Differential involvement of ventral tegmental GABAA and GABAB receptors in the regulation of the nucleus accumbens dopamine response to stress

doi:10.1016/j.brainres.2007.02.081

Brain Research

Volume 1150, 30 May 2007, Pages 62-68

https://doi.org/10.1016/j.brainres.2007.02.081 Get rights and content

Abstract

Evidence indicates that dopamine (DA) transmission in nucleus accumbens (NAcc) is modulated by glutamate (GLUT) projections from medial prefrontal cortex (PFC) to NAcc and the ventral tegmental area (VTA). Local NMDA receptor blockade in NAcc has previously been shown to enhance the DA stress response in this region as well as in the VTA. This raises the possibility that the NAcc DA stress response is regulated by GLUT acting at NMDA receptors located on NAcc GABA output neurons that project to the VTA where GABA is known to regulate DA cell activity. Thus, in the present study, we used voltammetry to examine the effects of intra-VTA administration of GABA_A and GABA_B agonists and antagonists on restraint stress-induced increases in NAcc DA. The results show that local VTA GABA_B receptor activation with baclofen (0.01, 0.1 and 1.0 nmol) dose-dependently inhibited the NAcc DA stress response whereas GABA_B receptor blockade with phaclofen had the opposite effect, resulting in a dose-dependent potentiation of the stress response. A similar potentiation of the NAcc DA stress response was observed following VTA GABA_A receptor blockade with bicuculline, but only at the highest dose (1.0 nmol). Interestingly, intra-VTA injection of the GABA_A receptor agonist, muscimol, at the lowest dose (0.01 nmol) but not at the higher doses (0.1 or 1.0 nmol) also potentiated the NAcc DA stress response, suggesting an action mediated primarily at GABA_A receptors located on non-DA neurons. These results indicate that the NAcc DA stress response is regulated by GABA afferents to VTA DA cells and that this action is differentially mediated by GABA_A and GABA_B receptors. The data suggest that the relevant GABA_B receptors are located on DA neurons whereas the GABA_A receptors are located on GABA interneurons and perhaps also on DA cells. The present findings are also consistent with the idea that the corticofugal GLUT input to NAcc indirectly regulates stress-induced DA release in this region through the GABA feedback pathway to VTA.

Introduction

Stress will stimulate dopamine (DA) transmission in both the medial prefrontal cortex (PFC) and the nucleus accumbens (NAcc) (Abercrombie et al., 1989). It appears, however, that the NAcc DA response to stress is modulated by a DA-sensitive mechanism in PFC such that increased DA transmission in this cortical region acts to dampen the NAcc DA response to a variety of stimuli including stress (Deutch et al., 1990, Doherty and Gratton, 1996, Vezina et al., 1991). There is evidence implicating also PFC glutamate- (GLUT-) containing neurons some of which are known to project to NAcc and to the ventral tegmental area (VTA) where the mesocorticolimbic DA system originates (Carr et al., 1999, Carr and Sesack, 2000, Sesack and Pickel, 1992).

