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VTA amphetamine pre-exposure facilitates the self-administration of amphetamine and cocaine. Different groups of rats were administered three infusions of VTA amphetamine (2.5 Xg 0.5 xl side solid bars), VTA saline (hatched bars), or amphetamine in sites adjacent to the VTA (open bar). Infusions were made once every third day. Starting 10 d later, rats were trained to self-administer amphetamine (200 Xg kg infusion, iv) or cocaine (300 Xg kg infusion, iv) and then tested on a...

Psychostimulantinduced Neuroadaptations In The Interactions Between Glutamate And Dopamine

Repeated psychostimulant consumption ultimately results in classic symptoms of addiction such as craving, compulsive drug use, and paranoia. Identifying the neuroadaptations mediating the emergence of these enduring behavioral alterations is key to the understanding of the neurobiology of psychostimulant addiction and developing rational therapies. In general, acute systemic administration of psychostimulants alters dopamine and glutamate neurotransmission throughout the motive circuit thus, it...

Cocaineinduced Lethality

Ideally, pharmacotherapies for the treatment of cocaine overdose should protect against the ultimate toxic endpoint, death. Since death from a cocaine overdose can occur suddenly or with short latency, a Saline ACEA1021 ACEA1031 ACEA1328 Fig. 5. Effect of NMDA glycine-site antagonists on cocaine-induced lethality. Pretreatment (white bars) of mice with NMDA glycine-site antagonists (ACEA1021, ACEA1031, and ACEA1328) significantly reduces the percentage of animals that die following a normally...

Blockade Of Cocaineinduced Conditioned Effects With Mk801

Conditioned effects of cocaine were established and evaluated using the paradigm described above in which PAIRED, UNPAIRED, and CONTROL animals are employed. In the initial study, we used a 1-d conditioning procedure to evaluate the effects of MK-801 on the acquisition of cocaine-conditioned increases in locomotor activity. PAIRED rats were pretreated with either saline or various doses of MK-801 (0.25-1.0 mg kg ip) 30 min prior to injections of 40 mg kg of cocaine ip and then placed in...

Introduction

Psychomotor-stimulant drugs such as the amphetamines and cocaine are self-administered by humans and laboratory animals and produce locomotor activation. Repeated exposure to these drugs produces long-term enhancements in their ability to elicit these locomotor responses so that subsequent re-exposure to the drug, weeks to months later, produces greater behavioral activation than seen initially. Most importantly, previous exposure to such sensitizing regimens of amphetamine injections has also...

Glutamate Neurotoxicity In Animal Models Of Neuronal Injury

Extracellular glutamate levels are elevated in brain following ischemia (82), seizures (83), and head trauma (84). Although Simon's original observation that NMDA antagonists attenuate hip-pocampal neuronal death following global ischemia has not been consistently confirmed (12) but see ref. 85 , AMPA receptor antagonists have reduced hippocampal injury following global ischemia in many studies (85-88) and also reduce infarct volume following focal ischemia (89,90). NMDA antagonists, especially...

Glutamate Mediation Of Dopamine And 5ht Toxicity

Although MA has been found to damage DA terminals in the striatum and 5-HT terminals in multiple brain regions, factors that mediate damage to these monoamine systems may differ on a fundamental level. A growing body of evidence suggests that DA-containing nerve terminals are inherently more vulnerable to damage following metabolic inhibition compared with 5-HT containing terminals. Additionally, increased extracellular glutamate may have a more direct effect in mediating toxicity to DA systems...

Glutamatergic Dysregulation In Ethanoldependent Patients

There is compelling preclinical evidence suggesting that adaptations within the brain to chronic ethanol administration contribute to the phenomena of tolerance and withdrawal. In response to the chronic blockade of NMDA receptors associated with sustained ethanol administration, there are increases the levels of mRNA or protein for NMDA receptor subunits and increased NMDA receptor function (2). These changes, combined with increased glutamate release, are temporally related to the expression...

Graeme Mason PhD and Louis Trevisan MD

Ethanol has multiple specific targets in the brain that combine to yield a complexly nuanced psychoactive agent (1). However, the study of glutamatergic targets of ethanol have been a recent development (2). The recency of these clinical studies may be surprising. Glutamate is the most prevalent excitatory neurotransmitter in the cerebral cortex and it mediates most output of the cortex and limbic system (3). Also, the V-methyl-d-aspartate (NMDA) subtype of glutamate receptor is among the...

