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B H Westerink

Publications and source records attributed to B H Westerink.

At least 37 records · Page 2Linked to original sources
PubMed1999

Effect of neostigmine on the hippocampal noradrenaline release: role of cholinergic receptors.

The effect of the cholinesterase inhibitor neostigmine on hippocampal noradrenaline (NA) release was studied using in vivo microdialysis. Local application of neostigmine significantly increased the release of NA. The effect was potentiated by coperfusion of the nicotinic antagonist mecamylamine but was completely blocked by the muscarinic antagonist atropine. The neostigmine-evoked NA release was not affected by the M2-selective muscarinic antagonist gallamine but was completely blocked by the M1-selective muscarinic antagonist pirenzepine. While muscarinic antagonists had no effect on the resting release of NA, mecamylamine increased it. Our data indicate that acetylcholine can stimulate the hippocampal NA release via M1 muscarinic receptors and that a population of nicotinic receptors mediate inhibitory tone on hippocampal NA release. The fact that neostigmine is able to enhance both cholinergic and noradrenergic neurotransmission may help to understand the beneficial effect of cholinesterase inhibitors in Alzheimer's disease.

Acetylcholine↗
PubMed1999

Comparison of effects of hypotension and handling stress on the release of noradrenaline and dopamine in the locus coeruleus and medial prefrontal cortex of the rat.

The effects of two different types of stress (hypotension and handling) on the release of dopamine, noradrenaline and DOPAC in the locus coeruleus (LC) and medial prefrontal cortex (mPFC) was studied by means of the dual-probe microdialysis technique. One probe was implanted in the vicinity of the LC and a second probe was implanted in the mPFC. Both probes were used to record simultaneously noradrenaline, dopamine and DOPAC. Samples from the LC were collected in the presence of nomifensine, which was added to the perfusion fluid in a concentration of 50 microM. Hypotension (20 min) induced by intravenous administration of nitroprusside stimulated the release of noradrenaline in the LC and mPFC to about 190% and 150%, of control values, respectively. Hypotension also strongly stimulated the release of dopamine in the mPFC (to 320% of control) and DOPAC in the LC (to 270% of control). The effect of hypotension on extracellular dopamine, noradrenaline and DOPAC was decreased by halothane anaesthesia, and was blocked by chloral hydrate anaesthesia. Handling stress (10 min) stimulated the release of noradrenaline in the LC and mPFC to 180% and 160% of control values, respectively. Handling stimulated the release of dopamine in the mPFC to about 160% of control. The effect of hypotension or handling stress was further evaluated in animals in which the LC was lesioned by an infusion of 6-OH-dopamine. Lesioning of the noradrenergic LC neurons did not the prevent the hypotension-related stimulation of dopamine release, but shortened the time course of the effect dramatically. Lesioning of the noradrenergic neurons had no effect on the stimulatory effect of handling on the release of dopamine in the mPFC. This study shows that mesocortical dopamine neurons, in contrast to noradrenaline neurons, respond much stronger to hemodynamic stress than to an emotional stress. During certain conditions like hypotension stress, but not during handling stress, the LC activity is able to modulate the release of dopamine from mesocortical neurons.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1999

Effects of acute and chronic administration of olanzapine in comparison to clozapine and haloperidol on extracellular recordings of substantia nigra reticulata neurons in the rat brain.

RATIONALE: Previously, we have shown that the atypical antipsychotics clozapine and risperidone, unlike haloperidol, decreased the firing rate of substantia nigra reticulata (SNR) neurons. As the SNR receives substantial input from the striatum, an area where motoric side-effects of antipsychotics are thought to be mediated, the SNR might be an interesting brain structure with regard to motor side-effects. OBJECTIVE: The newly developed atypical antipsychotic olanzapine was studied for its effects on the firing rate of SNR cells. In addition, to gain insight in the implications of our experimental setup for clinical use, responses upon clozapine, olanzapine and haloperidol were studied after chronic treatment. METHODS: In chloralhydrate-anaesthetized male Wistar rats, extracellular recordings were made from SNR neurons upon intravenously (i.v.) administered cumulative doses of the antipsychotics. Naive rats and rats that were subcutaneously (SC) injected for 21 days with an antipsychotic were used. RESULTS: Olanzapine (50-1600 mg/kg; i.v.), significantly inhibited the firing rate of the SNR neurons. Upon 21 days of treatment with a daily SC injection of 20 mg/kg clozapine, the challenge on day 22 with cumulative injections of clozapine (200 6400 mg/kg; i.v.) significantly inhibited the firing rate of the SNR neurons. Olanzapine (50-1600 mg/kg; i.v.) also significantly inhibited the SNR activity when pretreated with olanzapine in an SC administered dose of 1 mg/kg, but not 5 mg/kg. Haloperidol (12.5-800 microg/kg; i.v.) did not significantly affect the SNR activity in rats pretreated with SC administered 0.5 mg/kg haloperidol. CONCLUSIONS: Upon acute and chronic administration of clozapine and olanzapine versus haloperidol, differential effects on SNR neuronal firing could be obtained. The experimental setup seem to be valid for further studies into the mechanism of action of typical versus (relatively low doses of) atypical antipsychotics. The implications of the inhibitory effect of atypical antipsychotics on the SNR firing rate are presently unknown, but could be associated with the lower propensity to induced motoric side-effects. On the other hand, the SNR activity might also reflect non-motoric activity possibly related to negative symptoms.

