GABA Release In Globus Pallidus Research Articles

Extracellular GABA in globus pallidus increases during the induction of oral tremor by haloperidol but not by muscarinic receptor stimulation

Tremulous jaw movements in rats can be induced by several conditions associated with parkinsonism and tremorogenesis, including dopamine depletion, dopamine antagonism, and cholinomimetic drugs. Previous research indicates that neostriatal mechanisms are involved in the generation of tremulous jaw movements, but the striatal output pathways involved in these movements remain uncertain. One important pathway for striatal output is the GABAergic striatopallidal system. The present studies were undertaken to determine if extracellular levels of GABA in globus pallidus are associated with the induction of tremulous jaw movements by either a dopamine D2 antagonist (haloperidol) or a cholinomimetic (the muscarinic agonist pilocarpine). The first experiment studied the effects of both acute and repeated (i.e. 8 days) administration of the D2 antagonist haloperidol. In the second experiment, the effect of acute administration of the muscarinic agonist pilocarpine on GABA levels in the globus pallidus was examined. In both experiments, behavioral observations of tremulous jaw movements were conducted in parallel with the collection of microdialysis samples. Acute and repeated haloperidol treatment induced tremulous jaw movements, and significantly elevated extracellular GABA in globus pallidus. Pooling across all treatment groups, there was a significant positive correlation between pallidal GABA levels and the number of tremulous jaw movements induced during the first three samples collected after injection. However, injection of 4.0mg/kg pilocarpine had no effect on pallidal GABA release, despite the robust induction of tremulous jaw movements. These results indicate that the tremulous jaw movements induced by dopamine D2 antagonism and those induced through muscarinic receptor stimulation may be generated via distinct mechanisms.

The role of metabotropic glutamate receptor 7 (mGluR7) in drug dependence

The successful pharmacotherapy for drug addiction is a challenge for pharmacology in XXI century. We still do not have any registered medication for cocaine by FDA, alcohol therapies are not enough successful. High hopes concern metabotropic glutamate 7 receptor as a target for pharmacotherapy development of drug dependence. It is well documented the role of the mGluR7 in rewarding and motivational effects of cocaine and alcohol. The mGluR7 allosteric agonist AMN082 and antagonist MMPIP have become new tools in preclinical studies. AMN082 attenuated cocaine-enhanced electrical Brain Stimulation Reward (eBSR) in rats decreased cocaine self-administration, too, probably by counteracting cocaine-induced inhibition of the ventral pallidal GABA release. The mGluR7 activation reduced alcohol intake and preference in rats. The mGluR7 receptors take part in reinstatement of drug-seeking behavior after abstinence. The investigations showed that AMN082 suppressed cocaine-induced reinstatement of self-administrated rats via mGluR2/3 mechanism. It was mentioned also that mGluR7 allosteric agonist inhibited reinstatement of ethanol-induced CPP. Moreover, activation of the mGluR7 receptor exhibits less adverse reaction in comparison to other mGluRs and may give a promise for further development of drug dependence therapies in humans. However, some nonspecific effects of the mGluR7 in ethanol addiction have been recognized, so there are further investigations needed to explain the mechanisms of the mGluR7 action in rewarding and motivational effects of drugs.

Stimulation of delta opioid receptors located in substantia nigra reticulata but not globus pallidus or striatum restores motor activity in 6‐hydroxydopamine lesioned rats: new insights into the role of delta receptors in parkinsonism

The delta opioid peptide (DOP) receptor has been proposed as a target in the symptomatic therapy of Parkinson's disease. However, the circuitry underlying the antiparkinsonian action of DOP receptor agonists and their site of action have never been adequately investigated. Systemic administration of the DOP receptor agonist (+)-4-[(alphaR)-alpha-(2S,5R)-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl]-N-N-diethylbenzamide (SNC-80) attenuated akinesia/bradykinesia and improved motor activity in 6-hydroxydopamine hemilesioned rats. Opposite effects were produced by the selective DOP receptor antagonist naltrindole (NTD), suggesting that endogenous enkephalins tonically sustain movement under parkinsonian conditions. Microdialysis revealed that SNC-80 reduced GABA release in globus pallidus (GP) while NTD elevated it. Moreover, SNC-80 reduced GABA and glutamate release in substantia nigra reticulata (SNr) whereas NTD reduced GABA without affecting glutamate release. The bar test coupled to microdialysis showed that perfusion with NTD in SNr but not GP or striatum prevented the antiakinetic effect of systemic SNC-80 and its neurochemical correlates. Consistently, microinjections of SNC-80 into SNr or bicuculline in GP attenuated parkinsonian-like symptoms while SNC-80 microinjections in GP or striatum were ineffective. This study demonstrates that nigral DOP receptors mediate antiparkinsonian actions of SNC-80 and challenges the common view that DOP receptor agonists solely attenuate parkinsonism via pallidal mechanisms.