Nmda Receptors And The Development Of Opiate Sensitization

Wolf and co-workers were the first to report on the ability of NMDA receptor antagonists to inhibit opiate sensitization (74,95). These investigators noted that both MK-801 and the competitive NMDA receptor antagonist CGS 19755, at relatively low and selective doses, inhibited the development of sensitization to the locomotor-stimulant effect of morphine. The pattern observed was strikingly similar to that seen with morphine tolerance, in that the antagonists inhibited the development but not...

Clinical Implications

One of the most obvious possibilities for therapeutic intervention with NMDA receptor drugs is in the treatment of chronic pain. Because NMDA receptor antagonists have the ability to prevent the development of tolerance, sensitization, and physical dependence, these drugs may be useful adjuncts to opiates in situations in which long-term administration of opiates is necessary. Administration of an NMDA receptor antagonist together with an opiate should inhibit the development of tolerance,...

Glycine Site Ligands

Activation of NMDA receptors by glutamate requires the presence of a coagonist at a distinct recognition domain on the receptor complex referred to as the glycine site (54,55) (Fig. 1). More recently, the term glycineB site has been used to distinguish the regulatory coagonist site on NMDA receptors from the inhibitory strychnine-sensitive glycine receptor, a Cl- channel. Although glycine was originally believed to be the endogenous coagonist, recent evidence indicates that d-serine may serve...

Adriaan S Potgieter MD

The first double-blind, placebo-controlled study to test the efficacy of acamprosate in alcohol-dependent patients took place in France in 1982, and results were published by Lhuintre et al. in 1985 (1). Since then, more than 25 clinical studies have been performed, assessing various efficacy and safety criteria within the context of varying clinical settings and psychosocial support systems. Seventeen of these studies, which included a total of 4523 patients (2371 on acamprosate, 2152 on...

Laboratory Studies

Models of Physiological Dependence Development of Medication to Assist in Detoxification Physiological dependence, and the emergence of a withdrawal syndrome upon cessation of drug use, is a common feature of several substance-dependence syndromes (in particular, opioid dependence). Medications are frequently used to alleviate the signs and symptoms of withdrawal, a treatment known as medical detoxification. Most patients who enter treatment for opioid dependence need to undergo...

And HIVAssociated Dementia

Lipton, MD, PhD Neuronal injury and apoptosis may account, at least in part, for neurological complications associated with human immunodeficiency virus (HIV)-1 infection ranging from mild cognitive and motor impairment to dementia. The primary cell types infected in the brain are macrophages and microglia. These cells have been found in vivo and in vitro to release neurotoxic factors. Evidence has accumulated that neuronal apoptosis in HIV-related insults occurs...

Neurobiology Of Cocaineinduced Conditioned Increases In Locomotor Activity

We have employed a relatively simple design in some of our studies to evaluate the behavioral and neurobiological variables regulating the acquisition and expression of cocaine-induced conditioned effects. Basically, three groups of rats are employed in this paradigm. In its simplest form, on d 1 the first groups of rats (PAIRED) is injected with cocaine (30-40 mg kg ip) prior to placement in locomotor activity chambers (scented with peppermint) for 30 min. One hour following return to their...

Effect Of Nmda Receptor Antagonists On The Acquisition Of Cpp Produced By Drugs Of Abuse

To determine the putative effects of NMDA receptor antagonists on the acquisition of drug-induced CPP, one can give injections of NMDA receptor antagonists during conditioning. For morphine reward, such inhibitory effects have been demonstrated for the nonselective glutamate antagonist, kynurenic acid (17), MK-801 (dizocilpine, NMDA receptor channel blocker) (18-20), MRZ 2 570 and L-701,324 (glycine NMDA receptor antagonists) (21,22), MRZ 2 579 (NMDA receptor channel blocker) (21), and...

Cocaineinduced Convulsions

The incidence of convulsions in individuals who abuse cocaine is significant. Cocaine-induced convulsions can result from exposure to large doses of cocaine, typically in an overdose situation. In addition, convulsions can manifest as a result of kindling, in which increased sensitivity to cocaine is produced upon repeated exposure to the drug, eventually leading to seizures upon exposure to doses of cocaine that had previously been subconvulsive. These cocaine-kindled seizures have been...