In addition to stimulating DA transmission, stress will also increase PFC and NAcc levels of GLUT (Moghaddam, 1993) and there is evidence indicating that the NAcc DA response to stress is modulated locally by a GLUT-sensitive mechanism (Keefe et al., 1993, Saulskaya and Marsden, 1995, Wheeler et al., 1995). We have previously reported that the NAcc DA stress response is potentiated by local NMDA receptor blockade (Doherty and Gratton, 1997). In that study we also reported evidence that the local action of GLUT on the NAcc DA stress response is mediated by NMDA receptors located on NAcc output neurons that project to the VTA. Part of this output system comprises GABA neurons that project to VTA either directly or indirectly via the ventral pallidum (Kalivas et al., 1993, Walaas and Fonnum, 1980, Yim and Mogenson, 1980). In VTA, GABA is known to hyperpolarize DA cells, inhibiting their activity by a direct GABA_B receptor-mediated action (Chen et al., 2005, Erhardt et al., 2002). The activity of VTA DA cells is also regulated by GABA acting at GABA_A receptors although here the evidence indicates both a direct inhibitory action as well as a predominant indirect disinhibitory action presumably mediated presynaptically by GABA_A receptors on non-DA interneurons (Churchill et al., 1992, Johnson and North, 1992, Kalivas et al., 1990, Klitenick et al., 1992, O'Brien and White, 1987, Sugita et al., 1992). Local VTA GABA_A and GABA_B receptor activation has been shown previously to modulate DA transmission in NAcc and VTA (Kalivas et al., 1990, Klitenick et al., 1992, Westerink et al., 1996, Xi and Stein, 1998). However, to our knowledge, similar information has not been obtained for the NAcc DA response to stress. Thus, the present study was designed to examine the role of VTA GABA in the NAcc DA response to stress. To this end, we used voltammetry and monoamine selective probes to investigate the effects of intra-VTA administration of GABA_A and GABA_B receptor selective agonists and antagonists on the NAcc DA response to restraint stress.

Section snippets

Results

The animals used in the present study had been randomly assigned to one of three dose groups. On 5 consecutive daily sessions, animals in each group were stressed either without pretreatment (control) or following intra-VTA injections of vehicle (VEH) or of one dose of baclofen (BAC), muscimol (MUSC), phaclofen (PHAC) or bicuculline (BICU). All animals within a group received the same dose (0.01. 0.1 or 1.0 nmol) of each drug. Differences in the peak amplitude and the duration of stress-induced

Discussion

The results reported here indicate that the NAcc DA stress response is regulated by GABA afferents to VTA DA cells and that this action is differentially mediated by GABA_A and GABA_B receptors. Specifically, we show that local activation of VTA GABA_B receptors with baclofen dose-dependently attenuated the magnitude of the NAcc DA stress response whereas local GABA_B receptor blockade with phaclofen enhanced it. These findings are generally consistent with other lines of evidence indicating that

Animals

Male Long–Evans rats (Charles River, St. Constant, Québec) weighing approximately 300–350 g at the time of surgery were used. Animals were housed singly on a 12 h light/dark cycle (lights on at 08:00 h) with free access to food and water.

Surgery

Animals were pretreated with atropine sulfate (0.1 mg/kg i.p.), anesthetized with sodium pentobarbital (60 mg/kg i.p.) and placed in a stereotaxic frame. Animals were each implanted with a 22-gauge stainless steel guide cannula (Plastic One, Roanoke, VA) aimed

Acknowledgments

This research was supported by a Canadian Institutes of Health Research grant to A.G.

References (47)

M.P. Brazell et al.
An improved method for Nafion coating carbon fiber electrodes for in vivo electrochemistry
J. Neurosci. Methods
(1987)
A.Y. Deutch et al.
Prefrontal cortical dopamine depletion enhances the responsiveness of mesolimbic dopamine neurons to stress
Brain Res.
(1990)
M.D. Doherty et al.
Medial prefrontal cortical D1 receptor modulation of the meso-accumbens dopamine response to stress: an electrochemical study in freely-behaving rats
Brain Res.
(1996)
G.A. Gerhardt et al.
Methodology for coupling local application of dopamine and other chemicals with rapid in vivo electrochemical recordings in freely-moving rats
J. Neurosci. Methods
(1999)
F.G. Gonon
Nonlinear relationship between impulse flow and dopamine released by rat midbrain dopaminergic neurons as studied by in vivo electrochemistry
Neuroscience
(1988)
A.A. Grace et al.
Paradoxical GABA excitation of nigral dopaminergic cells: indirect mediation through reticulata inhibitory neurons
Eur. J. Pharmacol.
(1979)
P.W. Kalivas et al.
GABA and enkephalin projection from the nucleus accumbens and ventral pallidum to the ventral tegmental area
Neuroscience
(1993)
H.R. Olpe et al.
The action of baclofen on neurons of the substantia nigra and ventral tegmental area
Brain Res.
(1977)
N. Saulskaya et al.
Conditioned dopamine release: dependence upon N-methyl-d-aspartate receptors
Neuroscience
(1995)
M.F. Suaud-Chagny et al.
Relationship between dopamine release in the rat nucleus accumbens and the discharge activity of dopaminergic neurons during local in vivo application of amino acids in the ventral tegmental area
Neuroscience
(1992)

