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B D Kretschmer

Publications and source records attributed to B D Kretschmer.

At least 19 recordsLinked to original sources
PubMed2005

Modulation of ventral pallidal dopamine and glutamate release by the intravenous anesthetic propofol studied by in vivo microdialysis.

The intravenous anesthetic propofol is reported to have various psychological side effects as hallucinations, sexual disinhibition, or euphoria. Hedonic and rewarding states like these are modulated by the dopaminergic system in the nucleus accumbens, prefrontal cortex and also in the ventral pallidum and by the glutamatergic system in the neocortex and limbic system. In the present study, propofol was administered either alone or in combination with the GABAA receptor antagonist bicuculline via reverse microdialysis into the ventral pallidum of freely moving rats. Dialysis fractions were taken every 20 min and analyzed for dopamine and glutamate using high performance liquid chromatography. Application of propofol decreased dopamine levels in the ventral pallidum. This effect seems to be mainly mediated through GABAA receptors, since it was compensated by the GABAA receptor antagonist bicuculline. Propofol and propofol plus bicuculline exerted no effect on glutamate release in this brain region. The reduced dopamine release in ventral pallidum was most probably mediated through a GABAergic feedback loop from the ventral pallidum via the nucleus accumbens to the dopaminergic neurons of the ventral tegmental area or by long loop feedback. As an increase but not a decrease of dopamine release in the ventral pallidum is involved in hedonic and rewarding properties, similar symptoms induced by propofol seem to be unrelated to an action of propofol in the ventral pallidum.

Anesthetics, Intravenous↗
PubMed2000

Role of the substantia nigra pars reticulata in sensorimotor gating, measured by prepulse inhibition of startle in rats.

The substantia nigra pars reticulata (SNR) is one of the major output nuclei of the basal ganglia. It connects the dorsal and ventral striatum with the thalamus, superior colliculus and pontomedullary brainstem. The SNR is therefore in a strategic position to regulate sensorimotor behavior. We here assessed the effects of SNR lesions on prepulse inhibition (PPI) of the acoustic startle response (ASR), stereotypy and locomotion in drug-free rats, as well as after systemic administration of the dopamine agonist DL-amphetamine (2 mg/kg), and the NMDA receptor antagonists dizocilpine (0.16 mg/kg) and CGP 40116 (2 mg/kg). SNR lesions reduced PPI, enhanced spontaneous sniffing and potentiated the locomotor stimulation by dizocilpine and CGP 40116. PPI was impaired by dizocilpine and CGP 40116 in controls. The ASR was enhanced in controls by dizocilpine and amphetamine. SNR lesions prevented the enhancement of the ASR by amphetamine. A second experiment tested the hypothesis that the SNR mediates PPI via a GABAergic inhibition of the startle pathway. Infusion of the GABA(B) antagonist phaclofen but not the GABA(A) antagonist picrotoxin into the caudal pontine reticular nucleus reduced PPI. Hence, lesion of the SNR reduces sensorimotor gating possibly by elimination of a nigroreticular GABAergic projection interacting with GABA(B) receptors. Moreover, destruction of the SNR enhances the motor stimulatory effects of amphetamine and of the NMDA antagonists dizocilpine and CGP 40116. We conclude that the SNR exerts a tonic GABAergic inhibition on sensorimotor behavior that is regulated by the dorsal and the ventral striatum.

2-Amino-5-phosphonovalerate↗
PubMed2000

NMDA receptor antagonist-induced dopamine release in the ventral pallidum does not correlate with motor activation.