Glutamate Neurotransmission And The Limbic System

Excitatory amino acids represent the main excitatory neurotransmitters within the mammalian central nervous system and exert their effects through the interaction with ionotropic receptors of the N-methyl-d-aspartate (NMDA) and non-NMDA type and metabotropic receptors. In addition, glutamate also stimulates the synthesis of the diffusible messenger nitric oxide (NO). Through activation of NMDA receptors, glutamate promotes the influx of calcium into the postsynaptic neuron. In turn, binding to...

References

Crambes, A., Monassier, L., Chapleau, D., Roegel, J.-C., Feldman, J., and Bousquet, P. (1996) GABAergic and gluataminer-gic modulation of centrally evoked arrhythmias in rats. Hypertension 27, 148-154. 2. Olney, J. W., Collins, R. C., and Sloviter, R. S. (1986) Excitotoxic mechanisms of epileptic brain damage. Adv. Neurol. 44, 857-877. 3. West, M. and Huang, W. (1994) Spinal cord excitatory amino acids and cardiovascular autonomic responses. Am. J. Physiol. 267, H865-H873. 4. Yao, S. T.,...

Jean Lud Cadet MD

Oxygen and nitric oxide (NO) are essential elements for normal life. Indeed, the reduction of molecular oxygen represents one of the most important generators of energy for aerobic organisms. This occurs through the four-election reduction of dioxygen to yield water. Nevertheless, these substances can also participate in deleterious reactions that negatively impact lipid, protein, and nucleic acid. Thus, normal physiological function depends on a balance between these potentially toxic...

Metabotropic Receptors

Metabotropic glutamate receptors (mGluRs) are seven transmembrane domain G-protein-coupled receptors that are activated by glutamate and that regulate neuronal excitability by a multiplicity of postsynaptic and presynaptic mechanisms. Eight distinct mGluRs have been identified by molecular cloning, some of which exist in multiple alternatively spliced forms. The family of mGluRs can be divided into two major groups based on the second-messenger systems to which they are coupled those that...

Marina E Wolf PhD

Addiction may be defined as the gradual evolution from casual or controlled use into a compulsive pattern of drug-seeking and drug-taking behavior. Even after abstinence is achieved, patients remain vulnerable to episodes of craving and relapse triggered by stimuli previously associated with the availability of drug or the act of drug-taking (1). This transition fits the definition of neuroplasticity, defined as the ability of the nervous system to modify its response to a stimulus based on...

Sensitization And The Selfadministration Of Psychomotor Stimulant Drugs

Facilitation of Psychomotor-Stimulant Self-Administration It is now well established that animals previously exposed to sensitizing injection regimens of morphine, amphetamine, cocaine, or treatments with environmental stressors are subsequently more sensitive to the rewarding or incentive-motivational effects of these drugs as measured by the conditioned place-preference procedure (107-109). In addition, these animals are more susceptible to self-administer amphetamine and cocaine...

Summary And Directions For The Future

Opiate and cocaine addictions are complex disorders with a variety of processes that contribute to the maintenance of pathological behavior and relapse in abstinent individuals. Current animal paradigms are simplistic models of particular aspects of the disease and may be insufficient to predict the clinical utility and justify initiation of efficacy trials. We argue for the development of human laboratory paradigms and improvement of the methodology of small N clinical trials, both of which...

Toxicity in Mice

Matsumoto, PhD and Buddy Pouw, MD Abuse of cocaine can produce many adverse effects, including convulsions and lethality, especially in overdose situations. Previous efforts to develop pharmacotherapies for cocaine overdose have been limited in success, and there are, currently no effective treatments for this medical emergency. Much of the immediate toxicity associated with a cocaine overdose results from overstimulation of the central and peripheral nervous systems. Resultant symptoms...

Clinical Trials

NMDA Receptor Antagonists in the Treatment of Drug Withdrawal 4.1.1. Opiate Detoxification Laboratory animal studies consistently show that NMDAR antagonists in, particular channel blockers attenuate the severity of opioid withdrawal in dependent animals (1,3). The results of human laboratory studies are less decisive. Several preliminary trials have evaluated the utility of clinically available agents for opioid detoxification. The first published clinical study was conducted in Turkey by...