S. Sugita et al.

Synaptic inputs to GABA_A and GABA_B receptors originate from discrete afferent neurons

Neurosci. Lett.

(1992)

A.M. Thierry et al.

Electrophysiological evidence for non-dopaminergic mesocortical and mesolimbic neurons in the rat brain

Brain Res.

(1980)

B.L. Waszczak et al.

Intravenous GABA agonist administration stimulates firing of A10 dopaminergic neurons

Eur. J. Pharmacol.

(1980)

D. Wheeler et al.

The role of N-methyl-d-aspartate receptors in the regulation of physiologically released dopamine

Neuroscience

(1995)

Z.-X. Xi et al.

Nucleus accumbens dopamine release modulation by mesolimbic GABA_A receptors—an in vivo electrochemical study

Brain Res.

(1998)

C.Y. Yim et al.

Effect of picrotoxin and nipecotic acid on inhibitory response of dopaminergic neurons in the ventral tegmental area to stimulation of the nucleus accumbens

Brain Res.

(1980)

E.D. Abercrombie et al.

Differential effects of stress on in vivo dopamine release in striatum, nucleus accumbens, and medial prefrontal cortex

J. Neurochem.

(1989)

P.M. Beart et al.

Neurochemical studies of the mesolimbic dopaminergic pathway: somatodendritic mechanisms and GABAergic neurones in the rat ventral tegmentum

J. Neurochem.

(1980)

P. Capella et al.

Nafion-coated carbon fiber electrodes for neurochemical studies in brain tissue

Electroanalysis

(1990)

D.B. Carr et al.

Projections from the rat prefrontal cortex to the ventral tegmental area: target specificity in the synaptic associations with mesocortical and mesoaccumbens neurons

J. Neurosci.

(2000)

D.B. Carr et al.

Dopamine terminals in the rat prefrontal cortex synapse on pyramidal cells that project to the nucleus accumbens

J. Neurosci.

(1999)

Y. Chen et al.

GABAB receptor modulators potentiate baclofen-induced depression of dopamine neuron activity in the rat ventral tegmental area

Br. J. Pharmacol.

(2005)

L. Churchill et al.

Autoradiographic localization of gamma-aminobutyric acid-A receptors within the ventral tegmental area

Neurochem. Res.

(1992)

Cited by (35)

