Christopher S. Biggs

Regional Effects of Sodium Valproate on Extracellular Concentrations of 5-Hydroxytryptamine, Dopamine, and Their Metabolites in the Rat Brain: An In Vivo Microdialysis Study

Abstract: The effects of sodium valproate (VPA; 100, 200, and 400 mg/kg, i.p.) on ventral hippocampal and anterior caudate putamen extracellular levels ofdopamine (DA) and 5‐hydroxytryptamine (5‐HT) were examined using in vivo microdialysis. VPA induced dose‐related increases in dialysate DA, 3,4‐dihydroxyphenylacetic acid, and 5‐HT in the ventral hippocampus. Anterior caudate putamen dialysate 5‐HT was also dose dependently elevated by the drug, whereas DA levels tended to decrease with increasing VPA dose. In contrast, VPA (200, 400, and 800 mg/kg, i.p.) produced no significant elevation of DA in posterior caudate putamen dialysates, although 5‐HT levels were significantly elevated at the 400‐ and 800‐mg/kg doses. In all three regions studied, dialysate concentrations of 5‐hydroxyindoleacetic acid and homovanillic acid remained at basal levels following VPA treatments. The results are discussed with regard to the possible anticonvulsant mode of action of VPA.

MK-801 increases extracellular 5-hydroxytryptamine in rat hippocampus and striatum in vivo.

Abstract: The effect of MK‐801 (0.25 or 0.5 mg/kg) on the extracellular concentration of 5‐hydroxytryptamine (5‐HT) and 5‐hydroxyindoleacetic acid (5‐HIAA) in rat hippocampus and striatum was studied using intracerebral dialysis. The dialysate 5‐HT concentration was dose‐dependently increased by MK‐801 in both regions. In the hippocampus, at the higher drug dose a slow increase in the 5‐HIAA level was observed, and this became significant 3 h after treatment. In contrast to this, the extracellular 5‐HIAA content in the striatum was significantly decreased 150 min after administration of both doses of MK‐801. The data are discussed in the light of the known behavioural effects of MK‐801 and possible N‐methyl‐d‐aspartic acid receptor regulation of 5‐HT release.

The effect of sodium valproate on extracellular GABA and other amino acids in the rat ventral hippocampus: an in vivo microdialysis study

We report the effects of i.p. administration of sodium valproate (VPA) on extracellular concentrations of various amino acids in the rat ventral hippocampus studied using in vivo microdialysis, followed by HPLC with fluorometric detection. At the doses used (100, 200 and 400 mg/kg), VPA had no effect on extracellular aspartate, glutamine and taurine, whilst inducing a small, but not statistically significant increase in glutamate at 200 and 400 mg/kg. In contrast, VPA administration produced a biphasic effect on extracellular GABA levels which was dependent on the dose used. At 100 mg/kg, VPA reduced GABA concentrations by 50% when compared to basal. 200 mg/kg VPA had virtually no effect, whilst 400 mg/kg VPA raised extracellular GABA levels to 200% of basal. The results are discussed in relation to the known pharmacological and anticonvulsant actions of VPA.

Regional effects of MK-801 on dopamine and its metabolites studied by in vivo microdialysis.

The non-competitive N-methyl-D-aspartate receptor antagonist MK-801 was observed to have regionally specific effects on the extracellular concentration of dopamine and its metabolites. In rat anterior striatum, MK-801 transiently decreased extracellular dopamine, in spite of inducing intense circling behaviour which is generally associated with an increase in this neurotransmitter. In contrast, hippocampal extracellular dopamine was increased in a dose-related manner by MK-801. The possible significance of these data is discussed in relation to some of the known behavioural actions of MK-801.

N-methyl-D-aspartate receptors modulate extracellular dopamine concentration and metabolism in rat hippocampus and striatum in vivo

The effects of infusing N-methyl-D-aspartate (NMDA), and the specific NMDA receptor antagonist D-2-amino-5-phosphono-propionic acid (D-AP5) into rat hippocampus and striatum on extracellular dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were studied using intracerebral microdialysis. In striatum NMDA increased DA extracellularly in a concentration-dependent manner. Against a 10 microM concentration of NMDA the increase in striatal DA was opposed by D-AP5 (10 microM in all experiments), which when infused alone significantly reduced DA concentration. Infusion of NMDA altered DOPAC level in a complex manner, with 10 microM concentration causing a significant increase 2 h after infusion, while 100 microM NMDA caused a transient decrease in the metabolite. None of treatments altered striatal dialysate HVA. In hippocampus NMDA infusion decreased dialysate DA in a concentration-dependent manner, and the decrease caused by 10 microM NMDA was reversed by D-AP5. When given alone the antagonist was without effect. NMDA infusion elevated hippocampal dialysate DOPAC and HVA, while HVA was decreased following D-AP5 infusion. These data indicate that DA release is regionally controlled by excitatory amino acids, but in differential manner.