Conclusions

Glutamate plays a key role in drug dependence and associated behavioral and toxic effects of drugs of abuse. A range of experimental drugs is available to explore further the involvement of glutamate in drug abuse and for the discovery of potential therapeutic candidates. Although these compounds produce a host of common actions and effects, a difference in effects among compounds that appears to derive from the specific molecular targets upon which they act provide a rich diversity for...

Glutamate Neurotransmission And Cocaine Abuse

From a functional standpoint, excitatory amino acid neurotransmission within the limbic system appears to play an important role in the modulation of various behavioral consequences of exposure to psychostimulant drugs. Earlier studies had proposed a behavioral stimulatory role for excitatory amino acids in the nucleus accumbens on the basis of the increase in locomotor activity produced by local infusion of glutamate agonists, an effect accompanied by an increase in dopamine turnover (46,47)....

Glutamatedependent Synaptic Plasticity And Cocaine Addiction

An issue that deserves dedicated attention is the possibility that the relative contribution of excitatory amino acid neurotransmitters may become particularly significant during specific periods of exposure to cocaine. Excitatory amino acids are considered critical mediators of neural plasticity within the central nervous system, and this makes them ideal candidates as participating agents in the development of adaptive changes, which may represent integral parts of the addictive process...

Hiv1 Infection And Nmda Receptorrelated Neuronal Apoptosis

HIV-associated dementia eventually develops in approximately half of children and a quarter of adults infected with HIV-1 (7). Neuropathological features that may accompany this cognitive-motor complex include dendritic and synaptic damage, apoptosis and frank loss of neurons, myelin pallor, astrocytosis, and infiltration of macrophages, microglia, and multinucleated giant cells (7,20,21). Addiction to drugs, such as heroin, cocaine, and methamphetamine, is considered to be a major risk factor...

In Cocaine and Opioid Dependence

Fischman, PhD In the last 10 yr, a substantial amount of preclinical research has been dedicated to studying the role of excitatory amino acids, in particular, glutamate, in laboratory models of alcohol and drug dependence (1-4). As a result, we now have a wealth of information suggesting that glutamatergic neurotransmission is a major component of the neuroadaptive changes that mediate the development, maintenance, and expression of patterns of animal behavior...

Naaladase

Glutamate carboxypeptidase II (N-acetylated a-linked-acidic dipeptidase EC 3.4.17.21) or NAAL-ADase is a neuropeptidase that catalyzes the cleavage of glutamate from N-acetyl-aspartyl-glutamate (NAAG), the most prevalent and widely distributed neuropeptide in the mammalian nervous system (187). Thus, inhibition of NAALADase would decrease glutamate levels and increase levels of NAAG. Theoretically then, NAALADase inhibition would have the potential to negatively modulate gluta-matergic...

Nitric Oxide Synthase

Glutamate-gating of NMDA receptors permits Ca2+ entry that specifically activates neuronal nitric oxide synthase (nNOS), a Ca2+-dependent enzyme that catalyzes the synthesis of the free-radical nitric oxide (NO) from l-arginine (180) (Fig. 1). Because NO may act as an intercellular messenger mediating forms of neuronal plasticity, blockade of nNOS could potentially interfere with the long-term consequences of NMDA receptor activation and might thereby have an influence on the behavioral effects...

No Is Required For The Induction And Expression Of Behavioral Sensitization To Psychostimulants

Sensitization to Cocaine and Methamphetamine Postsynaptic DA receptors in the dorsal striatum and NAc are thought to be involved in psychostim-ulant-induced hyperactivity (16). The D1-class receptors may have a more prominent role than the D2-like DA receptors in the action of psychostimulants (17). However, repeated exposure to psychostimulants that cause behavioral sensitization is more complex and apparently involves multiple neurotransmitter systems. The development of behavioral...

Role Of Intracellular Protein Kinases

Activation of NMDA receptors initiates intracellular processes that may lead to neuroplastic changes. A common feature of NMDA receptor activation is an increase in intracellular Ca2+ concentration, which, in turn, initiates a number of second third-messenger-mediated intracellular processes. One such process is the redistribution (translocation from cytosolic to membrane-bound form) and activation of the Ca2+-sensitive protein kinase C (PKC). It is known that Ca2+-regulated PKC translocation...

Other Approaches

In the future, it may be possible to modulate brain glutamate systems by treatments that are designed to modify the expression of critical genes involved in glutamate signaling. Indeed, drugs of abuse produce prominent changes in gene transcription that may alter the expression of components of the glutamate-signaling pathways and these changes have been hypothesized to play a role in the development of drug dependence (193). Furthermore, drugs used to treat drug dependence may also operate...

