Free 3-nitrotyrosine causes striatal neurodegeneration in vivo.

Peroxynitrite formation has been demonstrated in several neurodegenerative disorders; thus far, protein nitration and consequent alterations in protein function are implicated as mechanistic events. Free 3-nitrotyrosine (free-3NT) is also elevated in these settings; a neurotoxic role for this modified amino acid has not been investigated. We tested the hypothesis that free-3NT is neurotoxic in vivo, using a mouse model of striatal degeneration.

NMDA antagonists block expression of sensitization of amphetamine- and apomorphine-induced stereotypy.

We have been studying sensitization of psychostimulant-induced stereotyped behavior in mice using both single and multiple pretreatment paradigms. In the present study, we tested whether NMDA receptor antagonists and an inhibitor of nitric oxide synthesis inhibit expression of sensitization in either of these models. Male CF-1 mice were pretreated with a single dose or with three daily doses of amphetamine (14 mg/kg) or apomorphine (40 mg/kg).

NMDA glutamate receptor role in the development of context-dependent and independent sensitization of the induction of stereotypy by amphetamine or apomorphine.

We have been studying sensitization of psychostimulant-induced stereotyped behavior in mice using both a context-dependent and a context-independent paradigm. In the present study, we tested whether N-methyl-D-aspartate (NMDA) receptor antagonists prevent development of sensitization in either of these models. Male CF-1 mice were pretreated with 20 mg/kg (+)3-(2-carboxypiperazine-4yl)-propyl-1-phosphonic acid (CPP), 0.

Importance of environmental context in the development of amphetamine- or apomorphine-induced stereotyped behavior after single and multiple doses.

The present study was designed to determine whether single and repeated pretreatment regimens with amphetamine or apomorphine differ in the context dependency of sensitization of stereotyped behavior. Male CF-1 mice that were pretreated with a single high dose of amphetamine (14 mg/kg, IP) or apomorphine (40 mg/kg, SC) only became sensitized to a lower test dose of amphetamine (7 mg/kg, IP) or apomorphine (3 mg/kg, SC) when placed in an environment that was the same as the pretreatment environment. However, animals pretreated with three high doses (24 h apart) of amphetamine (14 mg/kg, IP) or apomorphine (40 mg/kg, SC) did demonstrate sensitization to a lower test dose of amphetamine (7 mg/kg, IP) or apomorphine (3 mg/kg, SC) when placed in an environment that was different from the pretreatment environment.

Importance of environmental context in the development of amphetamine- or apomorphine-induced stereotyped behavior after single and multiple doses.

The present study was designed to determine whether single and repeated pretreatment regimens with amphetamine or apomorphine differ in the context-dependency of sensitization of stereotyped behavior. Male CF-1 mice that were pretreated with a single high dose of amphetamine (14 mg/kg intraperitoneally [IP]) or apomorphine (40 mg/kg subcutaneously [SC]) only became sensitized to a lower test dose of amphetamine (7 mg/kg IP) or apomorphine (3 mg/kg SC) when placed in an environment that was the same as the pretreatment environment. However, animals pretreated with 3 high doses (24-h apart) of amphetamine (14 mg/kg IP) or apomorphine (40 mg/kg SC) did demonstrate sensitization to a lower test dose of amphetamine (7 mg/kg IP) or apomorphine (3 mg/kg SC) when placed in an environment that was different from the pretreatment environment.

Sensitization of apomorphine-induced stereotyped behavior in mice is context dependent.

Rationale: The role of the environment in the sensitization of the stereotyped behavioral effects of apomorphine is unclear, since sensitization of this drug effect has either been difficult to demonstrate or has been shown to occur with a low but not a higher dose of apomorphine.

Objectives: The present study was designed to determine whether sensitization of the stereotyped behavioral effects induced by a single dose of apomorphine is dependent on environmental context.

Methods: CF-1 mice were pretreated with apomorphine or vehicle under different environmental conditions and tested for stereotyped behavior after apomorphine challenge.

Sensitization of stereotyped behavior to amphetamine is context and response dependent.

The present study was designed to determine whether the environmental context in which amphetamine is administered plays a role in the development of sensitization to the stereotyped behavioral effects of amphetamine in mice. In male CF-1 mice, the dose-response curve for stereotyped behavior elicited by amphetamine was shifted 1.9-fold to the left 48 h after pretreatment with 14 mg/kg amphetamine.