The ventral pallidum is the output structure of the nucleus accumbens in the ventral corticostriato-thalamocortical loop. Information processing in this loop is critically involved in motor behavior and reinforcement. The ventral pallidum receives a direct dopaminergic input from the ventral tegmental area, but also glutamatergic input from cortical and limbic areas. It has been assumed that dopamine release in the VP is indeed modulated by glutamate. The present study investigated the effects of NMDA receptor blockade on motor behavior and dopamine release in the ventral pallidum. In a first experiment, rats were implanted with microdialysis probes in the ventral pallidum and were systemically injected or locally perfused via the microdialysis probe with dizocilpine (0.32 mg/kg, 10 and 100 microM, respectively). Effects on dopamine and on locomotion were simultaneously monitored. In a second experiment, ventral pallidum was lesioned by quinolinic acid and the effects of systemic dizocilpine (0.08 and 0.16 mg/kg) on locomotion and stereotyped sniffing behavior were determined. It was found that systemic and local dizocilpine administration increased dopamine release in the ventral pallidum to a similar extent whereas only systemic treatment was accompanied by locomotor stimulation. Lesion of the ventral pallidum did not affect locomotion and stereotyped sniffing behavior induced by systemic dizocilpine treatment. Thus, DA release in the ventral pallidum that is elevated by blockade of NMDA receptors is not relevant for activation of motor behavior.

Animals↗
PubMed2000

Functional aspects of the ventral pallidum.

The ventral pallidum is part of the corticoaccumbo-thalamocortical loop of the basal ganglia. In the past the function of this structure was discussed as a pure relay station in the process of limbic-motor integration. Some recent studies, however, underline that on the level of the ventral pallidum motor behavior can be modulated. The stimulation and inhibition of the different transmitter systems that converge in the ventral pallidum (dopamine, glutamate, GABA, neuropeptides) have implications in repetitive-, disinhibited-, learning- and reinforced behavior. The present review summarizes available data of these parameter related to this behavior, i.e. locomotion, reward-related behavior, prepulse inhibition, memory and neurochemistry.

Animals↗
PubMed2000

Effect of intracerebral administration of NMDA and AMPA on dopamine and glutamate release in the ventral pallidum and on motor behavior.

The present study investigates the modulation of the ventral tegmental area (VTA)-ventral pallidum (VP) dopaminergic system by glutamate agonists in rats. The glutamate receptor agonists N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) were infused via reversed microdialysis into the VTA, and dopamine (DA), glutamate, and aspartate levels in the VTA and ipsilateral VP were monitored together with motor behavior screened in an open field. NMDA (750 microM) infusion, as well as AMPA (50 microM) infusion, induced an increase of DA and glutamate levels in the VTA, followed by an increase of DA levels in the ipsilateral VP and by enhanced locomotor activity. The increase of DA in the VP was similar after administration of these two glutamate agonists, although motor activity was more pronounced and showed an earlier onset after NMDA infusion. Glutamate levels in the VP were not increased by the stimulation of DA release. It is concluded that DA is released from mesencephalic DA neurons projecting to the VP and that these neurons are controlled by glutamatergic systems, via NMDA and AMPA receptors. Thus, DA in the VP has to be considered as a substantial modulator. Dysregulation of the mesopallidal DA neurons, as well as their glutamatergic control, may play an additional or distinct role in disorders like schizophrenia and drug addiction.

Animals↗
PubMed1999

State-dependent blockade of haloperidol-induced sensitization of catalepsy by MK-801.

NMDA receptor antagonists have been shown to block several forms of neural and behavioural plasticity. The prototypical and most widely-used noncompetitive NMDA receptor antagonist is dizocilpine (MK-801). Here we have examined the effect of MK-801 on the context-dependent augmentation ('sensitization') of catalepsy in rats which develops with repeated administration of haloperidol. It was found that over a 7-day treatment period animals receiving haloperidol (0.25 or 0.5 mg/kg) plus MK-801 (0.16 mg/kg) showed a context-dependent day-to-day increase in catalepsy similar to animals that received haloperidol alone. However, when all animals were treated with haloperidol alone on day 8 of the experiment, animals that had received haloperidol plus MK-801 before displayed a much smaller cataleptic response, similar to that observed in the haloperidol group on the first treatment day, i.e. the previously-established enhancement of catalepsy was no longer expressed. These results may be explained in terms of state-dependency effects induced by MK-801. Implications of these findings for the clinical use of NMDA receptor antagonists in the treatment of Parkinson's disease are discussed.

