Effects of

Repeated, intermittent administration of psychostimulants produces an enhancement of the subsequent behavioral effects of these drugs. This behavioral sensitization has been implicated in maintenance of and relapse to drug-taking. As a result, there has been great interest in elucidating the mechanisms underlying both the development and expression of sensitization. An accumulation of data from studies of stimulant-induced locomotor activity has implicated excitatory amino acids in the development of behavioral sensitization. In the present study, N-methyl-

Full-size image

-aspartate (NMDA) (0.6, 1.25 or 2.5 μg) infused bilaterally into the ventral tegmental area (VTA) produced dose-dependent locomotor activation. The locomotor activating effect of NMDA was increased following repeated NMDA administration (two exposures to intra-VTA NMDA), suggesting sensitization. However, repeated intra-VTA NMDA failed to sensitize rats to the locomotor activating effects of systemically administered cocaine (5.0, 10.0 or 20.0 mg/kg). These findings are consistent with the notion that repeated activation of NMDA receptors is sufficient for the development of behavioral sensitization to NMDA. Other neuroadaptations produced by repeated psychostimulant administration are required in order for the development of sensitization to the behavioral effects of those drugs.     

Unique properties of [

Repeated, intermittent administration of psychostimulants produces an enhancement of the subsequent behavioral effects of these drugs. This behavioral sensitization has been implicated in maintenance of and relapse to drug-taking. As a result, there has been great interest in elucidating the mechanisms underlying both the development and expression of sensitization. An accumulation of data from studies of stimulant-induced locomotor activity has implicated excitatory amino acids in the development of behavioral sensitization. In the present study, N-methyl-

Full-size image

-aspartate (NMDA) (0.6, 1.25 or 2.5 μg) infused bilaterally into the ventral tegmental area (VTA) produced dose-dependent locomotor activation. The locomotor activating effect of NMDA was increased following repeated NMDA administration (two exposures to intra-VTA NMDA), suggesting sensitization. However, repeated intra-VTA NMDA failed to sensitize rats to the locomotor activating effects of systemically administered cocaine (5.0, 10.0 or 20.0 mg/kg). These findings are consistent with the notion that repeated activation of NMDA receptors is sufficient for the development of behavioral sensitization to NMDA. Other neuroadaptations produced by repeated psychostimulant administration are required in order for the development of sensitization to the behavioral effects of those drugs.     

Neuropeptide Y antibody attenuates 2-deoxy-

Repeated, intermittent administration of psychostimulants produces an enhancement of the subsequent behavioral effects of these drugs. This behavioral sensitization has been implicated in maintenance of and relapse to drug-taking. As a result, there has been great interest in elucidating the mechanisms underlying both the development and expression of sensitization. An accumulation of data from studies of stimulant-induced locomotor activity has implicated excitatory amino acids in the development of behavioral sensitization. In the present study, N-methyl-

Full-size image

-aspartate (NMDA) (0.6, 1.25 or 2.5 μg) infused bilaterally into the ventral tegmental area (VTA) produced dose-dependent locomotor activation. The locomotor activating effect of NMDA was increased following repeated NMDA administration (two exposures to intra-VTA NMDA), suggesting sensitization. However, repeated intra-VTA NMDA failed to sensitize rats to the locomotor activating effects of systemically administered cocaine (5.0, 10.0 or 20.0 mg/kg). These findings are consistent with the notion that repeated activation of NMDA receptors is sufficient for the development of behavioral sensitization to NMDA. Other neuroadaptations produced by repeated psychostimulant administration are required in order for the development of sensitization to the behavioral effects of those drugs.     

