Research reportNucleus accumbens dopamine release modulation by mesolimbic GABAA receptors—an in vivo electrochemical study
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.
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