Beate D. Kretschmer

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 Parkinsons 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.

Modulation of the mesolimbic dopamine system by glutamate : Role of NMDA receptors

Abstract : Glutamate has been shown to modulate motor behavior, probably via N‐methyl‐d‐aspartate (NMDA) and α‐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.

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.

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.

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 γ-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 α-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.

The contribution of the different binding sites of the N-methyl-D-aspartate (NMDA) receptor to the expression of behavior.

The effects of competitive (CGP 37849 and CGP 39551) and noncompetitive (dizocilpine) N-methyl-D-aspartate (NMDA) antagonists were tested in three animal models (catalepsy, sniffing, locomotion) and, in addition, the modulation of these effects by an agonist of the strychnine-insensitive glycine binding site was investigated. Both competitive and non-competitive NMDA antagonists reduced neuroleptic-induced catalepsy. Weak sniffing was induced by the competitive antagonist but strong sniffing by the non-competitive NMDA antagonist. Due to muscle relaxation the competitive antagonist reduced locomotion, in contrast to stimulation of locomotor activity induced by the noncompetitive NMDA antagonist. The glycine agonist (D-cycloserine) potentiated the effects of the non-competitive but antagonized those of the competitive NMDA antagonist.

Anticataleptic potencies of glutamate-antagonists.

SummaryThe anticataleptic effects of non-competitive and competitive NMDA antagonists as well as those of an agonist at the allosteric glycine binding site of the NMDA receptor were tested in the catalepsy model. Some of these drugs were further tested in a reaction time task demanding rapid locomotor initiation. The results show that the non-competitive NMDA antagonists dizocilpine and memantine as well as the competitive antagonists CGP 39551, CGP 37849 and CPPene antagonized dopamine D2 receptor mediated catalepsy induced by haloperidol. D-cycloserine, a partial glycine agonist per se had no effects, but it enhanced the anticataleptic effects of dizocilpine when coadministered. However, the effects of CGP 37849 were abolished. Dopamine D1 receptor mediated catalepsy induced by SCH 23390 was antagonized by dizocilpine, memantine, CPPene, but not by CGP 37849. In the reaction time task dizocilpine, memantine and CGP 37849 were tested for their anti-akinetic and anti-bradykinetic potencies. All these compounds improved haloperidolinduced slowing of reaction time. However, they acted differentially on haloperidol-induced slowing of movement execution and decreased initial acceleration. Thus, antagonists at the NMDA receptor may have a therapeutic potential in the treatment of Parkinsons disease. Their potency can be manipulated specifically at the glycine binding site.

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 Parkinsons disease are discussed.

Effects of ibotenate pedunculopontine tegmental nucleus lesions on exploratory behaviour in the open field

The pedunculopontine tegmental nucleus (PPTg) as part of the mesencephalic locomotor region is discussed to be involved in motor activity. In this study, we examined whether the PPTg plays a role in exploratory behaviour. Therefore, we compared non-habituated motor behaviour of PPTg lesioned rats with sham lesioned rats under spontaneous, dizocilpine (MK-801) (0.1 and 0.16 mg/kg) and dl-amphetamine (1 and 2 mg/kg) conditions. In order to analyse exploratory behaviour only, session-times were limited to 5 min after placing the rats in an open field. The exploratory motor activity was compared to the motor activity obtained in rats habituated to the environment. PPTg lesions had no effect on spontaneous exploratory behaviour, but it intensified the enhanced motor activity induced by MK-801. However, PPTg lesions blocked the enhanced exploratory behaviour, i.e. horizontal activity, rearing and centre activity induced by amphetamine. These data indicate that the PPTg is involved in behaviour driven by the dopaminergic and glutamatergic systems, when the animals are in a particular motivational state, e.g. a state that increases motor activity for itself, like exploration. This is underlined by the finding that animals exploring their environment show a higher motor activity even after multiple sessions, than animals familiar to the environment.

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

Abstract 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.