N-Methyl-d-aspartate receptors modulate extracellular 5-hydroxytryptamine concentration in rat hippocampus and striatum in vivo

The effects of infusing N-methyl-D-aspartate (NMDA) and the specific NMDA receptor antagonist D-2-amino-5-phosphonopropionic acid (D-AP5) into rat hippocampus and striatum on extracellular 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxy-indoleacetic acid (5-HIAA) were studied using intracerebral microdialysis. In striatum, NMDA (1-100 microM) caused a concentration-dependent increase in 5-HT. D-AP5 (10 microM) infusion caused increased extracellular 5-HT. When the two drugs were co-infused, no effect on extracellular 5-HT was seen. D-AP5 alone was found to cause a delayed but sustained increase in dialysate 5-HIAA. In hippocampus, NMDA infusion caused a dose-dependent decrease in extracellular 5-HT while D-AP5 produced a transitory increase in 5-HT level. NMDA caused a decrease in dialysate 5-HIAA. In striatum, the effect of 10 microM NMDA infusion was abolished by co-infusion with tetrodotoxin (TTX; 1 microM). In hippocampus, 1 microM TTX caused a slight but non-significant augmentation of the effect of 10 microM NMDA alone. These data indicate that NMDA receptors mediate control over 5-HT release and metabolism in different brain regions and may in part explain the behavioural effects of non-competitive NMDA receptor antagonists.

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors modulate dopamine release in rat hippocampus and striatum

The effects of infusing the glutamate receptor agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) on the release of dopamine (DA) has been studied in rat hippocampus and striatum in vivo. In hippocampus, AMPA (1-10 microM) produced a dose related increase in dialysate DA, but at 100 microM AMPA a sustained decrease in extracellular DA was observed. However, when samples were collected at 5-min intervals 100 microM AMPA infusion revealed a brief increase in hippocampal dialysate DA. Infusion of 100 microM AMPA and 500 microM diazoxide, which blocks AMPA receptor desensitization, led to a marked increase in extracellular DA, as did diazoxide alone, although to a lesser extent. The AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3,-dione (CNQX; 200 microM) reversed the effect of AMPA and/or diazoxide infusion on dialysate DA and when infused alone, CNQX also decreased hippocampal dialysate DA. AMPA (50-500 microM) increased striatal DA release. The effect of AMPA on extracellular DA was reversed by CNQX (200 microM). Diazoxide infusion caused a decrease in striatal DA release, and this was not affected by CNQX. These data suggest that hippocampal, but not striatal AMPA receptor desensitization may play a role in regulating DA release.

Impulse-dependent and tetrodotoxin-sensitive release of GABA in the rat's substantia nigra measured by microdialysis.

gamma-Aminobutyric acid (GABA) release in the rat substantia nigra pars reticulata (SNR) was studied by microdialysis coupled with high-performance liquid chromatography and fluorimetric detection. Electrical stimulation of striatonigral axons in the internal capsule (IC) increased nigral GABA release in conscious and halothane-anaesthetized rats. This was prevented by intranigral infusion of tetrodotoxin (TTX) while basal GABA release was unaffected. Calcium-free, cobalt-containing (2 mM CoCl2) artificial cerebrospinal fluid reduced basal GABA overflow but not that evoked with high K+ (100 mM). Extracellular levels of glutamate (GLU) and taurine (TAU) were not modified by IC stimulation, TTX or 0 Ca2+ although high K+ promoted GABA and TAU release but not that of GLU. These data demonstrate an impulse-and sodium-dependent release of GABA from nigral afferent neurones which contribute little to the extracellular concentration of GABA under steady-state conditions.

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 Parkinsons 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. Circling was significantly lower in rats given UCN at either T = 0 or T = +7 compared with animals given 6‐OHDA or LPS and vehicle. Sham‐treated rats showed no circling. Consistent with these observations, striatal dopamine concentrations were markedly higher in 6‐OHDA/LPS + UCN rats vs. 6‐OHDA/LPS + vehicle groups. Additionally, l‐dihydroxyphenylalanine production by tyrosine hydroxylase was greatly reduced in the striata of 6‐OHDA/LPS + vehicle rats, whereas this was not the case in rats coadministered UCN. Finally, the numbers of tyrosine hydroxylase‐positive cells recorded in the substantia nigra of 6‐OHDA/LPS + vehicle‐treated animals were markedly lower than those of sham‐operated or 6‐OHDA/LPS + UCN rats. Critically, UCN was effective in reversing lesion‐induced deficits when given either at the same time as or 7 days after the neurotoxic insult. To our knowledge, this is the first time that such an effect has been demonstrated in vivo. The apparent ability of UCN to arrest the progression of or even reverse nigral lesions once established suggests that pharmacological manipulation of this system could have substantial therapeutic utility.

Dopamine and glutamate control each other's release in the basal ganglia : a microdialysis study of the entopeduncular nucleus and substantia nigra

This study utilized microdialysis in conscious rats to investigate dopaminergic control of excitatory amino acid release in the entopeduncular nucleus (EPN), and glutamatergic control of dopamine release in the substantia nigra pars reticulata (SNr). EPN dialysates contained both glutamate and aspartate, which were elevated by dopamine depletion with reserpine and 6-hydroxydopamine (6-OHDA), reduced by the D2/3 agonist LY 171555 and unaffected by the D1 agonist SKF 38393, in line with current theory. The D2/3 agonist RU 24213 was behaviourally active but paradoxically increased glutamate and aspartate release in EPN, possibly via kappa opioid receptor blockade. 6-OHDA-hemilesioned rats also showed a significant increase in glutamate and aspartate contralaterally, suggesting that nigrostriatal dopamine affects EPN neurotransmission bilaterally. In reserpine-treated rats, basal levels of dopamine in the SNr were greatly reduced, and were further lowered by focal application of NMDA antagonists, suggestive of the removal of a high glutamatergic tone. A threshold amount of L-DOPA applied to the SNr elevated dopamine output about two-fold and 5-HT output about 13-fold, indicating L-DOPA effects the release of monoamines other than dopamine. Concomitant addition of the NMDA antagonists potentiated these releases synergistically, suggesting that this could be how they facilitate the antiparkinsonian action of L-DOPA.