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The effects of local cholecystokinin-8 (CCK-8) administration on cortical extracellular levels of amino acids, catecholamines and metabolism products were studied in the halothane anaesthetized rat by in vivo microdialysis. CCK-8 (10 microM), administrated via a microdialysis probe, produced a significant increase in the levels of aspartate, glutamate and gamma-aminobutyric acid (GABA), but not of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), lactate and pyruvate, which were simultaneously monitored. The increase in aspartate and glutamate levels produced by CCK-8 was about 3-4-fold. The effect of CCK-8 on aspartate levels was significantly inhibited by the CCKB antagonist, L-365,260 (20 mg kg-1, s.c.), but not by the CCKA antagonist, L-364,718 (20 mg kg-1, s.c.). In contrast, the increase in glutamate levels was inhibited by both L-365,260 and L-364,718. GABA was slightly, but significantly increased (approximately 30%), by local CCK-8 and was inhibited by both CCK antagonists. The present results show that CCK-8 exerts a strong modulatory action on both aspartate and glutamate release in rat cortex. While the effect of CCK-8 on aspartate is selectively mediated via CCKB receptor subtype, the effect of CCK-8 on glutamate appears to be mediated via both CCKA and CCKB receptor subtypes.

Intracerebral microdialysis combined with electrocorticographic recordings was used in a patient subjected to epilepsy surgery. The patient developed a series of partial seizures during an 8 min period. Marked elevations of aspartate (79-fold), glycine (21-fold), glutamate (16-fold) and serine (8-fold) dialysate concentrations occurred in association with onset of the period with seizures. Recurrent seizures occurred, in spite of normalizing amino acid levels. Other amino acids analyzed (aspargine, threonine, arginine, alanine, taurine, tyrosine, phenylalanine, isoleucine and leucine) showed less pronounced changes (1-5 times the basal levels).

The effect of two consecutive administrations of amphetamine (1.5 mg/kg, s.c.; 2 h apart) on dopamine (DA) and acetylcholine (ACh) efflux in dorsolateral striatum and nucleus accumbens was studied with in vivo microdialysis in freely moving rats. Amphetamine was found to cause a more persistent increase of extracellular DA in the dorsolateral striatum than in the nucleus accumbens. The increase in DA overflow by amphetamine was accompanied by an increase of extracellular ACh in both brain areas. The results are inconsistent with the hypothesis of an amphetamine-induced inhibitory regulation by DA on ACh overflow.

In vivo microdialysis and in situ hybridization were combined to study dopaminergic regulation of gamma-amino butyric acid (GABA) neurons in rat caudate-putamen (CPu). Potassium-stimulated GABA release in CPu was elevated following a dopamine deafferentation. Local perfusion with exogenous dopamine (50 microM) for 3 h via the microdialysis probe attenuated the potassium-stimulated increase in extracellular GABA in CPu. Expression of glutamic acid decarboxylase (GAD) mRNA was also increased in the dopamine deafferented CPu. However, local perfusion with dopamine had no significant attenuating effect on the increased GAD mRNA expression. These findings indicate that dopaminergic regulation of GABA neurons in the dopamine deafferented CPu includes both a short-term effect at the level of GABA release independent of changes in GAD mRNA expression and a long-term modulation at the level of GAD gene expression.

Influence of striatal blood flow changes on recovery of extracellular lactate in vivo through a microdialysis probe implanted into the neostriatum was investigated in halothane anesthetized rats. Relative radioactivity loss of [14C]lactate from perfusate medium through a microdialysis probe was continuously measured in vivo as an indicator of relative recovery of extracellular lactate through the probe because both the relative recovery of lactate and the relative hot loss of [14C]lactate through a microdialysis probe were similar to each other in vitro. The relative hot loss of [14C]lactate decreased in parallel with decreases in the striatal blood flow, while it did not significantly change in response to increases in the blood flow up to 200% of control. These results demonstrate that recovery of extracellular lactate in vivo through the microdialysis probe is not directly influenced by changes in the cerebral blood flow.

The present study shows a novel administration form of the monoganglioside GM1, which following microencapsulation in human serum albumin was topically applied on cortical regions damaged by devascularization in rats. The effects of microencapsulated GM1 on extracellular levels of acetylcholine, choline and dopamine in the cortex and in the striatum were analyzed using in vivo microdialysis. Cholinergic neurons in the nucleus basalis magnocellularis were studied immunohistochemically using monoclonal antibodies raised against choline acetyltransferase (ChAT). It was found that cortical devascularizing lesions produced a decrease in extracellular levels of cortical acetylcholine and choline, and retrograde morphological changes in cholinergic neurons in the nucleus basalis magnocellularis. GM1 promoted (1) recovery of the retrograde morphological changes produced by the decortication in the nucleus basalis magnocellularis and (2) a parallel increase in cortical acetylcholine release. No changes were observed in the striatum, nor on cortical or striatal dopamine levels simultaneously measured in the same perfusates.