Dopaminergic agonists administered into the nucleus accumbens: effects on extracellular glutamate and on locomotor activity.

The hypothesis to be tested was that increased dopaminergic transmission induced by amphetamine in the nucleus accumbens results in increased glutamatergic neurotransmission in this brain area and that the increase in level of this neurotransmitter contributes to behavioral effects of psychostimulant drugs. Amphetamine (1 mg/kg, i. p.

Design and synthesis of enantiomers of 3,5-dinitro-o-tyrosine: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptor antagonists.

The R- and S-isomers of 3,5-dinitro-o-tyrosine (6a,b) have been synthesized through the use of chemoenzymatic synthesis and shown to bind differentially with the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA, 3) receptors. The phenolic functional group of these o-tyrosine analogues was designed to act as a bioisostere of the gamma-carboxyl group of glutamate. The S-isomer of 3,5-dinitro-o-tyrosine (6b) was 6.

Structure--activity studies for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid receptors: acidic hydroxyphenylalanines.

Antagonists of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptors may have therapeutic potential as psychotropic agents. A series of mononitro- and dinitro-2- and 3-hydroxyphenylalanines was prepared, and their activity compared with willardiine, 5-nitrowillardiine, AMPA, and 2,4,5-trihydroxyphenylalanine (6-hydroxydopa) as inhibitors of specific [3H]AMPA and [3H]kainate binding in rat brain homogenates. The most active compounds were highly acidic (pKa 3-4), namely, 2-hydroxy-3,5-dinitro-DL-phenylalanine (13; [3H]AMPA IC50 approximately equal to 25 microM) and 3-hydroxy-2,4-dinitro-DL-phenylalanine (19; [3H]AMPA IC50 approximately equal to 5 microM).

Differential effect of sensitizing regimen on induction of Fos-protein and locomotor activity elicited by apomorphine in rats.

At doses that elicit behavioral activation, apomorphine does not induce Fos-protein in the nucleus accumbens of control animals but does under conditions of denervation supersensitivity. The purpose of this study was to determine whether apomorphine induces Fos-protein in animals sensitized by repeated treatment with apomorphine and whether the magnitude of such induction parallels the magnitude of behavioral response observed after different sensitizing paradigms. Apomorphine did induce Fos-protein expression in animals pretreated with apomorphine; however, the rats showing highest levels of induction were not those showing the largest behavioral responses.

Comparison of sensitization elicited by amphetamine and pertussis toxin: characterization of locomotor behavior and limbic dopamine release.

1. Male, Sprague-Dawley rats were pretreated with one of several regimens of repeated, intermittent amphetamine or with a single-dose of intra-VTA pertussis toxin (PTX). 2.

Effects of repeated cocaine administration on sensory inhibition in rats: preliminary data.

We have recently reported that acute administration of cocaine to rats alters their sensory inhibitory capacity as tested in a paired click paradigm (S1/S2). Whether such acutely induced changes are persistent, is not known. In order to shed some light on the degree of spontaneous reversibility of cocaine-induced decreased sensory inhibition, rats were tested immediately after cocaine administration and 9 days after cessation of cocaine exposure.

Enhancement of the locomotor response to apomorphine in pertussis toxin-treated animals depends on the site of pertussis toxin injection into the ventral tegmental area.

The locomotor stimulant response to either systemic or intra-accumbens amphetamine was enhanced 1-2 weeks after pre-treatment with pertussis toxin (PTX) into any of 3 different sites in the ventral tegmental area (VTA). An enhanced response to either systemic or intra-accumbens apomorphine occurred only after pre-treatment into the central VTA. Thus, enhanced sensitivity to drugs of either pre- or post-synaptic elements in the nucleus accumbens may develop depending on the site of the PTX pre-treatment within the VTA.

Effect of pertussis toxin injected into the ventral tegmental area on amphetamine-induced Fos protein in the nucleus accumbens.

Amphetamine produces an enhanced locomotor stimulatory response in animals injected with pertussis toxin into the ventral tegmental area. This response is dependent on the activation of D1 receptors in the nucleus accumbens. The immediate early gene, c-Fos, has been used as a cellular marker for increases in dopamine neurotransmission in the nucleus accumbens.

Synthesis of chiral 1-(2'-amino-2'-carboxyethyl)-1,4-dihydro-6,7-quinoxaline-2,3-diones: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor agonists and antagonists.