Animals↗
PubMed1998

Striatal dopamine-glutamate interactions reflected in substantia nigra reticulata firing.

To gain insight into the role of striatal dopamine in basal ganglia functioning, dopaminergic drugs alone and in combination with the glutamate receptor agonist kainic acid were infused in the lateral striatum via a microdialysis probe, while single-unit recordings of substantia nigra reticulata neurons were made in chloral hydrate-anaesthetized rats. Striatal infusion of dopaminergic drugs did not significantly affect the firing rate of substantia nigra reticulata neurons, which was related to the low activity of striatal cells under basal conditions, illustrated by the lack of effect of striatal infusion of TTX on substantia nigra reticulata activity. Under glutamate-stimulated conditions, striatal infusion of d-amphetamine potentiated the inhibition of substantia nigra reticulata neurons induced by striatal kainic acid. Thus, under stimulated but not basal conditions, the modulatory role of dopamine in the striatum could be demonstrated. Dopamine potentiated the inhibitory effect of striatal kainic acid on the firing rate of the basal ganglia output neurons.

Action Potentials↗
PubMed1998

Antipsychotic drugs induce similar effects on the release of dopamine and noradrenaline in the medial prefrontal cortex of the rat brain.

In the present study we have compared the effects of the classical antipsychotic drug haloperidol and four different atypical antipsychotics (clozapine, risperidone, olanzapine, ziprasidone) on extracellular levels of dopamine and noradrenaline in the medial prefrontal cortex (MPFC) of conscious rats. Haloperidol (10, 100 and 800 nmol/kg), clozapine (0.3, 1, 10 and 30 micromol/kg), risperidone (100, 500 and 5000 nmol/kg), olanzapine (10, 100 and 500 nmol/kg) and ziprasidone (10, 100 and 1000 nmol/kg) were administered subcutaneously to rats. All compounds induced increases in dialysate levels of dopamine and noradrenaline in the medial prefrontal cortex. The increases induced by the four antipsychotic agents in extracellular levels of dopamine and noradrenaline displayed a striking co-variation both in dose and time. A similar co-variation was seen in the decrease of dopamine and noradrenaline, after administration of a low dose (30 nmol/kg, s.c.) of the dopamine D2/3 receptor agonist (+)-7-hydroxy-2-(N,N-di-n-propylamino) tetralin ((+)-7-OH-DPAT). It is concluded that there is a close coupling between the release of dopamine and noradrenaline in the medial prefrontal cortex. The mechanism of action of this interaction, that might be of importance for a better understanding of the mechanism of action of antipsychotic drugs, is discussed.

Animals↗
PubMed1998

GABA receptors and benzodiazepine binding sites modulate hippocampal acetylcholine release in vivo.

