Exendin-4 treatment enhances L-DOPA evoked release of striatal dopamine and decreases dyskinetic movements in the 6-hydoxydopamine lesioned rat.

Objectives: To determine whether the glucagon-like 1 peptide analogue exendin-4 (EX-4) augments the neurochemical effects of a single L-DOPA treatment and whether EX-4 can decrease L-DOPA induced dyskinesias (LIDS).

Methods: Rats were lesioned with 6-hydroxydopamine (6-OHDA) and 7 days later given EX-4 for 7 days. The following day, rats were given L-DOPA and extracellular dopamine was measured.

Neuroinflammation and the prospects for anti-inflammatory treatment of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder, the cause of which remains elusive. Neuroinflammation appears to be a ubiquitous pathological change in both patients and experimental models of PD, both of which present with the classical features of inflammation, but with evidence that the process has become uncontrolled. Therefore, the use of anti-inflammatory drugs in the treatment of PD appears to be a logical development.

Dopamine-dependent tuning of striatal inhibitory synaptogenesis.

Dopaminergic projections to the striatum, crucial for the correct functioning of this brain region in adulthood, are known to be established early in development, but their role is currently uncharacterized. We demonstrate here that dopamine, by activating D(1)- and/or D(2)-dopamine receptors, decreases the number of functional GABAergic synapses formed between the embryonic precursors of the medium spiny neurons, the principal output neurons of the striatum, with associated changes in spontaneous synaptic activity. Activation of these receptors reduces the size of postsynaptic GABA(A) receptor clusters and their overall cell-surface expression, without affecting the total number of clusters or the size or number of GABAergic nerve terminals.

Glucagon-like peptide 1 receptor stimulation as a means of neuroprotection.

Glucagon-like peptide 1 (GLP-1) is a relatively recently discovered molecule originating in the so-called L-cells of the intestine. The peptide has insulinotrophic properties and it is this characteristic that has predominantly been investigated. This has led to the use of the GLP-1-like peptide exendin-4 (EX-4), which has a much longer plasma half-life than GLP-1 itself, being used in the treatment of type II diabetes.

The CRF-like peptide urocortin greatly attenuates loss of extracellular striatal dopamine in rat models of Parkinson's disease by activating CRF(1) receptors.

We have recently observed that the corticotrophin releasing factor (CRF) related peptide urocortin reverses key features of nigrostriatal damage in two paradigms of Parkinson's disease. Here we have studied whether these effects are supported by a retention of striatal basal and evoked extracellular dopamine and the receptor(s) that may mediate this effect. Fourteen days following stereotaxic injections of 6-hydroxydopamine (6-OHDA) or lipopolysaccharide (LPS) and urocortin, extracellular dopamine levels in striata ipsilateral to injection sites of 6-OHDA/LPS and urocortin treated rats were comparable with sham injected rats, whilst rats given 6-OHDA/LPS and vehicle had considerably lower dopamine levels.

The CRF-like peptide urocortin produces a long-lasting recovery in rats made hemiparkinsonian by 6-hydroxydopamine or lipopolysaccharide.

We have recently observed that the corticotropin releasing factor related peptide urocortin (UCN) reverses key features of nigrostriatal neurodegeneration following intracerebral injection of either 6-hydroxydopamine (6-OHDA) or lipopolysaccharide (LPS). To determine the potential therapeutic utility of UCN here we have studied whether these effects are sustained for several weeks following peptide injection. In addition we have studied whether UCN still shows efficacy in rats with more pronounced nigrostriatal lesions.

Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson's disease.

Background: It has recently become apparent that neuroinflammation may play a significant role in Parkinson's disease (PD). This is also the case in animal paradigms of the disease. The potential neuroprotective action of the glucagon-like peptide 1 receptor (GLP-1R) agonist exendin-4 (EX-4), which is protective against cytokine mediated apoptosis and may stimulate neurogenesis, was investigated In paradigms of PD.

Urocortin, a CRF-like peptide, restores key indicators of damage in the substantia nigra in a neuroinflammatory model of Parkinson's disease.

We have recently observed that the corticotrophin releasing hormone (CRF) related peptide urocortin (UCN) reverses key features of nigrostriatal damage in the hemiparkinsonian 6-hydroxydopamine lesioned rat. Here we have studied whether similar effects are also evident in the lipopolysaccaride (LPS) neuroinflammatory paradigm of Parkinson's disease (PD). To do this we have measured restoration of normal motor behaviour, retention of nigral dopamine (DA) and also tyrosine hydroxylase (TH) activity.

The corticotrophin-releasing factor-like peptide urocortin reverses key deficits in two rodent models of Parkinson's disease.

The potential neuroprotective action of the corticotrophin-releasing factor-related peptide urocortin (UCN) was investigated in the rat 6-hydroxydopamine (6-OHDA) and lipopolysaccharide (LPS) paradigms of Parkinson's disease. UCN (20 fmol) was either given at the same time as (T = 0) or 7 days after (T = +7) intracerebral 6-OHDA or LPS injection. At 14 days after 6-OHDA or LPS injection, circling behaviour was measured following apomorphine challenge.

Effects of amantadine and budipine on antidepressant drug-evoked changes in extracellular dopamine in the frontal cortex of freely moving rats.

NMDA receptors play a role in the aetiology of depression with non-competitive NMDA receptor antagonists such as amantadine showing synergy with conventional antidepressants. To advance a neurochemical rational for these findings, we have studied the effects of administration of amantadine and budipine with the antidepressants reboxetine (REB), paroxetine (PAROX) and clomipramine (CLOM) on extracellular DA in rats using microdialysis. Acutely, amantadine (40 mg/kg) or budipine (10 mg/kg) did not significantly alter extracellular DA.