Animals↗
PubMed1999

Modulation of the mesolimbic dopamine system by glutamate: role of NMDA receptors.

Glutamate has been shown to modulate motor behavior, probably via N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors that are involved in the control of the mesolimbic dopamine (DA) system, that is, the ventral tegmental area (VTA)-nucleus accumbens (NAC). In the present study, we investigated the effects of uncompetitive (MK-801) and competitive [DL-2-amino-5-phosphonopentanoic acid (AP-5), CGP 40116] NMDA receptor antagonists and NMDA and AMPA on DA release in the mesolimbic system and on motor behavior. Systemic injection and intrategmental infusion of MK-801 increased DA levels in the VTA, but the systemic administration enhanced DA exclusively in the NAC and increased motor behavior. In contrast, intrategmental infusion of AP-5, but not the systemic administration of its lipophilic analogue CGP 40116, decreased the DA release in the two regions without affecting motor behavior. NMDA and AMPA infusion into the VTA increased DA levels in both areas. This increase was accompanied by a strong motor behavioral stimulation after NMDA but only a moderate increase after AMPA infusion. The present results indicate that mesolimbic DA neurons are controlled by the glutamatergic system and that the effects of uncompetitive and competitive NMDA receptor antagonists on DA release are mediated by an interaction with different brain areas. These findings may account for the different effects of NMDA receptor ligands on motor behavior.

2-Amino-5-phosphonovalerate↗
PubMed1999

Spatial learning deficit after NMDA receptor blockade and state-dependency.

The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) (0.08 and 0.12 mg/kg, i.p.) was used to examine whether spatial memory is learned state-dependently. Rats pre-treated with drug or saline were trained for 9 days in an eight-arm radial maze, in which four arms were baited. On the tenth day MK-801-treated rats were injected with saline and one group of saline-treated rats were injected with MK-801 (0.12 mg/kg) while another received saline. Performance of spatial memory was analysed for state-dependency. Neither rats treated with 0.08 mg/kg nor 0.12 mg/kg of MK-801 for 9 days were impaired in recall of spatial memory under saline. However, MK-801 impaired acquisition of spatial memory, with deficits in working memory and less marked deficits in reference memory. Motor activity (speed) was enhanced at both doses. Thus, learning under NMDA receptor blockade does not necessarily produce a condition that impedes the expression of the learning task under a different condition.

Animals↗
PubMed1998

The ventral pallidum mediates disruption of prepulse inhibition of the acoustic startle response induced by dopamine agonists, but not by NMDA antagonists.

Prepulse inhibition (PPI) of the acoustic startle response is observed when the startling noise pulse is preceded by a weak, non-startling stimulus. PPI has been considered as a measure for sensorimotor gating mechanisms. Disruption of PPI can be found in schizophrenic patients as well as after blockade of NMDA receptors or stimulation of dopamine receptors in rats. The neuronal circuitry which regulates PPI consists of cortico-limbic brain structures where the nucleus accumbens (NAC) plays a key role. The NAC exerts its modulating effects on PPI by way of a projection from the ventral pallidum (VP) to the pedunculopontine tegmental nucleus (PPTg). We recently postulated that the reduction of PPI by intra-NAC infusion of glycine-site NMDA antagonists is not mediated by the VP. We tested here this hypothesis in rats with excitotoxic lesions of the VP which were systemically treated with apomorphine or MK-801 or received intraNAC infusions of dopamine or the glycine-site NMDA antagonist 7-chlorokynurenic acid. Lesioned rats showed a marked deficit in PPI after MK-801 and 7-chlorokynurenate treatment but not after apomorphine or dopamine injection, in contrast to sham-lesioned controls showing deficits in PPI under all conditions. These data provide behavioral evidence for the existence of a pathway which does not include the VP for the mediation of sensorimotor gating deficits. We propose that a direct connection between the NAC and PPTg may be responsible for the effects of NMDA/glycine receptor blockade, whereas the VP is an indispensable relay for the disruptive effects on PPI exerted by the NAC dopamine system.