In the present study, the regulation of acetylcholine release from the ventral hippocampus by gamma-aminobutyric acid (GABA) was investigated in vivo. GABA receptor agonists and antagonists were administered locally in the medial septum and the adjacent vertical limb of the diagonal band of Broca, or in the hippocampus by retrograde dialysis. Acetylcholine release was measured in the ventral hippocampus. In addition, the modulation of acetylcholine release via septal benzodiazepine binding sites was assessed by intraseptal administration of an agonists and an antagonist at the benzodiazepine binding site. Intraseptal administration of the GABA(A) receptor agonist muscimol and the GABA(B) receptor agonist baclofen, but not the agonist of the benzodiazepine binding site midazolam, decreased acetylcholine release in the hippocampus. The GABA(A) receptor antagonist bicuculline and the antagonist of the benzodiazepine binding site flumazenil, but not the GABA(B) receptor antagonist 3-N-(3,4,-dichlorobenzyl) aminopropyl-P-diethoxymethyphosphinic acid (CGP 52432) increased acetylcholine release in the hippocampus upon intraseptal administration. The same GABA receptor ligands were administered in the ventral hippocampus. CGP 52432 induced a small increase in acetylcholine release, whereas baclofen, muscimol and bicuculline did not affect local acetylcholine release. Thus, endogenous GABA causes tonic inhibition of acetylcholine release in the ventral hippocampus via septal GABA(A) receptors and, to a lesser extent, via GABA(B) receptors in the medial septum and hippocampus. The GABAergic inhibition in the medial septum is reduced by antagonists of the benzodiazepine binding site.

Acetylcholine↗
PubMed1998

Involvement of medial septal glutamate and GABAA receptors in behaviour-induced acetylcholine release in the hippocampus: a dual probe microdialysis study.

In the present study, the role of medial septal receptors in behaviour-induced increase in acetylcholine (ACh) release in hippocampus was investigated using dual-probe microdialysis in combination with a simple behavioural procedure. gamma-Aminobutyric acid (GABA) and glutamate receptor agonists and antagonists were administered by retrograde dialysis into the medial septal area, while ACh was measured in the ventral hippocampus. Rats were behaviourally activated by immobilization or handling, but only handling was performed during drug-treatment. The GABAA receptor agonist muscimol did not affect ACh release, but blocked the handling-induced increase in ACh release completely. In addition, muscimol administration induced behavioural activity. Administration of the GABAA receptor antagonist bicuculline increased ACh release more than 2-fold. However, handling-induced increase in ACh release, expressed as percentage of drug-induced release, was similar to that of controls. Administration of the glutamate receptor agonists N-methyl-D-aspartate (NMDA) and (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) in the septal area increased hippocampal ACh levels, but reduced the handling-induced increase in ACh release. The NMDA antagonist, 3-((R)-2-carboxypiperazin-4-yl) (CPP) increased ACh levels moderately, and reduced handling-induced increase in ACh release. However, similarly to muscimol, CPP administration induced behavioural activity. The AMPA/kainate receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) did not affect behaviour or basal ACh levels, but attenuated the handling-evoked ACh release. We conclude that the handling-induced increase in hippocampal ACh levels is mediated via stimulation of septal non-NMDA, and possibly NMDA receptors, whereas GABAA receptors are probably not involved. The feasibility of the experimental design is further discussed.

Acetylcholine↗
PubMed1998

The role of afferents to the ventral tegmental area in the handling stress-induced increase in the release of dopamine in the medial prefrontal cortex: a dual-probe microdialysis study in the rat brain.

This study was aimed to identify the neuronal pathways that mediate the handling stress induced increase in the release of dopamine in the medial prefrontal cortex (mPFC) of the rat brain. For that purpose a microdialysis probe was implanted in the ventral tegmental area (VTA) and a second probe was placed in the ipsilateral mPFC. Receptor specific compounds acting on GABA(A) (20 microM muscimol), GABA(B) (50 microM baclofen), acetylcholine (100 microM atropine, 100 microM mecamylamine), NMDA (30, 100 and 300 microM CPP; 300 microM AP-5, 1 mM (+)-HA-966) and non-NMDA receptors (500 microM CNQX) were infused into the VTA by retrograde dialysis, whereas extracellular dopamine was recorded in the ipsilateral mPFC. Intrategmental infusion of muscimol, baclofen, CPP, AP-5, (+)-HA-966 and CNQX decreased extracellular dopamine in the ipsilateral mPFC; atropine and mecamylamine were without effect on the basal values. During infusion of the various compounds rats were gently handled for 15 min. The infusions of muscimol, atropine, mecamylamine and (+)-HA-966 did not modify the handling stress induced increase in extracellular dopamine in the mPFC. However, during intrategmental infusion of baclofen, CPP, AP-5 and CNQX the handling stress induced increase in extracellular dopamine (expressed as % of controls) in the mPFC was suppressed. These results indicate that a glutamatergic projection to the VTA, acting via both NMDA and non-NMDA-glutamate receptors, play a major role in the handling stress-induced increase in dopamine release in the mPFC. In addition the results suggest a certain role for GABAergic neurones, acting via GABA(B) receptors, in the handling response.

