GABAergic inhibition of neurons in the ventral tegmental area

Wolf, Peter; Olpe, H.-R.; Avrith, D. B.; Haas, Helmut L.

doi:10.1007/bf01921910

Cited by 73 publications

(18 citation statements)

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“…As previously reported (Wolfe et al, 1978;German et al, 1980;Yim and Mogenson, 1980;Wang, 198 lb), electrical stimulation of the NAc caused a poststimulus inhibition of Al 0 DA activity due to DA released upon antidromic invasion of the DA neurons (Korf et al, 1976;Wang, 198 1 b). The duration of the inhibition was directly related to the intensity of the current, presumably because higher currents spread through the NAc, recruiting more DA fibers and thereby increasing the number of DA neurons releasing dendritic DA in the VTA.…”

Section: Discussionsupporting

confidence: 54%

“…Although considerably less extensive than the striatonigral pathway, a NAc-VTA GABAergic (inhibitory) feedback pathway has been indicated by several anatomical (Nauta et al, 1978;Phillipson, 1979) biochemical (Waddington and Cross, 1978;Walaas and Fonnum, 1980) and electrophysiological (Wolfe et al, 1978;German et al, 1980;Yim and Mogenson, 1980;White and Wang, 1983a) studies. For example, the in-hibitory effects of electrical stimulation of the NAc on some A 10 DA neurons are enhanced by iontophoretic application of the GABA reuptake inhibitor nipecotic acid into the VTA, and blocked by similar administration of the GABA antagonist picrotoxin (Wolfe et al, 1978;Yim and Mogenson, 1980).…”

Section: Discussionmentioning

confidence: 99%

“…For example, the in-hibitory effects of electrical stimulation of the NAc on some A 10 DA neurons are enhanced by iontophoretic application of the GABA reuptake inhibitor nipecotic acid into the VTA, and blocked by similar administration of the GABA antagonist picrotoxin (Wolfe et al, 1978;Yim and Mogenson, 1980). In addition, lesions of the NAc decrease levels of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD) in at least some portions of the VTA (Waddington and Cross, 1978;Walaas and Fonnum, 1980).…”

Section: Discussionmentioning

confidence: 99%

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Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: studies in the ventral tegmental area

1988

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Extracellular single-cell recording and microiontophoretic techniques were used to characterize the effects of cocaine on the activity of mesoaccumbens A10 dopamine (DA) neurons in the rat ventral tegmental area (VTA), which have been implicated in the rewarding effects of this and other drugs of abuse. Because cocaine inhibits the reuptake of DA, norepinephrine (NE), and serotonin (5-HT), and exerts local anesthetic actions, the possible involvement of each of these various mechanisms in the effects of cocaine on A10 DA neurons was investigated. Intravenous administration of cocaine caused a significant, dose- dependent, partial inhibition (50–70%) of the firing of antidromically identified mesoaccumbens DA neurons. Similar partial inhibition of A10 neurons was observed following intravenous administration of nomifensine, GBR-12909, and norcocaine, all of which inhibit DA reuptake. Neither the selective 5-HT uptake inhibitor fluoxetine nor the selective NE uptake inhibitor desmethylimipramine (DMI) inhibited the firing of A10 DA neurons. The local anesthetic agent procaine, which lacks DA uptake blocking efficacy, caused a slight, transient increase in firing rate. These results suggest that the effects of cocaine on A10 DA neurons are due to inhibition of DA reuptake, a conclusion that has been supported by several other findings. Pretreatment with reserpine to deplete vesicular stores of DA significantly reduced the ability of intravenous cocaine to suppress A10 DA neuronal activity. Microiontophoretic administration of cocaine caused only a weak (15–20%) inhibition of the activity of A10 DA neurons, but significantly increased and prolonged the inhibition produced by iontophoretic DA. This effect was not observed with iontophoretically administered procaine iontophoresis of cocaine also significantly potentiated the inhibition of A10 DA activity caused by electrical stimulation of the nucleus accumbens (NAc). Both unilateral ibotenic acid lesions of the NAc and hemitransections of the brain rostral to the VTA significantly reduced the inhibitory effects of intravenous cocaine on A10 DA neurons, suggesting that both somatodendritic impulse-regulating DA autoreceptors and inhibitory NAc- VTA feedback processes are involved in the effects of intravenous cocaine on A10 DA neurons. Therefore, it is hypothesized that the relatively weak inhibitory effects of cocaine on A10 DA neurons may represent a poor compensatory response to enhanced DA neurotransmission within the NAc, and may help to explain the extremely potent rewarding effects of this important drug of abuse.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: studies in the ventral tegmental area