Acute stress differentially alters reward-related decision making and inhibitory control under threat of punishment
2024, Neurobiology of Stress
Acute stress has various effects on cognition, executive function and certain forms of cost/benefit decision making. Recent studies in rodents indicate that acute stress differentially alters reward-related decisions involving particular types of costs and slows choice latencies. Yet, how stress alters decisions where rewards are linked to punishment is less clear. We examined how 1 h restraint stress, followed by behavioral testing 10 min later altered action-selection on two tasks involving reward-seeking under threat of punishment in well-trained male and female rats. One study used a risky decision-making task involving choice between a small/safe reward and a large/risky one that could coincide with shock, delivered with a probability that increased over blocks of trials. Stress increased risk aversion and punishment sensitivity, reducing preference for the larger/risky reward, while increasing decision latencies and trial omissions in both sexes, when rats were teste. A second study used a “behavioral control” task, requiring inhibition of approach towards a readily available reward associated with punishment. Here, food pellets were delivered over discrete trials, half of which coincided with a 12 s audiovisual cue, signalling that reward retrieval prior to cue termination would deliver shock. Stress exerted sex- and timing-dependent effects on inhibitory control. Males became more impulsive and received more shocks on the stress test, whereas females were unaffected on the stress test, and were actually less impulsive when tested 24 h later. None of the effects of restraint stress were recapitulated by systemic treatment with physiological doses of corticosterone. These findings suggest acute stress induces qualitatively distinct and sometimes sex-dependent effects on punished reward-seeking that are critically dependent on whether animals must either choose between different actions or withhold them to obtain rewards and avoid punishment.
Simultaneous activation of muscarinic and GABA <inf>B</inf> receptors as a bidirectional target for novel antipsychotics
2019, Behavioural Brain Research
Citation Excerpt :
Ligands of these particular receptors were chosen for investigation because of their previously defined roles. Cholinergic and GABAB receptors have been shown to be expressed in brain circuits that are important in antipsychotic treatment, decreasing dopamine release via presynaptically expressed receptors in the striatum [43] and nucleus accumbens [44–49] and controlling the activity of entorhinal and perirhinal cortex projections, thus contributing to an improvement in cognitive functions [50–55]. This would be in line with our results showing, the efficacy of the compounds (and their combinations) in NOR rather than in social interaction test.
Recent preclinical studies point to muscarinic and GABA_B receptors as novel therapeutic targets for the treatment of schizophrenia. This study was aimed to assess the role of muscarinic and GABA_B receptor interactions in animal models of schizophrenia, using positive allosteric modulators (PAMs) of GABA_B receptor (GS39783), muscarinic M₄ (VU0152100) and M₅ (VU0238429) receptor, and partial allosteric agonist of M₁ receptor (VU0357017).
DOI-induced head twitches, social interaction and novel object recognition tests were used as the models of schizophrenia. Analyses of DOI-induced increases in sEPSCs (spontaneous excitatory postsynaptic currents) were performed as complementary experiments to the DOI-induced head twitch studies. Haloperidol-induced catalepsy and the rotarod test were used to examine the adverse effects of the drugs.
All three activators of muscarinic receptors were active in DOI-induced head twitches. When administered together with GS39783 in subeffective doses, only the co-administration of VU0152100 and GS39783 was effective. The combination also reduced the frequency but not the amplitude of DOI-induced sEPSCs. Neither VU0357017 nor VU0238429 were active in social interaction test when given alone, and also the combination of VU0152100 and GS39783 failed to reverse MK-801-induced deficits observed in this test. All muscarinic activators when administered alone or in combination with GS39783 reversed the MK-801-induced disruption of memory in the novel object recognition test, and their actions were blocked by specific antagonists. None of the tested compounds or their combinations influenced the motor coordination of the animals. The compounds had no effect on haloperidol-induced catalepsy and did not induce catalepsy when administered alone. Pharmacokinetic analysis confirmed lack of possible drug-drug interactions after combined administration of GS39783 with VU0357017 or VU0152100; however, when the drug was co-administered with VU0238429 its ability to pass the blood-brain barrier slightly decreased, suggesting potential drug-drug interactions.
Our data show that modulation of cholinergic and GABAergic systems can potentially be beneficial in the treatment of the positive and cognitive symptoms of schizophrenia without inducing the adverse effects typical for presently used antipsychotics.
GABA<inf>A</inf> receptors in the ventral tegmental area control the outcome of a social competition in rats
2018, Neuropharmacology