Overall Summary And Clinical Implications

Of the various subtypes of glutamate receptor, the NMDA receptor appears the most promising target for the development of drugs to treat acute cocaine overdose. NMDA receptor antagonists significantly attenuate cocaine-induced convulsions and lethality in preclinical studies in rodents. In contrast, AMPA kainate and metabotropic glutamate receptor antagonists are limited in effectiveness on their own against cocaine overdose, but may provide modulatory influences that could be beneficial as...

Role Of Glutamate In The Conditioned Effects Of Cocaine

Although dopamine appears to be important for the formation of both the associative and nonasso-ciative components of sensitization, it has become apparent that other neurotransmitter systems are involved as well. Of particular importance is glutamate. Karler and colleagues (25,26) were the first to report that the development of sensitization to cocaine and amphetamine in mice was prevented by pretreatment with MK-801, a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) type of...

The Role of mGluR5 in the Effects of Cocaine Implications for Medication Development

Investigations over the past several years have yielded insights into the contributions of metabotropic glutamate receptors (mGluRs) to the effects of psychostimulants. Recently, an important role was demonstrated for the mGluR subtype 5 in the locomotor stimulant and reinforcing effects of cocaine (1). The data obtained in that report will be summarized here, followed by a brief discussion of the implications of this evidence for the development of medications to treat cocaine dependence....

Uncompetitive Antagonists

NMDA receptor-channel blockers are uncompetitive antagonists because their binding and blocking action requires the receptor-channel to be gated in the open state. Occupancy of a binding site within the ionophore of the channel by these compounds prevents the flux of cations through the ion channel, thus producing a functional block of NMDA-receptor responses (6,7). Unlike competitive NMDA recognition site antagonists (see Section 2.2.), uncompetitive antagonists share with other...

Candidate Mechanisms For Stable Druginduced Changes In The Brain

Based on animal studies, one can identify several categories of adaptations produced by chronic drug administration that are candidates for triggering long-lasting changes in brain. The first is changes in gene expression, leading to altered activity of neurons expressing these genes and, ultimately, to alterations in the activity of neuronal circuits. This subject was the topic of an excellent and very recent review, which focused on two transcription factors strongly implicated in addiction,...

Interactions Between Nmda Receptormediated Mechanisms Of Opioid Tolerance And Neuropathic Pain

Opioid Tolerance and Neuropathic Pain As discussed above, NMDA receptor-mediated cellular and intracellular changes occur within the rat's spinal cord following repeated exposure to opioids. Similar cellular and intracellular changes have been observed at the spinal cord level in animal models of neuropathic pain. Several lines of evidence suggest that these NMDA receptor-mediated changes are the neural basis of spinal cord neuroplastic changes responsible for the behavioral manifestations...

Neural Substrates Of Cocaine Abuse

A critical issue for the understanding of drug dependence is what neurochemical changes occur during the various phases of the course of addiction. Psychostimulant dependence has been a major focus of investigation, especially following the cocaine epidemic of the 1980s. Despite early misconceptions that considered cocaine as a recreational drug devoid of abuse and addictive potential, the recent cocaine epidemic has revealed the harmful consequences of cocaine use and its high abuse liability....

The Effects of Glutamate Receptor Subtype Ligands on Morphine Withdrawal Symptoms

Cessation of the repeated administration of opiates results in a characteristic morbidity in humans, including anxiety, nausea, insomnia, hot and cold flashes, muscle aches, perspiration, and diarrhea (1). Great strides have been made in understanding the neurophysiology underlying these opiate-withdrawal symptoms. Several neurotransmitter systems have been shown to play an important role in opiate withdrawal, including the dopaminergic (2-4) and cholinergic (5-7) systems. This chapter will...

Chronic Ethanol Tolerance

Hyperexcitability of the CNS is a characteristic component of ethanol withdrawal, and there is good evidence for both a reduction in GABA-mediated inhibitory neurotransmission and an increase in glu-tamate-mediated excitatory neurotransmission following chronic ethanol exposure. Studies using primary neuronal cultures have shown that prolonged exposure to ethanol leads to a supersensitization of NMDA receptor-mediated events, such as Ca2+ influx (49) and Ca2+-dependent processes, including...