1988

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“…The cocaineinduced increase in VTA DA levels activates autoreceptors (D 2 R) that, together with GABA B R-dependent feedback (Waddington and Cross, 1978;Wolf et al, 1978), temper VTA DA neuron excitability (Einhorn et al, 1988). Pharmacological blockade or genetic suppression of G protein-dependent inhibitory feedback pathways in midbrain DA neurons alters behavioral effects of cocaine, including locomotor activation and self-administration (Steketee and Kalivas, 1991;Bello et al, 2011;Holroyd et al, 2015;de Jong et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Selective Ablation of GIRK Channels in Dopamine Neurons Alters Behavioral Effects of Cocaine in Mice

McCall

Kotecki

Domínguez-López

et al. 2016

Neuropsychopharmacol

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The increase in dopamine (DA) neurotransmission stimulated by in vivo cocaine exposure is tempered by G protein-dependent inhibitory feedback mechanisms in DA neurons of the ventral tegmental area (VTA). G protein-gated inwardly rectifying K + (GIRK/Kir3) channels mediate the direct inhibitory effect of GABA B receptor (GABA B R) and D 2 DA receptor (D 2 R) activation in VTA DA neurons. Here we examined the effect of the DA neuron-specific loss of GIRK channels on D 2 R-dependent regulation of VTA DA neuron excitability and on cocaine-induced, reward-related behaviors. Selective ablation of Girk2 in DA neurons did not alter the baseline excitability of VTA DA neurons but significantly reduced the magnitude of D 2 R-dependent inhibitory somatodendritic currents and blunted the impact of D 2 R activation on spontaneous activity and neuronal excitability. Mice lacking GIRK channels in DA neurons exhibited increased locomotor activation in response to acute cocaine administration and an altered locomotor sensitization profile, as well as increased responding for and intake of cocaine in an intravenous self-administration test. These mice, however, showed unaltered cocaine-induced conditioned place preference. Collectively, our data suggest that feedback inhibition to VTA DA neurons, mediated by GIRK channel activation, tempers the locomotor stimulatory effect of cocaine while also modulating the reinforcing effect of cocaine in an operant-based self-administration task.

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“…Thus, it is known already for some considerable time that GABA is influencing the firing of the nigrostriatal, mesolimbic, and mesocortical DA tracts. For instance, an inhibitory effect on DA neuronal firing has been demonstrated by iontophoretic application of GABA and GABA antagonists into the substantia nigra (SA) and ventral tegmental area (VTA) (Wolf et al, 1978;Waszczak and Walters, 1979). In addition, electrical stimulation of the targets of these tracts, that is, the nucleus caudatus and nucleus accumbens, exerts a reciprocal inhibition of the SA and VTA, which is blocked by the GABA antagonist bucculline (Yoshida and Precht, 1971;Wolf et al, 1978).…”

Section: Sirmentioning

confidence: 99%

Reply: Valproate Treatment in Schizophrenia: Interaction of GABA with Dopamine?

Winterer¹,

Schmitt²,

Schmidt³

2004

Neuropsychopharmacol

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GABAergic inhibition of neurons in the ventral tegmental area

Abstract: Stimulation of the nucleus accumbens evokes a potent inhibition in neurons of the ventral tegmental area. GABA is likely to act as a transmitter in this descending inhibitory system.

Cited by 73 publications

References 10 publications

Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: studies in the ventral tegmental area

Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: studies in the ventral tegmental area

Selective Ablation of GIRK Channels in Dopamine Neurons Alters Behavioral Effects of Cocaine in Mice

Reply: Valproate Treatment in Schizophrenia: Interaction of GABA with Dopamine?

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