Acoustic Stimulation↗
PubMed1998

Ligands of the NMDA receptor-associated glycine recognition site and motor behavior.

Motor behavior critically depends on glutamatergic functions in the basal ganglia (BG). The dorsal and ventral striatum--the main input structures of the BG--are involved in modulation of stereotyped sniffing behavior, locomotion, catalepsy and prepulse inhibition. The effects of the NMDA receptor have been well characterized in respect to motor behavior in the past. The function of the allosteric glycine site was however disregarded until now, because brain penetrating ligands were missing. The present study summarized the motor behavioral profile of several glycine site ligands (7-chlorokynurenate, ACEA 1021, MRZ-2/576, (+) HA-966, D-cycloserine and felbamate). It is shown that through blockade of the glycine site of the NMDA receptor a distinct behavioral profile can be obtained.

Animals↗
PubMed1998

Riluzole, a glutamate release inhibitor, and motor behavior.

Riluzole (2-amino-6-trigluoromethoxy benzothiazole) has neuroprotective, anticonvulsant, anxiolytic and anesthetic qualities. These effects are mediated by blockade of glutamate transmission, stabilizing of sodium channels and blockade of gamma-aminobutyric acid (GABA) reuptake. The action profile of riluzole is dominated by its effects on glutamate transmission which are predominately mediated by N-methyl-D-aspartate (NMDA) receptor-linked processes in vitro. In vivo studies show that blockade and stimulation of the different NMDA receptor complex binding sites or AMPA receptors modulate motor behavior in a characteristic manner. It was therefore interesting to examine if blockade of glutamatergic transmission by riluzole induced similar behavioral effects as direct NMDA/AMPA receptor antagonists and if these effects are mediated by a specific receptor. The effects of riluzole alone and in combination with several other neuroactive compounds on the central nervous system was assessed by behavioral paradigms to evaluate sniffing behavior, locomotion, ataxia and rigidity. Accompanying compounds included the NMDA receptor agonist NMDA, the partial glycine site agonist D-cycloserine (DCS), and the alpha-amino-3-hydroxy-5-phenyl-4-isoxazolepropionic acid (AMPA) receptor antagonist GYKI 52466 [1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzo-diazepine HCl]. Riluzole influenced neither stereotyped sniffing behavior nor locomotion but impaired motor coordination and attenuated rigidity induced by blockade of dopamine D1 and D2 receptor antagonists when given alone. At higher doses spontaneous behavioral activity decreased and motor coordination was more impaired. Augmentation of the riluzole effects were observed when NMDA, but not GYKI 52466, was coadministered. The glycine site agonist DCS increased the anticataleptic properties of riluzole. The results indicate that when given alone, riluzole has a behavioral profile resembling that of competitive NMDA receptor antagonists. However, coadministration of riluzole with NMDA/AMPA receptor ligands suggests that this assumption is incorrect, and that riluzole affects glutamatergic transmission by a more indirect mechanism. Nevertheless, the profile of riluzole together with its pre- and postsynaptic blockade of glutamatergic transmission implies beneficial properties in diseases where an overactive glutamate system induces chronic neurotoxicity and/or acute behavioral effects.

Animals↗
PubMed1997

ACEA 1021, a glycine site antagonist with minor psychotomimetic and amnestic effects in rats.