Recently discovered 6,7-disubstituted quinoxaline-2,3-diones, 1, have been found to antagonize specific binding and functional responses to both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and kainic acid. Although a variety of studies have analyzed the activity of quinoxaline-2,3-diones with various substitutions at positions 6 and 7, there is little information regarding the effects of N-substitution. A racemic mixture of 1-(2'-amino-2'-carboxyethyl)-1,4-dihydroquinoxaline-2, 3-dione (QXAA, 2, R1 = R2 = H) has been synthesized from 1 (R1 = R2 = H).

Induction of locomotor activity by the glutamate antagonist DNQX injected into the ventral tegmental area.

DNQX, an antagonist of AMPA/kainate receptors, was injected into the ventral tegmental area (VTA) to test the hypothesis that AMPA/kainate receptors in this brain region might be involved in regulation of locomotor activity. Bilateral injection of 1 microgram DNQX into the VTA increased locomotor activity. In addition, unilateral injection of DNQX into this site produced contraversive turning, which was potentiated by coadministration of amphetamine (1 mg/kg, i.

Role of dopaminergic mechanisms in the stimulatory effects of MK-801 injected into the ventral tegmental area and the nucleus accumbens.

The bilateral administration of 10 micrograms of (+)MK-801, but not (-)MK-801, into either the VTA or the N.Ac. stimulated locomotor activity.

Spontaneous and drug-stimulated locomotor activity after the administration of pertussis toxin into the ventral tegmental area.

Pertussis toxin (PTX) injected into the ventral tegmental area (VTA) produces an enhanced locomotor response to amphetamine. In the present study, we have evaluated the role of dopamine receptors on spontaneous locomotor activity and the enhanced locomotor response to dopaminergic agonists after the administration of PTX into the VTA. PTX injected into the VTA of rats produced a delayed increase in spontaneous locomotor activity with a latency of 4 d.

DNQX in the nucleus accumbens inhibits cocaine-induced conditioned place preference.

Several lines of evidence suggest that activation of both AMPA/kainate receptors and dopaminergic receptors in the nucleus accumbens may be required for psychostimulant drug induced reward. However, it has been reported that dopaminergic antagonists fail to block acquisition of conditioned place preference to cocaine. The goal of these experiments was to determine whether AMPA receptor antagonist injected into the nucleus accumbens could block conditioned place preference elicited by cocaine under conditions where dopaminergic antagonists do not inhibit acquisition of place preference.

Interaction of permanently charged metoclopramide analogs with D-2 dopamine receptors.

1. The binding of permanently charged benzamides to the D-2 dopamine receptor of striatal membranes was compared with that of tertiary amine benzamides. 2.

Effects of cocaine on sensory inhibition in rats: preliminary data.

The purpose of this study was to determine the effect of cocaine on inhibitory sensory processing mechanisms in the brain. To accomplish this aim, recording electrodes were surgically placed into the vertex region of 12 rats. After recovery from surgery, rats were injected once daily for 5 days with either cocaine (20 mg/kg, IP) or saline.

The role of dopamine and AMPA/kainate receptors in the nucleus accumbens in the hypermotility response to MK801.

The purpose of this study was to evaluate the role of endogenous dopamine in the hypermotility response to MK801. The administration of MK801 (0.1 mg/kg, SC) to rats produced an intense stimulation of coordinated locomotor activity, which was not associated with stereotyped behavior.

AMPA/kainate antagonists in the nucleus accumbens inhibit locomotor stimulatory response to cocaine and dopamine agonists.

The purpose of this study was to determine whether AMPA/kainate excitatory amino acid receptors in the nucleus accumbens (NAc) play a role in the locomotor stimulation produced by cocaine and dopamine receptor agonists. The stimulation of locomotor activity produced by the systemic administration of cocaine was markedly attenuated by either the D1 receptor antagonist SCH23390 or the D2 receptor antagonist eticlopride administered directly into the NAc. This indicates that both dopaminergic receptor subtypes in the NAc are involved in the motor stimulant response to cocaine.

The interaction of ammonium, sulfonium, and sulfide analogues of metoclopramide with the dopamine D2 receptor.

A series of permanently charged ammonium and sulfonium analogues of metoclopramide as well as a permanently uncharged sulfide analogue were synthesized and evaluated for their ability to inhibit apomorphine-induced responses on mouse striatal slices. Three of the four permanently charged analogues were found to inhibit apomorphine's effects, although at higher concentrations than either metoclopramide or its dimethyl analogue. In contrast, the sulfide analogue was inactive at concentrations up to 100 microM.