain Res.

    (1977)
  • H.R Olpe et al.

    Rotational behavior induced in rats by intranigral application of GABA-related drugs and GABA antagonists

    Eur. J. Pharmacol.

    (1977)
  • R.D Pinnock

    Hyperpolarizing action of baclofen on neurons in the rat substantia nigra slice

    Brain Res.

    (1984)
  • H.H Samson et al.

    Neurobiology of alcohol abuse

    TIPS

    (1992)
  • M Santiago et al.

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

    Eur. J. Pharmacol.

    (1992)
  • M Santiago et al.

    Regulation of the prefrontal cortical dopamine release by GABAA and GABAB receptor agonists and antagonists

    Brain Res.

    (1993)
  • I Smolders et al.

    Tonic GABAergic modulation of striatal dopamine release studied by in vivo microdialysis in the freely moving rat

    Eur. J. Pharmacol.

    (1995)
  • S Sugita et al.

    Synaptic inputs to GABAA and GABAB receptors originate from discrete afferent neurons

    Neurosci. Lett.

    (1992)
  • M Takebayashi et al.

    γ-Aminobutyric acid increases intracellular Ca2+ concentration in cultured cortical neurons: role of Cl transport

    Eur. J. Pharmacol.

    (1996)
  • T Tanner

    GABA-induced locomotor activity in the rat after bilateral injection into the ventral tegmental area

    Neuropharmacology

    (1979)
  • E.J Wagner et al.

    GABAergic regulation of tuberoinfundibular dopaminergic neurons in the male rat

    Brain Res.

    (1994)
  • I Walaas et al.

    The distribution and origin of glutamate decarboxylase and choline acetyltransferase in ventral pallidum and other basal forebrain regions

    Brain Res.

    (1979)
  • J.R Walters et al.

    Effect of muscimol on single unit activity of substantia nigra dopamine neurons

    Eur. J. Pharmacol.

    (1978)
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