Reversal of levodopa-induced motor fluctuations in experimental parkinsonism by NMDA receptor blockade.

Dopaminoceptive system alterations in the basal ganglia have been implicated in the pathogenesis of wearing-off fluctuations that complicate levodopa therapy of Parkinson's disease. To evaluate the contribution of glutamatergic mechanisms to the associated changes in striatal efferent pathway function, we examined the ability of N-methyl-D-aspartate (NMDA) receptor blockade to modify the motor response changes produced by chronic levodopa administration to hemiparkinsonian rats. Unilaterally 6-hydroxydopamine lesioned rats, given levodopa/benserazide (25/6.

MK-801 reverses effects of chronic levodopa on D1 and D2 dopamine agonist-induced rotational behavior.

The effect of dizocilpine (MK-801) on dopaminergic agonist-induced rotational behavior was investigated in rats with 6-hydroxydopamine lesions of the nigrostriatal pathway after chronic administration of levodopa. The rotational response to the D2 agonist quinpirole was markedly increased in levodopa-treated animals compared with rats chronically administered saline. The increase in responsiveness to quinpirole was reversed by co-administered MK-801.

NMDA receptor blockade reverses motor response alterations induced by levodopa.

Motor fluctuations that ultimately complicate the response of most parkinsonian patients to levodopa therapy might represent a form of behavioral or neuronal plasticity. Since various forms of neuronal plasticity appear to be mediated by glutamate transmission through the N-methyl-D-aspartate (NMDA) receptor, the effect of NMDA receptor blockade on the development of alterations in the motor response to chronic levodopa was evaluated in hemiparkinsonian rats. Repeated levodopa administration decreased rotational behavior induced by a D1 dopamine receptor agonist, increased D2 agonist-induced rotation and progressively reduced the duration of the motor response to levodopa itself.

Excitatory amino acid receptor antagonists modify regional cerebral metabolic responses to levodopa in 6-hydroxydopamine-lesioned rats.

Excitatory amino acid receptor antagonists have been proposed as novel therapeutic agents to be used with levopoda in the treatment of Parkinson's disease. We examined the neural substrates for the interaction between levodopa and antagonists of either the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid or N-methyl-D-aspartate type of excitatory amino acid receptor using 2-deoxyglucose autoradiography. Thus, we compared the effects of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (10 mg/kg, i.

Influence of previous exposure to levodopa on the interaction between dizocilpine and dopamine D1 and D2 agonists in rats with 6-hydroxydopamine-induced lesions.

The potential antiparkinson activity of N-methyl-D-aspartate antagonists was investigated by examining the effects of dizocilpine (MK-801) on rats with 6-hydroxydopamine-induced lesions of the nigrostriatal pathway. MK-801, when administered alone to these animals, elicited ipsilateral rotation, which could be blocked by haloperidol. MK-801, at doses that did not produce rotation when given alone, inhibited the contralateral rotation produced by the D2 receptor agonist quinpirole but had no effect on the rotation induced by the D1 agonist SKF 38393 [(+-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8- diolhydrochloride].

Behavioral and electrophysiological comparison of ketamine with dizocilpine in the rat.

We have compared the effects of MK 801 and ketamine on a measure of anesthesia (loss of righting reflex) and two measures of basal ganglia dopamine (DA) function: apomorphine (APO)-induced stereotypy and APO-induced excitation of type II globus pallidus (GP) neurons. As expected, ketamine induced anesthesia. High-dose MK 801 administered IP induced ataxia, but not anesthesia.

N-methyl-D-aspartate receptor blockade differentially modifies regional cerebral metabolic responses to D1 and D2 dopamine agonists in rats with a unilateral 6-hydroxydopamine lesion.

Dopamine and the excitatory amino acids play important roles in the control of motor behavior by the basal ganglia; elucidating the manner in which these transmitter systems interact may provide new therapeutic approaches to the treatment of movement disorders such as Parkinson's disease. The 2-deoxyglucose autoradiographic technique was used to examine the effect of N-methyl-D-aspartate receptor blockade on regional cerebral metabolic responses to D1 and D2 dopamine receptor stimulation in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway. The D1 agonist SKF 38393 (5 mg/kg, i.

Opposite effects of NMDA and AMPA receptor blockade on catalepsy induced by dopamine receptor antagonists.

Excitatory amino acid antagonists have been proposed as novel therapeutic agents for Parkinson's disease due to their ability to reverse akinesia in animal models of this disorder. To further evaluate this therapeutic potential, we examined the effects of a N-methyl-D-aspartate (NMDA) and an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist on catalepsy produced by dopamine D1 or D2 receptor antagonists in rats. Male Sprague-Dawley rats were injected with dizocilpine (MK-801 0.

NBQX inhibits AMPA-induced locomotion after injection into the nucleus accumbens.

The role of glutamate receptors in locomotor activity was investigated by examining the ability of 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX), a non-NMDA antagonist, to inhibit the stimulation of locomotion produced by the activation of various excitatory amino acid receptors in the nucleus accumbens. NBQX inhibited the stimulation of locomotor activity produced by intra-accumbens alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) at doses which had no effect on the locomotion produced by kainate or NMDA. Furthermore, this dose of NBQX had no effect on locomotion when injected alone into this brain region.