Animals↗
PubMed1998

Disinhibition of the mediodorsal thalamus induces fos-like immunoreactivity in both pyramidal and GABA-containing neurons in the medial prefrontal cortex of rats, but does not affect prefrontal extracellular GABA levels.

Stimulation of the mediodorsal and midline thalamic nuclei excites cortical neurons and induces c-fos expression in the prefrontal cortex. Data in the literature data suggest that pyramidal neurons are the most likely cellular targets. In order to determine whether cortical interneurons are also impacted by activation of mediodorsal/midline thalamic nuclei, we studied the effects of thalamic stimulation on (1) Fos protein expression in gamma-aminobutyric acid (GABA)-immunoreactive neurons and on (2) extracellular GABA levels in the prefrontal cortex of rats. Perfusion of the GABA-A receptor antagonist bicuculline for 20 minutes through a dialysis probe implanted into the mediodorsal thalamus induced Fos-like immunoreactivity (IR) approximately 1 hour later in the thalamus and in the medial prefrontal cortex of freely moving rats. Immunohistochemical double-labeling for Fos-like IR and GABA-like IR showed that about 8% of Fos-like IR nuclei in the prelimbic and infralimbic areas were located in GABA-like IR neurons. Fos-like IR was detected in three major subsets of GABAergic neurons defined by calbindin, parvalbumin, or vasoactive intestinal peptide (VIP)-like IR. Dual probe dialysis showed that the extracellular levels of GABA in the prefrontal cortex did not change in response to thalamic stimulation. These data indicate that activation of thalamocortical neurons indeed affects the activity of GABAergic neurons as shown by the induction of Fos-like IR but that these metabolic changes are not reflected in changes of extracellular GABA levels that are sampled by microdialysis.

Animals↗
PubMed1998

Effects of neostigmine and atropine on basal and handling-induced acetylcholine output from ventral hippocampus.

The involvement of muscarinic autoreceptors in the regulation of hippocampal acetylcholine levels during acetylcholinesterase inhibition was examined by perfusing the acetylcholinesterase inhibitor neostigmine bromide (10, 100 or 1000 nM) alone and in the presence of the muscarinic receptor antagonist atropine methylnitrate (10 microM), in resting and behaviourally-activated animals. In resting animals, local perfusion of neostigmine caused a dose-dependent increase in acetylcholine levels. Coadministration of atropine did not affect basal levels in the presence of 10 nM neostigmine, but increased acetylcholine levels approximately four and 11-fold in the presence of 100 nM and 1000 nM neostigmine, respectively. In animals which were behaviourally activated by handling, acetylcholine levels increased two- to three-fold in the presence of all neostigmine concentrations. However, the handling-induced increase in acetylcholine levels was somewhat smaller with 1000 nM neostigmine as compared to 10 nM neostigmine. Atropine had no effect on handling-induced acetylcholine output in the presence of 10 nM neostigmine, but caused greater and longer increases in the presence of 100 nM and 1000 nM neostigmine. These data indicate that acetylcholine levels are greatly reduced by autoinhibition at higher levels of acetylcholine esterase inhibition. The handling-evoked increase in acetylcholine levels is only moderately affected by the level of acetylcholinesterase inhibition, despite the participation of autoreceptors in the handling effect at higher levels of acetylcholinesterase inhibition.

Acetylcholine↗
PubMed1998

New generic approach to the treatment of organophosphate poisoning: adenosine receptor mediated inhibition of ACh-release.