2,5-Anhydro-

Repeated, intermittent administration of psychostimulants produces an enhancement of the subsequent behavioral effects of these drugs. This behavioral sensitization has been implicated in maintenance of and relapse to drug-taking. As a result, there has been great interest in elucidating the mechanisms underlying both the development and expression of sensitization. An accumulation of data from studies of stimulant-induced locomotor activity has implicated excitatory amino acids in the development of behavioral sensitization. In the present study, N-methyl-

Full-size image

-aspartate (NMDA) (0.6, 1.25 or 2.5 μg) infused bilaterally into the ventral tegmental area (VTA) produced dose-dependent locomotor activation. The locomotor activating effect of NMDA was increased following repeated NMDA administration (two exposures to intra-VTA NMDA), suggesting sensitization. However, repeated intra-VTA NMDA failed to sensitize rats to the locomotor activating effects of systemically administered cocaine (5.0, 10.0 or 20.0 mg/kg). These findings are consistent with the notion that repeated activation of NMDA receptors is sufficient for the development of behavioral sensitization to NMDA. Other neuroadaptations produced by repeated psychostimulant administration are required in order for the development of sensitization to the behavioral effects of those drugs.     

Inhibition of NMDA-induced increase in brain temperature by N-ω-nitro-

Repeated, intermittent administration of psychostimulants produces an enhancement of the subsequent behavioral effects of these drugs. This behavioral sensitization has been implicated in maintenance of and relapse to drug-taking. As a result, there has been great interest in elucidating the mechanisms underlying both the development and expression of sensitization. An accumulation of data from studies of stimulant-induced locomotor activity has implicated excitatory amino acids in the development of behavioral sensitization. In the present study, N-methyl-

Full-size image

-aspartate (NMDA) (0.6, 1.25 or 2.5 μg) infused bilaterally into the ventral tegmental area (VTA) produced dose-dependent locomotor activation. The locomotor activating effect of NMDA was increased following repeated NMDA administration (two exposures to intra-VTA NMDA), suggesting sensitization. However, repeated intra-VTA NMDA failed to sensitize rats to the locomotor activating effects of systemically administered cocaine (5.0, 10.0 or 20.0 mg/kg). These findings are consistent with the notion that repeated activation of NMDA receptors is sufficient for the development of behavioral sensitization to NMDA. Other neuroadaptations produced by repeated psychostimulant administration are required in order for the development of sensitization to the behavioral effects of those drugs.     

Characterization of [

Repeated, intermittent administration of psychostimulants produces an enhancement of the subsequent behavioral effects of these drugs. This behavioral sensitization has been implicated in maintenance of and relapse to drug-taking. As a result, there has been great interest in elucidating the mechanisms underlying both the development and expression of sensitization. An accumulation of data from studies of stimulant-induced locomotor activity has implicated excitatory amino acids in the development of behavioral sensitization. In the present study, N-methyl-

Full-size image

-aspartate (NMDA) (0.6, 1.25 or 2.5 μg) infused bilaterally into the ventral tegmental area (VTA) produced dose-dependent locomotor activation. The locomotor activating effect of NMDA was increased following repeated NMDA administration (two exposures to intra-VTA NMDA), suggesting sensitization. However, repeated intra-VTA NMDA failed to sensitize rats to the locomotor activating effects of systemically administered cocaine (5.0, 10.0 or 20.0 mg/kg). These findings are consistent with the notion that repeated activation of NMDA receptors is sufficient for the development of behavioral sensitization to NMDA. Other neuroadaptations produced by repeated psychostimulant administration are required in order for the development of sensitization to the behavioral effects of those drugs.     

Modulatory effect of

Repeated, intermittent administration of psychostimulants produces an enhancement of the subsequent behavioral effects of these drugs. This behavioral sensitization has been implicated in maintenance of and relapse to drug-taking. As a result, there has been great interest in elucidating the mechanisms underlying both the development and expression of sensitization. An accumulation of data from studies of stimulant-induced locomotor activity has implicated excitatory amino acids in the development of behavioral sensitization. In the present study, N-methyl-

Full-size image

-aspartate (NMDA) (0.6, 1.25 or 2.5 μg) infused bilaterally into the ventral tegmental area (VTA) produced dose-dependent locomotor activation. The locomotor activating effect of NMDA was increased following repeated NMDA administration (two exposures to intra-VTA NMDA), suggesting sensitization. However, repeated intra-VTA NMDA failed to sensitize rats to the locomotor activating effects of systemically administered cocaine (5.0, 10.0 or 20.0 mg/kg). These findings are consistent with the notion that repeated activation of NMDA receptors is sufficient for the development of behavioral sensitization to NMDA. Other neuroadaptations produced by repeated psychostimulant administration are required in order for the development of sensitization to the behavioral effects of those drugs.     