Dopaminergic modulation of striatal neuropeptides: differential effects of D1 and D2 receptor stimulation on somatostatin, neuropeptide Y, neurotensin, dynorphin and enkephalin.

Dopaminergic modulation of neuropeptides in rat striatum was investigated by examining the effects of prolonged D1 or D2 receptor stimulation on levels of somatostatin, neuropeptide Y, neurotensin, dynorphin and enkephalin. Rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway were treated for 7 days with either the D1 agonist SKF 38393 (12.5 mg/kg/day) or the D2 agonist quinpirole (1 mg/kg/day).

Stimulation of locomotor activity by intra-accumbens AMPA is not inhibited by neonatal 6-hydroxydopamine-induced lesions.

The involvement of dopamine in the hypermotility responses to amphetamine s.c. or AMPA injected into the nucleus accumbens was evaluated in adult rats depleted of dopamine as neonates with 6-hydroxydopamine.

Deprenyl effects on levodopa pharmacodynamics, mood, and free radical scavenging.

Clinical evidence suggests that deprenyl may slow progression of Parkinson's disease, although mechanisms underlying this putative neuroprotective action remain poorly understood. To address this issue, we studied deprenyl in 12 parkinsonian patients using a single-blind, placebo-controlled, crossover design. After 1 month, deprenyl (10 mg/d) decreased the optimal levodopa requirement by 24% (oral) and 16% (intravenous).

The role of endogenous dopamine in the hypermotility response to intra-accumbens AMPA.

The present study was designed to investigate the role of dopamine in the locomotor stimulant response produced by the bilateral administration of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) into the nucleus accumbens. The hypermotility produced by lower doses of AMPA (up to 0.25 microgram) was inhibited by either SCH23390 or sulpiride, a D1 and D2 receptor antagonist, respectively.

The kappa-opioid receptor agonist spiradoline differentially alters the rotational response to dopamine D1 and D2 agonists.

The effect of the selective kappa-opioid agonist, spiradoline, on rotational behavior induced by a dopamine D1 or D2 agonist was examined in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway. Spiradoline reduced the rotational response to the D1 agonist SKF 38393 in a dose-dependent manner. Spiradoline had no effect on the total number of turns elicited by the D2 agonist quinpirole, but did alter the pattern of quinpirole-induced rotation at the highest dose tested.

The importance of dopaminergic neurotransmission in the hypermotility response produced by the administration of N-methyl-D-aspartic acid into the nucleus accumbens.

The bilateral injection of N-methyl-D-aspartic acid (NMA) into the nucleus accumbens of rats has been shown to stimulate locomotor activity. This response is antagonized by drugs that interfere with dopaminergic neurotransmission, such as reserpine, alpha-methyl-p-tyrosine (AMPT) and haloperidol, suggesting that NMA may exert its effects by stimulating the release of dopamine (DA) from nerve terminals. To test this hypothesis, the ability of NMA to release endogenous DA from slices of nucleus accumbens, which were incubated in magnesium-free medium was evaluated.

Effect of permanently charged and uncharged dopaminergic agonists on the potassium-induced release of [3H]acetylcholine from striatal slices.

The effects of chemical analogs of dopamine, which are permanently charged or which lack a net positive charge, on the potassium-evoked release of [3H]acetylcholine from mouse striatal slices were studied in order to determine whether a positive charge on the dopamine agonist molecule is required to activate dopaminergic receptors. The striatal slices were first preincubated with [3H]choline, transferred to a superfusion chamber, and then superfused in physiological medium. [3H]Acetylcholine release was evoked by exposure of the slices to a high potassium medium and potential dopamine agonist drugs were added to the medium 10 min before superfusing with high potassium.

Activation of excitatory amino acid receptors may mediate the folate-induced stimulation of locomotor activity after bilateral injection into the rat nucleus accumbens.

Folic acid (FA) and 5-formyltetrahydrofolic acid (FTHF) have been shown previously to produce a marked stimulation of locomotor activity after bilateral injection into the rat nucleus accumbens. This study was designed to determine whether the hypermotility response produced by the folates is mediated through the activation of excitatory amino acid receptors in the nucleus accumbens. Although FA stimulated locomotor activity, pteroic acid, a congener of FA that lacks the glutamate moiety, was ineffective, suggesting that the glutamate portion of the molecule is essential for the hypermotility response.

Behavioral effects of a dimethylsulfonium analog of dopamine after injection into the nucleus accumbens and the striatum.

We have previously synthesized a chemical analog of dopamine (DA) in which the amine group has been replaced by a permanently charged dimethylsulfonium group. In the present study, we have determined whether this compound can exert DA agonist activity in the nucleus accumbens by comparing its effects with those of DA. When DA was injected into the nucleus accumbens of rats pretreated with nialamide, a monoamine oxidase inhibitor, there was marked stimulation of locomotor activity.

Effect of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) on monoamine neurotransmitters in mouse brain & heart.

The effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was studied on dopamine (DA), norepinephrine (NE), serotonin (5HT) and gamma-aminobutyric acid (GABA) neurons in mouse brain and on NE neurons of mouse heart. MPTP (45 mg/kg) was administered s.c.