The effects of adenosine A2A receptor antagonists on haloperidol-induced movement disorders in primates

Adenosine and dopamine interact within the striatum to control striatopallidal output and globus pallidus GABA release. Manipulating striatal adenosine transmission via blockade of the A2A receptor subtype can compensate for the reduced dopamine activity within the striatum that underlies movement disorders such as antipsychotic-induced extrapyramidal syndrome (EPS) and Parkinson's disease (PD). Preclinical studies in the rat have demonstrated that adenosine A2A receptor antagonists can attenuate behaviors reflecting reduced dopamine activity, such as haloperidol-induced catalepsy and hypoactivity. In the present studies using nonhuman primates, adenosine antagonists were tested against haloperidol-induced EPS in Cebus apella and haloperidol-induced catalepsy in Saimiri sciureus (squirrel monkey). Specifically, the A2A receptor antagonists, SCH 412348 (0.3-30 mg/kg PO) and KW-6002 (3-100 mg/kg PO); the A1/A2A receptor antagonist, caffeine (1-30 mg/kg PO and IM); and the A1 receptor antagonist, DPCPX (3-30 mg/kg PO) were tested in at least one of these models. SCH 412348 (10-30 mg/kg), KW-6002 (57-100 mg/kg), and caffeine (30 mg/kg) significantly increased the time to EPS onset. Additionally, SCH 412348, KW-6002, and caffeine afforded protection from the onset of EPS for at least 6 h in some of the primates. SCH 412348 (10 mg/kg) and caffeine (10 mg/kg) significantly reduced haloperidol-induced catalepsy. DPCPX produced a very slight attenuation of EPS at 30 mg/kg, but had no effect on catalepsy. These findings suggest that adenosine A2A receptor antagonists may represent an effective treatment for the motor impairments associated with both antipsychotic-induced EPS and PD.

Receptor–receptor interactions as studied with microdialysis. Focus on NTR/D2 interactions in the basal ganglia

Using mono and dualprobe(s) microdialysis in the basal ganglia of the freely moving rat evidence has been obtained that neurotensin (NT) in threshold concentrations can counteract the D(2) agonist (intrastriatally perfused) induced inhibition of striatal dopamine (DA) release and of pallidal GABA release from the striato-pallidal GABA pathway, effects that are blocked by a NTR(1) antagonist SR48692. These results indicate the existence of antagonistic intramembrane NTR/D(2) receptor interactions in the striatal DA terminals and in the somato-dendritic regions of the striato-pallidal GABA neurons. By the NT-induced reduction of the D(2) mediated signals at the striatal pre- and postjunctional level DA transmission is switched towards a D(1) mediated transmission leading to increased activity in the striatopallidal and striatonigral GABA pathways. The former action will contribute to the motor inhibition and catalepsy found with NT treatment and underlies the use of NT receptor antagonists as a treatment strategy for Parkinson's disease. Nigral NT by an antagonistic NTR/D(2) receptor interaction in the DA cell body and dendrites may also increase nigral DA release leading to a D(2) mediated inhibition of the nigrothalamic GABA pathway. Such an effect, will instead result in antiparkinsonian actions. Thus, increases in NT transmission will have different consequences for the motor system depending upon where in the basal ganglia the increase takes place.

GABA-opioid interactions in the globus pallidus: [D-Ala2]-Met-enkephalinamide attenuates potassium-evoked GABA release after nigrostriatal lesion.

The motor signs of Parkinson's disease have been partly attributed to an overinhibition of the external globus pallidus (GP) that results from hyperactivity of striatopallidal GABA/enkephalinergic neurons. The goals of this study were to measure basal levels of extracellular fluid GABA in the GP of normal cats, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated parkinsonian cats and cats spontaneously recovered from MPTP-induced parkinsonism, and to examine the effects of opioid receptor activation on potassium (K+)-evoked GABA release in the GP in these animals. Basal GP GABA levels were increased 75% from normal in parkinsonian animals 1 week after MPTP administration and returned to control levels in recovered animals 6 weeks after MPTP administration. No significant differences were observed in K+-evoked GABA release across conditions. The opioid receptor agonist [D-Ala2]-Met-Enkephalinamide (DALA) significantly attenuated K+-evoked GABA release in the GP of MPTP-treated symptomatic and recovered cats, but had no significant effect on GABA release in normal animals. These data show that basal GP GABA levels are elevated coincident with expression of parkinsonian signs and return to normal in animals that have functionally compensated for a nigrostriatal lesion. DALA-induced inhibition of pallidal GABA release after a dopamine-depleting lesion, suggests that enkephalin may attenuate GABA release in the GP specifically after striatal dopamine loss.