Monoamine oxidase-dependent metabolism of dopamine in the striatum and substantia nigra of

Repeated, intermittent administration of psychostimulants produces an enhancement of the subsequent behavioral effects of these drugs. This behavioral sensitization has been implicated in maintenance of and relapse to drug-taking. As a result, there has been great interest in elucidating the mechanisms underlying both the development and expression of sensitization. An accumulation of data from studies of stimulant-induced locomotor activity has implicated excitatory amino acids in the development of behavioral sensitization. In the present study, N-methyl-

Full-size image

-aspartate (NMDA) (0.6, 1.25 or 2.5 μg) infused bilaterally into the ventral tegmental area (VTA) produced dose-dependent locomotor activation. The locomotor activating effect of NMDA was increased following repeated NMDA administration (two exposures to intra-VTA NMDA), suggesting sensitization. However, repeated intra-VTA NMDA failed to sensitize rats to the locomotor activating effects of systemically administered cocaine (5.0, 10.0 or 20.0 mg/kg). These findings are consistent with the notion that repeated activation of NMDA receptors is sufficient for the development of behavioral sensitization to NMDA. Other neuroadaptations produced by repeated psychostimulant administration are required in order for the development of sensitization to the behavioral effects of those drugs.     

Effects of acute and repeated administration of N-methyl-d-aspartate (NMDA) into the ventral tegmental area: locomotor activating effects of NMDA and cocaine

Repeated, intermittent administration of psychostimulants produces an enhancement of the subsequent behavioral effects of these drugs. This behavioral sensitization has been implicated in maintenance of and relapse to drug-taking. As a result, there has been great interest in elucidating the mechanisms underlying both the development and expression of sensitization. An accumulation of data from studies of stimulant-induced locomotor activity has implicated excitatory amino acids in the development of behavioral sensitization. In the present study, N-methyl-

Full-size image

-aspartate (NMDA) (0.6, 1.25 or 2.5 μg) infused bilaterally into the ventral tegmental area (VTA) produced dose-dependent locomotor activation. The locomotor activating effect of NMDA was increased following repeated NMDA administration (two exposures to intra-VTA NMDA), suggesting sensitization. However, repeated intra-VTA NMDA failed to sensitize rats to the locomotor activating effects of systemically administered cocaine (5.0, 10.0 or 20.0 mg/kg). These findings are consistent with the notion that repeated activation of NMDA receptors is sufficient for the development of behavioral sensitization to NMDA. Other neuroadaptations produced by repeated psychostimulant administration are required in order for the development of sensitization to the behavioral effects of those drugs.     

Comparison of glutamate and N-methyl-D-aspartate toxicities on rat mesencephalic primary cell cultures

Excitotoxicitiesof glutamate and NMDA were studied on primary cultures of rat embryonic substantia nigra. The toxicity of the general neuronal population (identified with neuron specific enolase-NSE) was compared with that of dopaminergic neurons (identified with TH antibodies).We have shown that there exists a time-dependent toxicity to glutamate in 9 d old cultures in vitro and exposures as short as 5 min are significantly toxic. By comparing the effects of long time exposures (24 h) to NMDA and glutamate, we can show dose-dependent toxicity ; however NMDA shows a less marked effect, especially at high doses (>500–1000 μM) as opposed to less potent lower doses (<500 μM).In comparison to the general population of NSE-positive mesencephalic neurons, TH-positive neurons seem to exhibit a similar vulnerability to EAA. The fact that TH-positive neurons are only partially protected against glutamate toxicity by the non-competitive NMDA antagonist TCP indicates that they are more susceptible to non-NMDA mediated neurotoxicity than the general neuronal population.     