Antagonists of the allosteric glycine site of the NMDA receptor complex have been suggested to be beneficial in the treatment of neurodegenerative disorders. However, unwanted side effects like psychomotor stimulation and amnesia must be expected. ACEA 1021 (5-nitro-6,7-dichloro-1,4-dihydroquioxaline-2,3dione) is one of the first high-selective glycine site antagonists which passes the blood-brain barrier and which has promising anticonvulsive and neuroprotective properties. In the present study the effects of ACEA 1021 (5, 7.5, 8, 10, 15 and 20 mg/kg i.p.) on sniffing stereotypy, locomotor activity, prepulse inhibition of the acoustic startle response, the anti-cataleptic properties and spatial learning were tested. Only 7.5 mg/kg ACEA 1021 induced a sniffing stereotypy which was antagonized by the partial glycine site agonist D-cycloserine (D-4-amino-3-isoxazolidinone). ACEA 1021 had neither an effect on motor behavior measured in the open field nor on the acoustic startle response in the prepulse inhibition paradigm nor on the acquisition of spatial learning in the 8-arm-radial maze. Anti-cataleptic properties of ACEA 1021 in dopamine D2 (haloperidol (4'fluoro-4-(1-(4-hydroxy-4-p-chlorophenyl-piperidino)-butyrophe non)) or D1 (SCH 23390 (7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaze pin e hydrochloride)) receptor antagonist-pretreated rats were only minor. Thus, ACEA 1021 is a glycine site antagonist with minimal psychotomimetic side effects and with no amnesia properties. However, it has only minor anti-parkinsonian effects.

Amnesia↗
PubMed1997

Role of the strychnine-insensitive glycine binding site in the nucleus accumbens and anterodorsal striatum in sensorimotor gating: a behavioral and microdialysis study.

This study examined the role of the strychnine-insensitive glycine binding site of the NMDA receptor in prepulse inhibition (PPI) of the acoustic startle response (ASR) in rats. PPI is an operational measure of gating processes which normally lead to a diminished ASR when a startling stimulus is preceded by a weak prepulse. PPI is impaired in schizophrenics and, therefore, experimentally induced PPI deficits in rats can be regarded as a model for gating deficits in schizophrenia. Local administration of 7-chlorokynurenate (7-CLKYN), an antagonist of the strychnine-insensitive glycine site of the NMDA receptor, into the nucleus accumbens reduced PPI. This sensorimotor gating deficit was antagonized by systemic pretreatment of the rats with the glycine site agonist D-cycloserine, indicating that the effect of 7-CLKYN was due to a blockade of the NMDA receptor associated glycine binding site. A similar deficit in PPI was observed after intra-accumbal administration of the competitive NMDA receptor antagonist AP-5. PPI was normal after injecting these drugs into the anterodorsal striatum. The hypothesis that the PPI deficit is accompanied by a change in dopamine release was tested by a neurochemical analysis of the effects of local injection of 7-CLKYN. Microdialysis data showed no increase of accumbal and striatal dopamine release after blockade of the glycine site with 7-CLKYN. Our data demonstrate that the glycine/NMDA receptor in the nucleus accumbens plays a important role in sensorimotor information processing that depends not on a hyperactive dopamine system.

Animals↗
PubMed1997

Behavioural pharmacology of glutamate receptors in the basal ganglia.

Glutamate receptors play a major role in the transmitter balance within the basal ganglia (BG). N-methyl-D-aspartate (NMDA) receptor stimulation within the striatum acts behaviourally depressant while intrastriatal as well as systemic administration of NMDA receptor-antagonists have rather stimulatory effects despite the different profiles of non-competitive-, competitive NMDA receptor- and glycine site-antagonists. In animal models of Parkinson's disease all these NMDA receptor antagonists counteract parkinsonian symptoms or act synergistically with L-3,4-dihydroxyphenylalanine (L-DOPA). The strong locomotion-inducing effect of the non-competitive NMDA receptor antagonists is partly, but not fully, mediated by a dopamine (DA) release in the nucleus accumbens. Manipulations at alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors produce poor behavioural effects. These, however, are different or even opposed to NMDA receptor mediated effects. Local infusions of AMPA receptor-antagonists into the BG output nuclei have an anti-parkinsonian effect but systemic injections are ineffective. These drugs even counteract the anti-parkinsonian effect of DA agonists and of non-competitive NMDA receptor antagonists as well as the DA releasing effects of the latter drugs. Only few data on the role of metabotropic receptors exist but the different receptor subtypes with different regional distribution represent a promising target for pharmacological interventions.