Functional neuroanatomy of the ventral striopallidal GABA pathway: New sites of intervention in the treatment of schizophrenia

Microdialysis was employed to investigate the dopamine, cholecystokinin (CCK) and neurotensin receptor regulation of ventral striopallidal GABA transmission by intra-accumbens perfusion with selective receptor ligands and monitoring local or ipsilateral ventral pallidal GABA release. In the dual probe studies intra-accumbens perfusion with the dopamine D 1 and D 2 receptor agonists SKF28293 and pergolide had no effect on ventral pallidal GABA, while both the D 1 and D 2 receptor antagonists SCH23390 and raclopride increased ventral pallidal GABA release. In contrast, intra-accumbens CCK decreased ventral pallidal GABA release and this was reversed by local perfusion with the CCK 2 receptor antagonist PD134308 but not the CCK 1 receptor antagonist L-364,718. In a single probe study intra-accumbens neurotensin increased local GABA release, which was strongly potentiated when the peptidase inhibitor phosphodiepryl 08 was perfused together with neurotensin. In addition, the neurotensin receptor antagonist SR48692 counteracted this phosphodiepryl 08 induced potentiated increased in GABA release. Taken together, these findings indicate that mesolimbic dopamine and CCK exert a respective tonic and phasic inhibition of ventral pallidal GABA release while the antipsychotic activity associated with D 1 and D 2 receptor antagonists may be explained by their ability to increase ventral striopallidal GABA transmission. Furthermore, the findings suggest that CCK 2 receptor antagonists and neurotensin endopeptidase inhibitors may be useful antipsychotics.

Differential effects of intra-accumbens perfusion with KCL on local and ventral pallidal GABA release in the rat. A dual probe microdialysis study in intact conscious brain

Differential effects of intra-accumbens perfusion with KCL on local and ventral pallidal GABA release in the rat. A dual probe microdialysis study in intact conscious brain

Tolerance to catalepsy following chronic haloperidol is not associated with changes in GABA release in the globus pallidus

In vivo microdialysis was used to investigate the relationship between extracellular GABA levels in rat globus pallidus following acute (1st injection) and chronic (29th injection) haloperidol (Hal) (0.25 mg kg −1 day −1, s.c.) with the presence and absence of catalepsy, respectively. There was no difference in basal pallidal GABA levels in the drug naive and chronically treated rats. Furthermore, pallidal GABA release was not affected following injection with Hal in either group although there was a prolonged catalepsy in the drug naive group and a tolerance to catalepsy in the chronically treated group. A previous microdialysis study employing similar experiment protocol showed that Hal increases striatal GABA release in drug naive rats and increases basal striatal GABA levels following chronic treatment. The results of the current study demonstrate that these effects are not reflected in the globus pallidus and suggest that striatal GABA interneurons and/or GABA projection neurons to extrapallidal nuclei such as the substantia nigra pars reticulata may be involved in initiating catalepsy following acute Hal and mediating the tolerance to catalepsy observed following chronic Hal.

Differential effects of intrastriatal neurotensin(1-13) and neurotensin(8-13) on striatal dopamine and pallidal GABA release. A dual-probe microdialysis study in the awake rat.

In the present dual-probe microdialysis study the effects of intrastriatal perfusion with the tridecapeptide neurotensin(1-13) [NT(1-13)] and its active fragment NT(8-13) on striatopallidal GABA and striatal dopamine release were investigated. The modulatory action of NT(1-13) on D2 receptor-mediated inhibition of striatal and pallidal GABA release was also studied. Both intrastriatal NT(1-13) (100 nM) and NT(8-13) (100 nM) increased striatal (139 and 149% respectively) and pallidal (130 and 164%) GABA release, and this effect was antagonized by intrastriatal perfusion with the neurotensin receptor antagonist SR48692 (100 nM). A similar increase (155%) in striatal dopamine release was observed following intrastriatal NT(1-13) (100 nM), but not NT(8-13) (100 and 500 nM). However, at the highest concentration studied (1 microM) NT(8-13) was associated with a rapid increase (130%) in striatal dopamine release. In a second study intrastriatal NT(1-13) (10 nM) counteracted the inhibition of striatal and pallidal GABA release induced by pergolide (500 and 1500 nM). The inhibitory action of the D2 agonist was restored when SR48692 (100 nM) was added to the perfusion medium. These results suggest that in the neostriatum the neurotensin receptor located postsynaptically on the striatopallidal GABA neurons seems to differ from the neurotensin receptor located on dopaminergic terminals, as indicated by the relative lack of effect of NT(8-13) on striatal dopamine release. Furthermore, the ability of NT(1-13) to counteract the pergolide-induced inhibition of both striatal and pallidal GABA release strengthens the evidence for antagonistic receptor-receptor interaction between postsynaptic striatal neurotensin and D2 receptors located on striatopallidal GABA neurons.