Social dominance can be attained through social competitions. Recent work in both humans and rodents has identified trait anxiety as a crucial predictor of social competitiveness. In addition, the anxiolytic GABA_A positive modulator, diazepam, injected either systemically or into the ventral tegmental area (VTA) was shown to increase social dominance. Here, we investigated the impact of pharmacologically targeting GABA_A receptors in the VTA for the outcome of a social competition between two unfamiliar male rats, one of them infused with vehicle and the other one with the drug under study. We show that infusion of the GABA_A receptor agonist, muscimol, reduced anxiety-like behaviors and enhanced social competition, the GABA_A receptor antagonist, bicuculline had the opposite effects. Importantly, intra-VTA muscimol administration also counteracted the disadvantage of high anxious rats to win a social competition against low anxious rats. Furthermore, we assessed the effectiveness of targeting specific GABA_A receptor subunits by infusing zolpidem (α1-subunit agonist) or TCS1105 (a benzodiazepine ligand with α2-subunit agonistic and α1-subunit antagonistic effects) into the VTA. While zolpidem infusion did not affect the outcome of the social competition, TCS1105 enhanced social dominance. Our data highlight GABAergic mechanisms involving the engagement of α2-subunit containing GABA_A receptors in the VTA in the attainment of dominance rank. The involvement of α2-subunit containing GABA_A receptors in the VTA in the regulation of social competitiveness supports the potential therapeutic relevance of targeting these receptors to ameliorate anxiety-related social dysfunctions.
Nucleus Accumbens Subnuclei Regulate Motivated Behavior via Direct Inhibition and Disinhibition of VTA Dopamine Subpopulations
2018, Neuron
Citation Excerpt :
Accordingly, VTA GABAAR activation could result in an increase in DA transmission in the NAcLat via disinhibition of NAcLat-projecting DA neurons and a decrease in DA transmission in the NAcMed due to direct suppression of DA neurons projecting to NAcMed. It has been suggested that within the VTA, GABAARs and GABABRs are anatomically and functionally dissociable (Cameron and Williams, 1993; Doherty and Gratton, 2007; Klitenick et al., 1992; Laviolette and van der Kooy, 2001; Panagis and Kastellakis, 2002; Sugita et al., 1992; Xi and Stein, 1998). This widely held assumption has gained momentum with a recent study showing that NAc neurons inhibited VTA GABA neurons through GABAARs and inhibited VTA DA neurons via GABABRs (Edwards et al., 2017).
Mesolimbic dopamine (DA) neurons play a central role in motivation and reward processing. Although the activity of these mesolimbic DA neurons is controlled by afferent inputs, little is known about the circuits in which they are embedded. Using retrograde tracing, electrophysiology, optogenetics, and behavioral assays, we identify principles of afferent-specific control in the mesolimbic DA system. Neurons in the medial shell subdivision of the nucleus accumbens (NAc) exert direct inhibitory control over two separate populations of mesolimbic DA neurons by activating different GABA receptor subtypes. In contrast, NAc lateral shell neurons mainly synapse onto ventral tegmental area (VTA) GABA neurons, resulting in disinhibition of DA neurons that project back to the NAc lateral shell. Lastly, we establish a critical role for NAc subregion-specific input to the VTA underlying motivated behavior. Collectively, our results suggest a distinction in the incorporation of inhibitory inputs between different subtypes of mesolimbic DA neurons.
Neurobiological consequences of juvenile stress: A GABAergic perspective on risk and resilience
2017, Neuroscience and Biobehavioral Reviews
ALBRECHT, A., MÜLLER, I., ARDI, Z., ÇALIŞKAN, G., GRUBER, D., IVENS, S., SEGAL, M., BEHR, J., HEINEMANN, U., STORK, O., and RICHTER-LEVIN, G. Neurobiological consequences of juvenile stress: A GABAergic perspective on risk and resilience. NEUROSCI BIOBEHAV REV XXX-XXX, 2016. – Childhood adversity is among the most potent risk factors for developing mood and anxiety disorders later in life. Therefore, understanding how stress during childhood shapes and rewires the brain may optimize preventive and therapeutic strategies for these disorders.
To this end, animal models of stress exposure in rodents during their post-weaning and pre-pubertal life phase have been developed. Such ‘juvenile stress’ has a long-lasting impact on mood and anxiety-like behavior and on stress coping in adulthood, accompanied by alterations of the GABAergic system within core regions for the stress processing such as the amygdala, prefrontal cortex and hippocampus. While many regionally diverse molecular and electrophysiological changes are observed, not all of them correlate with juvenile stress-induced behavioral disturbances. It rather seems that certain juvenile stress-induced alterations reflect the system’s attempts to maintain homeostasis and thus promote stress resilience. Analysis tools such as individual behavioral profiling may allow the association of behavioral and neurobiological alterations more clearly and the dissection of alterations related to the pathology from those related to resilience.
Pharmacology of baclofen and use in alcohol-dependent patient. An update for the clinician
2016, Pharmacien Hospitalier et Clinicien
Le baclofène est une molécule ancienne (1962), dont l’indication initiale est neurologique (décontractant musculaire et anti-spastique). L’utilisation empirique du baclofène dans l’alcoolo-dépendance semble prometteuse selon certaines études. Le baclofène pourrait être un traitement efficace dans les stratégies de réduction de consommation chez le patient alcoolo-dépendant bien que cette efficacité ne soit pas scientifiquement démontrée à ce jour. Le baclofène n’est pas hépatotoxique et peut donc être administré à des insuffisants hépatiques. De nombreux effets indésirables sont décrits à des doses thérapeutiques. Il existe un risque de syndrome de sevrage lors de l’arrêt brutal du traitement. Des intoxications graves ont été décrites lors de prises très importantes de baclofène. Il n’existe pas d’antidote, mais dans les cas d’intoxication grave, l’hémodialyse est un traitement efficace.
Baclofen is an old drug (1962), with an initial indication in neurology (muscle relaxant and anti-spastic). The empirical use of baclofen in alcohol dependence shows promising results in some studies. Baclofen may be an effective treatment in consumption reduction strategies for alcohol-dependent patients but this effectiveness is not scientifically demonstrated to date. Baclofen is not hepatotoxic and can be administered to patients with hepatic impairment. Many side effects are described at therapeutic doses. There is a risk of withdrawal symptoms when baclofen is stopped abruptly. Severe poisoning have been described in excessive intake of baclofen. There is no antidote, but in cases of severe intoxication hemodialysis is an effective treatment.