Animals↗
PubMed1996

Behavioral effects mediated by the modulatory glycine site of the NMDA receptor in the anterodorsal striatum and nucleus accumbens.

The striatum and the nucleus accumbens are the main input structures of the basal ganglia (BG). They contribute differently to motor behavior controlled by the BG in rats, e.g., stereo-typed behavior, catalepsy, and locomotion. Whereas the striatum is predominantly involved in the control of sniffing behavior and catalepsy, the nucleus accumbens contributes to control of locomotion. To test whether the allosteric glycine site of the NMDA receptor complex modulates these behavioral variables, we injected the glycine-site antagonist 7-chlorokynurenate and the glycine-site agonist D-serine into the anterodorsal striatum and the nucleus accumbens and studied their influence on stereotypical snout contacts and locomotion. Additionally, the effects of intrastriatal injections of 7-chlorokynurenate on haloperidol- and SCH 23390-induced catalepsy were investigated. 7-Chlorokynurenate enhanced stereotypical snout contacts in the anterodorsal striatum and in the nucleus accumbens but did not change spontaneous locomotion in either of these structures. Haloperidol- but not SCH 23390-induced catalepsy was attenuated by intrastriatally administered 7-chlorokynurenate. The glycine-site agonist D-serine had no effect on stereotypical snout contacts and locomotion. The results suggest that motor behavior mediated by the striatopallidal output pathway is modulated by the glycine site, whereas motor behavior mediated by the accumbopallidal and striatonigral output pathway is not.

Animals↗
PubMed1995

Behavioral and neurochemical actions of the strychnine-insensitive glycine receptor antagonist, 7-chlorokynurenate, in rats.

The present study investigated if blockade of the modulatory glycine receptor of the NMDA receptor complex influences the expression of behavior (sniffing stereotypy and locomotion) and dopamine metabolism in rats as it has been shown for NMDA receptor antagonists. The glycine receptor antagonist, 7-chlorokynurenate (7-chloro-4-hydroxyquinoline-2-carboxylic acid), induced a dose-dependent sniffing stereotypy but had no effect on locomotion when it was given i.c.v. The glycine receptor agonist, D-cycloserine (D-4-amino-3-isoxazolidinone), antagonized the sniffing stereotypy. 7-Chlorokynurenate had no influence on dopamine metabolism in the striatum and the nucleus accumbens, but moderately decreased the metabolism in the prefrontal cortex. Comparison of behavioral and neurochemical outcomes suggests that the failure to induce locomotion correlates with the unchanged dopamine metabolism in the basal ganglia, while sniffing stereotypy does not. These results show that blockade of the glycine receptor of the NMDA receptor complex induces a behavioral and neurochemical profile similar to that of competitive NMDA receptor antagonists.

Animals↗
PubMed1994

Felbamate, an anti-convulsive drug, has anti-parkinsonian potential in rats.

The potency of felbamate, an anti-convulsive drug, to influence dopamine D1 (SCH 23390) and D2 (haloperidol) receptor-mediated catalepsy (akinesia and bradykinesia) was studied in rats. In the catalepsy test, felbamate antagonized dopamine D2 receptor- but not D1 receptor-induced akinesia. Bradykinesia in the open field was never influenced. The results demonstrate that felbamate has similar anti-parkinsonian potential as glycine site antagonists blocking the N-methyl-D-aspartate (NMDA) receptor complex.

Animals↗