Kynurenic acid (KYNA) production from its bioprecursor L-kynurenine (KYN) was assessed in vivo by intrastriatal microdialysis in freely moving rats. In the absence of KYN, the extracellular concentration of KYNA was below the limit of assay sensitivity (i.e. less than 8 pmol/30 microliters). In the presence of KYN (50-2000 microM), KYNA concentration in the dialysate increased continuously to reach steady-state levels after 2h of perfusion. Introduction of the unspecific transaminase inhibitor aminooxyacetic acid (AOAA) through the dialysis probe caused a progressive decrease of extracellular KYNA, which reached dose-dependent minimal levels within 2 h. One mM AOAA caused an almost complete depletion of KYNA in the dialysate. These data demonstrate that extracellular KYNA can be assessed by microdialysis and that AOAA can be used as a tool to examine the neurobiology of KYNA in awake, freely moving animals.

Cerebral blood flow (CBF) and extracellular lactate in the parietal cortex were simultaneously measured in halothane-anesthetized rats. Focal electrical stimulation of the magnocellular nucleus of the basal forebrain (nucleus basalis of Meynert; NBM) for 10 min produced a significant increase in cortical CBF without any significant changes in extracellular lactate in the parietal cortex or in systemic arterial blood pressure (BP). Cutaneous pinching of a hindpaw for 10 min increased cortical CBF and BP, but did not influence extracellular cortical lactate. Systemic hypoxia for 10 min reducing the end-tidal O2 concentration from 18% to 6-8% produced a remarkable increase in extracellular cortical lactate. It was suggested that the increased cortical CBF following either NBM stimulation or pinching of a hindpaw was not due to metabolic changes in the cortical neurons of anesthetized rats.

Tissue levels and in vivo release of glutamate were measured in caudate-putamen of rat brain after a unilateral 6-hydroxydopamine lesion of meso-striatal/meso-cortico-limbic dopamine neurons. The results were compared with glutamate levels from corresponding regions in sham-injected animals. The unilateral dopamine lesion induced a bilateral increase of tissue levels of glutamate (45% ipsilateral and 39% contralateral to the lesion). Extracellular levels of glutamate as measured by microdialysis were also bilaterally increased (107% ipsilateral and 94% contralateral to the lesion). The results indicate that mesencephalic dopamine neurons regulate neuronal glutamate in ipsilateral as well as contralateral caudate-putamen.

Extracellular (EC) ascorbate concentrations were measured in microdialysates from the cerebral cortex in rats subjected to cortical compression-contusion trauma. The trauma induced a transient, dramatic increase in EC ascorbate compared to the basal level before the insult and compared to control animals. The data support the presence of a releasable intracellular pool of ascorbate in the neocortex. The possibility that ascorbate may influence traumatic brain damage by its proposed neuromodulatory property and/or by its ability to induce lipid peroxidation is considered.

Presynaptic dopamine and acetylcholine transmission in the anteroventral (limbic) caudate-putamen were studied by microdialysis in freely moving rats during cocaine self-administration sessions. Acute cocaine exposure elevated dopamine (DA) overflow in drug-naive animals. However, during repeated cocaine administration, the drug-induced elevation of DA was attenuated in animals previously exposed (during the prior 9 days) to cocaine. The diminished dopamine response in repeatedly treated animals while self-administering cocaine was speculated to be due to increased activity of DA transport carrier and/or supersensitive receptors modulating DA release. During repeated cocaine administration, extracellular acetylcholine levels in animals previously exposed to cocaine were found to be significantly decreased compared with controls. The findings of the study may suggest a functional development of supersensitive DA receptors postsynaptic to the DA terminal (located on cholinergic neurons) as a consequence of previous cocaine exposure. Such supersensitivity would allow for a reduced DA signal to be amplified at the postsynaptic level during repeated cocaine self-administration.

Striatal microdialysis was performed in awake rats in an attempt to produce extracellular quinolinic acid (QUIN) from its putative bioprecursors L-tryptophan, L-kynurenine and 3-hydroxyanthranilic acid (3HANA). Test compounds were included in the microperfusion solution. QUIN concentrations in the dialysate remained below the assay sensitivity (i.e. less than 20 nM) under baseline conditions or after extensive perfusion with 1 mM L-tryptophan or L-kynurenine. 3HANA (10-300 microM) caused dose-dependent increases in extracellular QUIN, which attained steady-state concentrations after 4 h. The initial rate of QUIN production was significantly increased in the ibotenate-lesioned striatum, suggesting a pivotal role of astroglia in the deposition of brain QUIN.