View all citing articles on Scopus

View full text

Research ReportDifferential involvement of ventral tegmental GABAA and GABAB receptors in the regulation of the nucleus accumbens dopamine response to stress

Abstract

Introduction

Section snippets

Results

Discussion

Animals

Surgery

Acknowledgments

J. Neurosci. Methods

Brain Res.

Brain Res.

J. Neurosci. Methods

Neuroscience

Eur. J. Pharmacol.

Neuroscience

Brain Res.

Neuroscience

Neuroscience

Neurosci. Lett.

Brain Res.

Eur. J. Pharmacol.

Neuroscience

Brain Res.

Brain Res.

Differential effects of stress on in vivo dopamine release in striatum, nucleus accumbens, and medial prefrontal cortex

J. Neurochem.

Neurochemical studies of the mesolimbic dopaminergic pathway: somatodendritic mechanisms and GABAergic neurones in the rat ventral tegmentum

J. Neurochem.

Nafion-coated carbon fiber electrodes for neurochemical studies in brain tissue

Electroanalysis

Projections from the rat prefrontal cortex to the ventral tegmental area: target specificity in the synaptic associations with mesocortical and mesoaccumbens neurons

J. Neurosci.

Dopamine terminals in the rat prefrontal cortex synapse on pyramidal cells that project to the nucleus accumbens

J. Neurosci.

GABAB receptor modulators potentiate baclofen-induced depression of dopamine neuron activity in the rat ventral tegmental area

Br. J. Pharmacol.

Autoradiographic localization of gamma-aminobutyric acid-A receptors within the ventral tegmental area

Neurochem. Res.

Research Report
Differential involvement of ventral tegmental GABA_A and GABA_B receptors in the regulation of the nucleus accumbens dopamine response to stress