The secretory trypsin inhibitor like-peptide, PEC-60 increases dopamine D 2 receptor agonist induced inhibition of GABA release in the dorsolateral neostriatum of the awake freely moving rat. An in vivo microdialysis study

The effects of local perfusion with the secretory trypsin inhibitor like-peptide, PEC-60 on dompamine and γ-aminobutyric acid (GABA) release in the dorsolateral neostriatum and GABA release in the globus pallidus were studied using in vivo microdialysis in the awake freely moving rat. Local perfusion with PEC-60 (500 nM and 1 μM) increased dopamine release in the dorsolateral neostriatum while the highest (1 μM) concentration of PEC-60 decreased striatal but not pallidal GABA release. An inactive form of the peptide, S-carboxyamidomethylated PEC-60 (1 μM) failed to influence either striatal dopamine and GABA or pallidal GABA release. In addition, when PEC-60, at a dose which did not affect striatal and pallidal GABA release (100 nM), was co-perfused together with the dopamine D 2 receptor agonist pergolide (500 nM), a potentiation in the ability of pergolide to reduce GABA release in the dorsolateral neostriatum was observed and this effect was counteracted by co-perfusion with the selective dopamine D 2 receptor antagonist raclopride (1 μM). In contrast, the pergolide induced inhibition of striatal dopamine release was unaffected by PEC-60 (100 nM). These data indicate that PEC-60 differentially regulates dopamine and GABA release in the dorsolateral neostriatum by a selective and facilitory interaction with the postsynaptic dopamine D 2 receptor possibly involving high-affinity PEC-60 like-peptide binding sites located on local axon collaterals of a discrete subpopulation of efferent GABA neurons and/or on GABA interneurons.

Striatal grafts in the ischemic striatum improve pallidal GABA release and passive avoidance

Fetal Striatal cells were grafted into the ischemic striatum of rats and pallidal GABA release, and behavioral improvement were investigated. Intraluminal occlusion of the middle cerebral artery (MCA) for 1 h induced ischemic infarcts in the lateral Striatum and the adjacent cortex. In ischemic rats, the performance of a passive avoidance task was disturbed, and the pallidal GABA level detected by microdialysis decreased to about a half of control. After the graft, the deficit in the passive avoidance was partially alleviated and the GABA level recovered moderately and increased further by the infusion of an uptake blocker. The data indicate that fetal Striatal cell grafts in the ischemic striatum partially restored both chemical and behavioral deficits.

Striatal grafts in rats with unilateral neostriatal lesions—II. In vivo monitoring of gaba release in globus pallidus and substantia nigra

GABA release was recorded in vivo by push-pull perfusion from the globus pallidus and substantia nigra of control rats, rats with unilateral ibotenic acid lesions of the neostriatum, and rats with embryonic striatal tissue grafts implanted in the lesioned striatum. The lesions reduced baseline levels of GABA release to 5% of control levels in the globus pallidus and to 13% of control levels in the substantia nigra pars reticulata. GABA release was substantially restored in both the globus pallidus and substantia nigra of the grafted rats, to 34 and 60%, respectively. Peripheral injection of the dopaminergic stumulant methamphetamine induced a short (lasting approximately 20 min) 4–5 fold increase in GABA release in the intact globus pallidus and a longer (lasting longer than 80 min) increase in the substantia nigra. The stimulatory effect of methamphetamine on GABA release was completely abolished in both sites by the striatal lesions, suggesting that the effect was mediated via a direct or indirect dopaminergic action on striatal output neurons. The grafts reinstated methamphetamine-induced stimulation of GABA release in striatal output targets to a level (as a proportion of baseline) that was similar to that seen in the control rats. The results support the view that activation of the dopaminergic inputs to the striatum is functionally excitatory on the major striatal output projections to the globus pallidus and substantia nigra pars reticulata. The results also support the hypothesis that striatal grafts have the capacity to become functionally incorporated by reciprocal graft-host connections into the neural circuitry of the host brain.