This study examined and compared the effects of acute clozapine administration over a range of doses on the release of dopamine (DA) and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in dorsolateral and fundus striata. Basal extracellular DA levels were significantly higher in the dorsolateral striatum. However, DOPAC levels were similar in both regions. Acute treatment with clozapine (40 mg/kg) was associated with an increase in extracellular dopamine in the dorsolateral striatum but not in the fundus. In contrast, an increase in extracellular DOPAC was seen in both regions following all doses of the drug; however, clozapine was more potent in the dorsolateral striatum than in the fundus. These results illustrate the functional heterogeneity of the striatum and in addition, indicate a possible dissociation between the effect of acute clozapine on DA release and DA metabolism.

The effect of 10 days treatment with haloperidol (0.5 or 2 mg/kg/day) or sulpiride (10 or 100 mg/kg/day) on regional brain tissue levels of GABA, glutamate, aspartate and glutamine was studied in the rat. The GABA levels were increased in the nucleus (nuc.) accumbens and striatum by haloperidol, but not by sulpiride. The glutamate and glutamine levels were increased in the nuc. accumbens by both drugs. The aspartate levels were increased in the nuc. accumbens by sulpiride. Tissue levels of all 4 amino acids studied remained unchanged in the substantia nigra following the drug treatment. These results indicate that dopaminergic activity has a region-specific influence on the utilization of aspartate, glutamate and GABA in rat brain.

In vivo release of substance P (SP) was measured by microdialysis in the nucleus tractus solitarii (nTS) in adult cats. Small perfused semipermeable tubules (microdialysis probes) were implanted stereotaxically in the nTS, at the position of respiration-related neurons and perfused with artificial CSF. SP was determined by radioimmunoassay of the perfusate. Increased extracellular concentrations of SP-like immunoreactivity (SP-LI) were measured during hypoxia induced in artificially ventilated cats. In addition, a prolonged increase in the extracellular SP-LI concentration was encountered after cervical vagotomy. The results corroborate the suggestion that SP is a mediator of the central response to hypoxia.

Extracellular (EC) ascorbate concentrations were measured in microdialysates from the striatum bilaterally in rats subjected to unilateral middle cerebral artery occlusion (MCAO). The focal cerebral ischemia induced a dramatic increase in ascorbate on the ipsilateral (operated) side while the levels remained at the preocclusion level in the striatum of the contralateral (control) hemisphere. The possibility that ascorbate may aggravate ischemic neuronal damage by its proposed neuromodulatory properties and/or by its ability to induce lipid peroxidation is discussed.

This experiment was designed to determine whether the release of gamma-aminobutyric acid (GABA) in the globus pallidus (GP) is affected by a lesion of the nigrostriatal pathway. Rats were lesioned with 6-hydroxydopamine 4 weeks prior to study of the in vivo release of GABA. A microdialysis probe was stereotaxically implanted in halothane-anesthetized animals in a vertical position on both GPs. The perfusates were analyzed for their GABA content with a high performance liquid chromatography technique. Compared to unlesioned controls, a marked decrease in the overflow of GABA was observed in the GP contralateral to the lesion, whereas the ipsilateral GP showed a slight increase. The differences between the sides were exaggerated after KCl (100 mmol) administration. The results are discussed in terms of a possible bilateral influence of dopamine terminals in the striatum on GABA transmission.

Results obtained in a study using an in vivo microdialysis technique show that dopamine is detected in perfusates collected from the frontoparietal (sensorimotor) cortex of control rats (dopamine = 0.7 +/- 0.2 nM, n = 10) or of rats with cortical lesions produced by the neurotoxin kainic acid (0.9 +/- 0.2 nM, n = 4). However, cortical dopamine levels were strongly reduced (0.07 +/- 0.06 nM, n = 4) following deafferentation induced by mesencephalic 6-hydroxydopamine injection. Dopamine levels, but not its metabolites could be increased by local KCl application, supporting the idea that extracellular dopamine collected by microdialysis reflects a pool of releasable neurotransmitter.

Extracellular levels of striatal gamma-aminobutyric acid (GABA) and taurine were monitored during insulin-induced hypoglycemia using microdialysis. At the onset of isoelectricity in the electroencephalogram (EEG), a transient 5-fold increase in the levels of GABA occurred. Taurine levels increased 5 min following the onset of isoelectricity and continued to increase during the entire isoelectric period. The results demonstrate that events associated with the onset of isoelectricity during hypoglycemia trigger an increase in extracellular concentrations of GABA and taurine. The discrepancy in time-course of these changes may reflect differences in compartmentation, function and metabolism of the two amino acids.