Current treatment of acute organophosphate (OP) poisoning includes a combined administration of a cholinesterase reactivator (oxime), a muscarinic receptor antagonist (atropine) and an anticonvulsant (diazepam). This treatment is not adequate since it does not prevent neuronal brain damage and incapacitation. Here, as in a recent review it is stated that other therapeutic approaches may improve protection. Former studies on the "direct effects" of oximes led to the conclusion that drug-induced inhibition of acetylcholine (ACh)-release shortly (1 min) after the acute OP-intoxication, could prevent and counteract convulsions and improve survival. In general, the accumulation of ACh in the synaptic cleft is considered to be responsible for the symptoms that ultimately lead to death. Therefore, prevention or suppression of this excessive accumulation of ACh could be a generic approach to antagonize OP-poisoning. Preliminary evidence for this concept has been put forward. Evaluation of drugs that would be able to prevent and counteract ACh accumulation, led to the conclusion that adenosine receptor agonists could be promising candidates. Pilot experiments demonstrated that intramuscular administration of the adenosine receptor agonists NECA (5'-N-ethylcarboxamido-adenosine) or CPA (N6-cyclopentyl adenosine) 1 min following a subcutaneous soman poisoning (1.5-2LD50) in rats, resulted in (1) prevention or postponement of chewing, salivation, convulsive activity, and respiratory distress (cholinergic symptoms), (2) improvement of survival rate (24 h), (3) a low level of extracellular brain ACh, as opposed to high levels of extracellular brain ACh in untreated animals. It is concluded that (1) adenosine agonists protect acutely soman-poisoned rats without the need of additional treatment with atropine, oxime or diazepam, (2) prevention of ACh accumulation in this way may be a new generic approach in the treatment of OP-poisoning.

Adenosine-5'-(N-ethylcarboxamide)↗
PubMed1998

The pharmacology of mesocortical dopamine neurons: a dual-probe microdialysis study in the ventral tegmental area and prefrontal cortex of the rat brain.

Receptor-specific compounds were applied by retrograde microdialysis to the ventral tegmental area (VTA) of the rat brain. The effects of intrategmental infusions on extracellular dopamine in the ipsilateral prefrontal cortex (PFC) were recorded with a second microdialysis probe. Intrategmental infusion of tetradotoxin (1 microM), muscimol (20 microM) or baclofen (50 microM) decreased extracellular dopamine in the PFC. Infusion of N-methyl-D-aspartate (NMDA) (300 microM; 1 mM, 15 min) or kainate (50 microM, 15 min) increased extracellular dopamine in the PFC. The effects of the excitatory amino acids were suppressed by co-infusion with (+/-)-3(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (300 microM), with (+/-)-2-amin-5-phosphonopentanoic acid (500 microM), with dizocilpine maleate (500 microM) (partly) or with 6-cyano-7-nitroquinoxaline-2,3-dione (500 microM) (partly). Intrategmental infusion of carbachol (50 microM) increased extracellular dopamine in the PFC. These results provide evidence for the localization of GABAA, GABAB, NMDA, non-NMDA and cholinergic receptors on mesocortical neurons in the VTA. Intrategmental infusion of AP-5, (+/-)-2-amino-5-phosphonopentanoic acid (500 microM), of (+/-)-3(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (300 microM), of (+)-3-amino-1-hydroxy-2-pyrrolidone (1 mM) and of 6-cyano-7-nitroquinoxaline-2,3-dione (500 microM) decreased extracellular dopamine in the PFC. Infusion of mecamylamine, of atropine, and of 3-[[(3, 4)-dichlorophenyl)methyl]propyl](diethoxymethyl) phosphonic acid into the VTA did not modify extracellular dopamine in the PFC. Infusion of bicuculline (50 microM) and that of (-)-sulpiride (50 microM) were followed by an increase in extracellular dopamine in the PFC. These data suggest that mesocortical dopamine neurons, at the level of the VTA, are tonicly excitated by glutamatergic neurons by acting on NMDA and non-NMDA receptors and are tonicly inhibited by GABA and dopamine by acting on GABAA and D2 receptors, respectively. No tonic stimulation by cholinergic neurons was detected. The effects on mesocortical neurons and earlier published data on mesolimbic and nigrostriatal dopamine neurons are compared and discussed.

Animals↗
PubMed1997

The locus coeruleus noradrenergic system in the rat brain studied by dual-probe microdialysis.