Effects of a nitric oxide synthase inhibitor on NMDA receptor function in organotypic hippocampal cultures

Nitric oxide (NO) has been proposed to trigger long-term potentiation (LTP) at CA3 to CA1 synapses. We previously reported that NO synthesis inhibitors and blockers reduce an electrophysiological index of NMDA receptor activation in acute hippocampal slices. We now show that the NOS inhibitor, N^G-methyl-

Full-size image

-arginine (MLA), also reversibly prevents LTP induction in organotypic hippocampal slices and significantly reduces a biochemical index of NMDA receptor function. These results further indicate that MLA inhibits LTP induction by interfering with NMDA receptor functions.     

Dopamine D1- and D2-dependent catalepsy in the rat requires functional NMDA receptors in the corpus striatum, nucleus accumbens and substantia nigra pars reticulata

This study investigated the anticataleptic activity of MK-801 versus the D₁ antagonist SCH 23390 and the D₂ antagonist raclopride, using the horizontal bar test in the rat. MK-801, 0.2 mg/kg i.p., strongly opposed the cataleptogenic actions of SCH 23390 and raclopride administered systemically (1 and 3 mg/kg i.p., respectively), or directly into the corpus striatum (CS) or nucleus accumbens (NAc; 1 and 10 μg, respectively). Conversely, intraCS and intraNAc pretreatment with MK-801 (10 μg) markedly attenuated the cataleptic response to a systemic injection of SCH 23390 or raclopride. In the latter experiments the anticataleptic effect of MK-801 was pronounced and sustained (>2 h), except with intraCS MK-801 versus raclopride, where it was initially profound but only short-lived (15 min). Stereotaxic injection of MK-801 (1 μg) into the substantia nigra pars reticulata (SNr) prevented catalepsy developing to either dopamine D₁ or D₂ receptor antagonism. These results indicate there must be unimpeded glutamate neurotransmission in the CS and NAc before catalepsy can develop fully to D₁ and D₂ dopamine receptor blockade in these structures. The weaker glutamate–D₂ interaction in the CS than in the NAc may be related to differences in the N-methyl-

Full-size image

-aspartate receptor subpopulations in these nuclei. Finally, the ability of intranigral MK-801 to diminish both D₁- and D₂-dependent catalepsy suggests the SNr acts as a common output pathway for the expression of both forms of catalepsy in the rat.     

Distribution of d-amino acid oxidase (DAO) activity in the medulla and thoracic spinal cord of the rat: implications for a role for d-serine in autonomic function

The activity and regional distribution of

Full-size image

-amino acid oxidase (DAO), an enzyme that inactivates

Full-size image

-serine, were examined in the medulla and spinal cord of the rat by biochemical and histochemical procedures. DAO activity was noticeably low or absent in the nucleus of the solitary tract, ventrolateral medulla and intramediolateral cell column of the spinal cord. This may be indicative of a neuromodulatory role for endogenous

Full-size image

-serine (at the NMDA-glycine site) in the central control of blood pressure.     

Brainstem-mediated locomotion and myoclonic jerks. II. Pharmacological effects

Previous studies in our laboratory have demonstrated that microinjection of N-methyl-

Full-size image

-aspartate (NMDA) agonist into the nucleus magnocellularis (NMC) of the medial medulla increases muscle tone and/or produces locomotion, while injection of corticotropin-releasing factor (CRF) and non-NMDA agonists into the same or nearby sites suppresses muscle tone. In the first paper of this series, we report that myoclonic twitches or coordinated rhythmic leg movement (locomotion) can be induced by either NMDA or hemorrhagic bilateral lesion of the ventral mesopontine junction (vMPJ). In this paper, we report that microinjection of CRF (10 nM) or non-NMDA agonists, kainic acid (0.1–0.2 mM) and quisqualic acid (1–10 mM), into the NMC block locomotion and myoclonic twitches. The latency and duration of CRF and non-NMDA agonist-induced blockade of motor activity were short, at 34 s and 3.6 min, respectively. However, microinjection of the NMDA antagonists

Full-size image

-2-amino-5-phosphonovaleric acid (APV; 50 mM) or

Full-size image

-2-amino-5-phosphonopentanoic acid (AP5, 20 mM) block myoclonus at a latency of 0.6–3 min with the block lasting for a mean of 7 h. Thus, activation of non-NMDA receptors or inactivation of NMDA receptors in NMC can block myoclonus. An imbalance between the inputs to these receptor systems may contribute to the generation of abnormal motor activation in waking and sleep.     