Chronic treatment with antidepressant drugs reversibly alters NMDA mediated regulation of extracellular 5-HT in rat frontal cortex.

Treatment of depression is largely based upon the monoamine theory of the illness. However, current therapies are only efficacious in 70-80% of patients indicating that other factors are involved. One mechanism could involve glutamatergic NMDA receptors since NMDA receptor antagonists have antidepressant like properties in paradigms of the illness.

Unexpected effects of nitric oxide synthase inhibitors on extracellular nitrite levels in the hippocampus in vivo.

The aim of this study was to determine whether extracellular nitric oxide levels in the hippocampus of freely moving animals were reduced by the administration of nitric oxide synthase (NOS) inhibitors via a microdialysis probe. Our results show that extracellular nitrite levels were increased following the infusion of N-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI), in the case of the latter, the response was biphasic. In contrast, infusion of both inhibitors together resulted in a substantial reduction in nitrite when compared to control.

Release of arginine, glutamate and glutamine in the hippocampus of freely moving rats: Involvement of nitric oxide.

Using in vivo microdialysis, we have monitored the release of three amino acids (arginine, glutamate and glutamine) in the hippocampus of freely moving rats in response to various drugs. In response to N-methyl-d-aspartate (NMDA) infusion, extracellular glutamate was increased, glutamine was decreased and arginine remained unchanged. By contrast, alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) elicited an increase in arginine release but had no effect on either glutamate or glutamine.

Effects of amantadine and budipine on antidepressant drug-evoked changes in extracellular 5-HT in the frontal cortex of freely moving rats.

1. Evidence has recently suggested that NMDA receptors may play a role in the aetiology and possible treatment of depression and that weak noncompetitive NMDA receptor antagonists such as amantadine can synergize with conventional antidepressants in a model of the illness. 2.

Lamotrigine, carbamazepine and phenytoin differentially alter extracellular levels of 5-hydroxytryptamine, dopamine and amino acids.

We have studied the effects of treatment with the anticonvulsants lamotrigine (LTG), phenytoin (PHN) and carbamazepine (CBZ) on basal and stimulated extracellular aspartate (ASP), glutamate (GLU), taurine (TAU), GABA, 5-hydroxytryptamine (5-HT) and dopamine (DA) in the hippocampus of freely moving rats using microdialysis. All of the drugs investigated have had inhibition of Na(+) channel activity implicated as their principal mechanism of action. Neither LTG (10-20 mg/kg), PHN (20-40 mg/kg) or CBZ (10-20 mg/kg) had an effect on the basal extracellular concentrations of any of the amino acids studied with the exception of glutamate, which was decreased at the highest LTG dose.

Effects of combined lamotrigine and valproate on basal and stimulated extracellular amino acids and monoamines in the hippocampus of freely moving rats.

The antiepileptic drugs sodium valproate (VPA) and lamotrigine (LTG) are increasingly used in combination in patients in whom monotherapy has failed to control seizures. Although these drugs are known to interact pharmacokinetically, several authors have proposed a pharmacodynamic interaction between the two. In order to investigate this we have studied the effects of combined treatment with LTG and VPA on basal and stimulated extracellular aspartate (ASP), glutamate (GLU), taurine (TAU), gamma amino butyric acid (GABA), 5-hydroxytryptamine (5-HT) and dopamine (DA) release in the hippocampus of freely moving rats using microdialysis.

Arginine release from rat cerebellar astrocytes: autocrine roles for glutamate and nitric oxide?

In this study we have investigated the relationship between glutamate and arginine release from cultured cerebellar astrocytes. We found that the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) promoted the release of both amino acids in a concentration-dependent manner, and that these responses were partially reversed by a guanylate cyclase inhibitor. Application of the non-NMDA glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) resulted in a 60% reduction in basal arginine release but no change in that of glutamate.

Effects of acute and chronic lamotrigine treatment on basal and stimulated extracellular amino acids in the hippocampus of freely moving rats.

The antiepileptic drug lamotrigine (LTG) is a relatively novel anticonvulsant frequently used in polytherapy and increasingly in monotherapy. LTG is believed to act by reducing excitatory glutamate (GLU) release due to an inhibition of Na(+) channels. In the present study, we have investigated the effects of acute and chronic (up to 21 days) treatment with LTG on basal and either veratridine- or KCl-stimulated release of aspartate (ASP), GLU, taurine (TAU) and GABA in the hippocampus of freely moving rats using microdialysis.

Effect of acute and chronic lamotrigine on basal and stimulated extracellular 5-hydroxytryptamine and dopamine in the hippocampus of the freely moving rat.

1. We have studied the effects of acute and chronic treatment with the anticonvulsant lamotrigine (LTG) on basal and stimulated extracellular 5-hydroxytryptamine (5-HT), dopamine (DA) and their metabolites in the hippocampus of freely moving rats using in vivo microdialysis. 2.

Regulatory role of nitric oxide over extracellular taurine in the hippocampus of freely moving rats.

We have studied the effects of drugs which manipulate nitric oxide (NO) levels as well the effect of N-methyl-d-aspartate (NMDA) infusion on extracellular taurine in rat hippocampus using in vivo microdialysis. The NO donor S-nitroso-N-acetylpenicillamine (SNAP) increased dialysate taurine in a concentration-dependent manner, and this effect was blocked by the inhibitor of soluble guanylate cyclase1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ). NMDA (100 microM) increased hippocampal taurine release, an effect that was reversed by the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5; 10 microM).

Reboxetine modulates norepinephrine efflux in the frontal cortex of the freely moving rat: the involvement of alpha 2 and 5-HT1A receptors.

The effect of reboxetine on norepinephrine (NE) efflux in the frontal cortex of freely moving rats has been studied using in vivo microdialysis. Reboxetine was administered either by injection (10 and 30 mg/kg i.p.