A dual-probe microdialysis technique was applied to the locus coeruleus (LC) and prefrontal cortex (PFC) of the brain of conscious rats. One probe was implanted close to the LC and was used to apply receptor-specific compounds by retrograde microdialysis. The effects of the LC infusions were recorded by a sampling noradrenaline by a second probe that was implanted in the ipsilateral prefrontal cortex. Infusion of sodium channel blocker tetrodotoxin (1 microM; 90 min) into the LC decreased extracellular noradrenaline in the PFC to approximately 20% of control values. Infusion of alpha2-adrenoceptor agonist clonidine (100 microM, infused during 15 or 45 min) near to the LC, decreased extracellular noradrenaline in the PFC to 35 and 20% of controls, respectively. These results indicate that > 80% of the extracellular levels of noradrenaline in the PFC is derived from LC innervation, and confirms the importance of alpha2-autoreceptors on noradrenergic neurons in the LC. Infusion of the cholinergic receptor agonist, carbachol (100 microM, 45 min) near to the LC increased extracellular noradrenaline in the PFC to approximately 150% of controls. Infusions of the excitatory amino-acid agonists NMDA and kainate into the LC caused marked increases in extracellular noradrenaline in the PFC to 240 and 200% of controls, respectively. The experiments with clonidine, carbachol, NMDA and kainate were repeated in anesthetized rats. Clonidine and carbachol were similarly effective as in conscious animals but the effects of NMDA and kainate on extracellular noradrenaline in the PFC were clearly suppressed: 145 and 130% of controls, respectively. These results suggest that increased arousal or behavioural activation might have contributed to the increases in extracellular noradrenaline that was seen after infusion of the glutamate agonists. These results also provide evidence for localization of cholinergic-, NMDA-, non-NMDA-receptor on noradrenergic neurons in the LC. Finally it is concluded that dual-probe microdialysis is a useful method to further investigate the pharmacology of LC-noradrenergic neurons. Carbachol and clonidine are suitable tools for a rapid and reversible stimulation or inhibition, respectively, of noradrenergic LC neurons.

Adrenergic Fibers↗
PubMed1997

Characterization of the effect of dopamine D3 receptor stimulation on locomotion and striatal dopamine levels.

By examining the effect of dopamine (DA) D3 receptor stimulation on locomotor activity and extracellular levels of DA in striatum we show that inhibition of locomotor activity induced by DA D3 receptor-selective agonists is mediated by two interacting mechanisms: (1) directly via the stimulation of DA D3 receptors that inhibit locomotor activity, and (2) indirectly via a decrease in extracellular levels of DA. Thus, the moderately DA D3 receptor-selective agonist R-(+)-7-OH- DPAT (R-(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetralin) decreased locomotor activity after administration of 10 nmol/kg and extracellular DA levels in accumbens and striatum after administration of 30 nmol/kg. A decrease in locomotor activity that coincided with a decrease in extracellular DA levels in striatum was observed after administration of 100 nmol/kg of the DA D3 receptor-selective agonist PD128907 ((+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3 b]-1,4-oxasin-9-ol. In combination with the partial, DA D3 receptor-selective agonist PD151328 (2-[4[3-(4-phenyl)-1- piperazinyl)propoxy]phenyl]-benzamidazole), a reversal of the attenuating effect of PD128907 on locomotor activity was observed, without an effect on extracellular levels of DA. In combination with a low--10 nmol/kg--dose of haloperidol, a reversal of the inhibitory effect of PD128907 on locomotor activity was observed that coincided with an increase in extracellular levels of DA. In the presence of 0.5 mg/kg amphetamine, PD128907 decreased amphetamine-induced locomotor activity. This effect could be reversed by PD151328.

Animals↗
PubMed1997

Effects of risperidone, clozapine and haloperidol on extracellular recordings of substantia nigra reticulata neurons of the rat brain.

Risperidone has proven to be effective as an antipsychotic drug and has fewer extrapyramidal side-effects than classic neuroleptics. In addition to its dopamine D2 receptor antagonistic properties, this antipsychotic agent is a potent 5-HT2 receptor antagonist. The atypical antipsychotic, clozapine, also possesses both dopamine D2 and 5-HT2 receptor affinity next to affinities for other receptors. To gain an insight in the consequences for basal ganglia activity of treatment with these atypical neuroleptics vs. typical neuroleptics, the effects of cumulative doses of risperidone, clozapine and haloperidol on the firing rate of substantia nigra reticulata neurons were studied. Extracellular recordings were performed in chloralhydrate-anaesthetized male Wistar rats. Both risperidone (50-3200 micrograms/kg i.v.) and clozapine (100-6400 micrograms/kg i.v.) dose dependently decreased substantia nigra reticulata activity maximally to 70% of the basal activity. With both treatments, a dose of 800 micrograms/kg was significantly effective. In contrast, haloperidol (12.5-800 micrograms/kg i.v.) gradually induced a slight increase in substantia nigra reticulata activity, which was identical to the substantia nigra reticulata activity after saline treatment. Therefore, these results indicate that typical and atypical neuroleptics affect differentially the output of the basal ganglia in the substantia nigra reticulata. To evaluate the involvement of 5-HT2 receptors in the effect of risperidone, the 5-HT2 receptor agonist, quipazine (0.5 mg/kg i.p.), was administered 15 min preceding risperidone treatment. A 4-fold higher dose of risperidone was needed to significantly affect the substantia nigra reticulata firing rate. Thus, the 5-HT2 component of the effect of risperidone is, at least partly, responsible for the difference in effect on substantia nigra reticulata neurons in comparison to haloperidol.