Characterization of α,β-Methylene ATP Binding Sites in Mouse Crude Synaptic Membranes

Since ATP has been reported to be a potent excitatory transmitter in the mammalian central nervous system (CNS), we studied the neurochemical characters of the binding sites of

Full-size image

,

Full-size image

-methylene ATP, an agonist of P_2X receptors, in mouse crude synaptic membranes. ATP and its related compounds inhibited [³H]

Full-size image

,

Full-size image

-methylene ATP binding in a concentration-dependent manner. The potency order in the inhibition of the binding was as follows;

Full-size image

,

Full-size image

-methylene

Full-size image

>

Full-size image

> ATP ≥ ADP >

Full-size image

,

Full-size image

-methylene ATP UTP > 2-methylthio ATP. And adenosine did not affect the binding. The order was different from those reported in peripheral tissues. And Sr²⁺, Ca²⁺, Mg²⁺, and Cd²⁺ enhanced the binding. These results suggest that

Full-size image

,

Full-size image

-methylene ATP binding sites in CNS have different characters from those in peripheral tissues.     

l-DOPA neurotoxicity is mediated by glutamate release in cultured rat striatal neurons

The exposure of cultured rat striatal neurons to

Full-size image

-DOPA caused marked cell death. The

Full-size image

-DOPA cytotoxicity was inhibited by the addition of Mg²⁺ to and by the removal of Ca²⁺ from the culture medium, and also by the application of tetrodotoxin. Moreover, prolonged application of

Full-size image

-DOPA increased the glutamate content in the culture medium. These results indicate that

Full-size image

-DOPA produces neurotoxicity by facilitating glutamate release.     

Polyamines prevent apoptotic cell death in cultured cerebellar granule neurons

Polyamines play critical roles during the development of brain neurons. In the present study we examined the effects of polyamines on neuronal apoptotic death. Rat cerebellar granule neurons were cultured in the presence of a depolarizing concentration of KCl (25 mM) in the medium. Apoptotic neuronal death was induced by changing the medium to that containing 5.6 mM KCl without serum. Spermine as well as spermidine and putrescine prevented cell death in a concentration-dependent manner with the order of potency being spermine>spermidine>putrescine. The effect of spermine was partially blocked by several NMDA-type glutamate receptor antagonists including (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801). MK-801-sensitive neuroprotection by spermine depended on cell density. Activation of CPP32 (caspase-3/Yama/apopain)-like proteolytic activity, a key mediator of apoptosis, precedes neuronal death, and polyamines prevented an increase in this activity. These results demonstrate that polyamines protect neurons from apoptotic cell death through both NMDA receptor-dependent and -independent mechanisms, acting upstream from the activation of CPP32-like protease(s). © 1997 Elsevier Science B.V. All rights reserved.     

Suppression of neuropathic pain by a naturally-derived peptide with NMDA antagonist activity

Chronic pain may result from hyperexcitability following activation of spinal NMDA receptors. A naturally-derived mammalian peptide, histogranin, may possess NMDA antagonist activity. This study explored the possibility that stable analog [Ser¹]Histogranin (SHG) could reduce chronic pain. Neuropathic pain was induced using the chronic constriction injury model (CCI). Intrathecal injection of SHG markedly attenuated the hyperalgesia and allodynia resulting from CCI, nearly normalizing responses. These results suggest that the natural peptide histogranin may be a novel adjunct in neuropathic pain management.