Animals↗
PubMed1997

Electrical stimulation of the substantia nigra reticulata: detection of neuronal extracellular GABA in the ventromedial thalamus and its regulatory mechanism using microdialysis in awake rats.

A combination of electrical stimulation and microdialysis was used to study the nigrothalamic gamma aminobutyric acid (GABA)ergic system and its regulatory mechanisms in awake rats. Extracellular GABA levels in the ventromedial nucleus of the thalamus were detected in 3-min fractions collected before, during and after a 10-min stimulation period of the substantia nigra reticulata. Electrical stimulation of the substantia nigra reticulata increased the GABA levels to 155% of basal values in the ventromedial thalamus only during the first 3-min interval upon stimulation. The increase in GABA levels was tetrodotoxin-dependent, implicating an exocytotic origin. The basal levels of extracellular GABA in the ventromedial thalamus were of nonexocytotic origin. To study the mechanism underlying the fast compensatory response in neuronal GABA release after nigral stimulation, local infusions into the ventromedial thalamus of reuptake inhibitors and GABA antagonists were performed and the effect of nigral stimulation was examined under the various applications. Local infusion of the reuptake inhibitors nipecotic acid (500 microM) and SKF 89976-A (20 and 50 microM) increased extracellular GABA levels to 350%, 180% and 600%, respectively, of basal values in the ventromedial thalamus tetrodotoxin-independently. Under these conditions, the increase in extracellular GABA was absent (nipecotic acid) or suppressed (20% of basal values; SKF 89976-A for both doses), leaving it unsolved whether or not the uptake system was responsible for the fast compensation in neuronal GABA after stimulation. The GABA-A antagonist bicucilline (50 microM) was ineffective when infused locally in the ventromedial thalamus, but prolonged the increase in neuronal GABA release after nigral stimulation; the GABA levels were increased during two 3-min samples to approximately 165%, indicating a functional role for GABA-A receptors in regulating the release of GABA from nigrothalamic GABAergic neurons. The GABA-B receptor antagonist CGP 35348 (50 microM) did not affect GABA levels when infused locally in the ventromedial thalamus and neither affected the response in neuronal GABA after stimulation. This finding does not support a role for GABA-B receptors in controlling the release from the nigrothalamic neurons.

Animals↗
PubMed1997

Brain microdialysis of GABA and glutamate: what does it signify?

Microdialysis has become a frequently used method to study extracellular levels of GABA and glutamate in the central nervous system. However, the fact that the major part of GABA and glutamate as measured by microdialysis does not fulfill the classical criteria for exocytotic release questions the vesicular origin of the amino acids in dialysates. Glial metabolism or reversal of the (re)uptake sites has been suggested to be responsible for the pool of nonexocytotically released amino-acid transmitters that seem to predominate over the neuronal exocytotic pool. The origin of extracellular GABA and glutamate levels and, as a consequence, the implications of changes in these levels upon manipulations are therefore obscure. This review critically analyzes what microdialysis data signify, i.e., whether amino-acid neurotransmitters sampled by microdialysis represent synaptic release, carrier-mediated release, or glial metabolism. The basal levels of GABA and glutamate are virtually tetrodotoxin- and calcium-independent. Given the fact that evidence for nonexocytotic release mediated by reversal of the uptake sites as a release mechanism relevant for normal neurotransmission is so far limited to conditions of "excessive stimulation," basal levels most likely reflect a nonneuronal pool of amino acids. Extracellular GABA and glutamate concentrations can be enhanced by a wide variety of pharmacological and physiological manipulations. However, it is presently impossible to ascertain that the stimulated GABA and glutamate in dialysates are of neuronal origin. On the other hand, under certain stimulatory conditions, increases in amino-acid transmitters can be obtained in the presence of tetrodotoxin, again suggesting that aspecific factors not directly related to neurotransmission underlie these changes in extracellular levels. It is concluded that synaptic transmission of GABA and glutamate is strictly compartmentalized and as a result, these amino acids can hardly leak out of the synaptic cleft and reach the extracellular space where the dialysis probe samples.

Animals↗