Z

Zinc flux, glutamate neurotoxicity, 53 Color Plate 1, Fig. 1. (See full caption and discussion in Chapter 1, p. 4). Example of physiological roles of mGluRs at the Schaffer collateral synapse in CA1 in the hippocampus. Color Plate 2, Fig. 3. (See full caption and discussion in Chapter 1, p. 9). Glutamate receptor topology and crystal structure of the agonist-binding pocket. Color Plate 3, Fig. 1. (See discussion in Chapter 2, p. 25). A representation of the NMDA receptor with associated binding...

Role Of Glutamate In Alcohol Withdrawal Kindling

Alcohol Nmda Receptor

Mechanisms underlying alcohol withdrawal sensitization or kindling are not well understood. In fact, the terms sensitization and kindling are used interchangeably here to describe observed exacerbation of withdrawal signs (noted in both clinical and preclinical studies) rather than infer a particular mechanism, per se. Both neuroadaptive changes in response to alcohol exposure as well as changes unique to withdrawal from alcohol most likely play a joint role in the final expression of the...

And L Judson Chandler PhD

Perirhinal Cortex

Alcohol is a major drug of use and abuse in the United States. An estimated 15 million Americans (1988 NHIS study) are alcohol abusers or alcohol dependent. Lifetime prevalence of alcohol dependence is estimated at 13 and 4 for American men and women over 18 yr of age, respectively (1). It is well established that chronic excessive ethanol consumption produces marked deficits in cognitive and motor abilities (2,3). Alcohol is a leading cause of adult dementia in the United States, accounting...

Howard C Becker PhD and Nicole Redmond PhD

It is well known that continued excessive alcohol consumption can lead to the development of physiological dependence. When drinking is abruptly terminated or substantially reduced in the dependent individual, a characteristic withdrawal syndrome ensues. As with other central nervous system (CNS) depressants, withdrawal symptoms associated with cessation of chronic alcohol use are opposite in nature to the effects of intoxication. Thus, clinical features of alcohol withdrawal include signs of...

Summary And Conclusions

Human and animal studies have clearly established that chronic alcohol intake causes a loss of brain mass as a result of ethanol-induced brain damage. Although human studies show loss of brain tissue and the loss of specific brain nuclei after years of alcohol consumption, recent animal studies have indicated that neuronal loss can occur after only a few days of binge drinking. The neuropathol-ogy in humans involves both gray and white matter, whereas the animal studies have focused on neuronal...

W Zieglgansberger G Rammes R Spanagel W Danysz and Ch Parsons

The taurine analog acamprosate (calcium acetylhomotaurinate) has received considerable attention in Europe for its ability to prevent relapse in abstained alcoholics (1) Chapter 28 and has been suggested to act by reducing craving associated with conditioned withdrawal (2,3). 2. ANTICRAVING AND ANTIRELAPSE PROPERTIES OF ACAMPROSATE Novel aspects of addictive behavior to alcohol (craving, relapse, and sensitization processes) are uncovered by a new animal model of long-term, free-choice, alcohol...

Drugs Of Abuse Influence Synaptic Plasticity In The Nucleus Accumbens

The NAc occupies a key position in the neurocircuitry of motivation and reward and is the site of many persistent changes associated with chronic drug exposure (96). Neurons in the NAc consist of medium spiny GABA neurons (90 ) and several populations of interneurons (10 ). The medium spiny neurons are the output neurons of the NAc and receive convergent DA and glutamate inputs. The interneurons play important roles in information processing within the NAc and may also be regulated by DA and...

Glutamate And Dopamine Interactions In The Motive Circuit

Glutamate and Dopamine Receptors Extracellular dopamine binds to two major families of receptors D1-like, which consists of D1 and D5 receptors, and D2-like, which consists of D2, D3, and D4 receptors. The receptor subtypes within each group share molecular and pharmacological properties but can differ in their anatomical distribution. The D1 receptor family is coupled to G proteins and is associated with the activation of adenylyl cyclase. In contrast, the family of D2 receptors are...

Robert W Peoples PhD

Alcohol is arguably the oldest drug known to man, its use dating back at least 10,000 yr to the dawn of human civilization (1). Although illicit drug use often receives more attention in contemporary society, alcohol abuse exacts a devastating toll In the United States at present, over 7 of the population meet diagnostic criteria for alcohol abuse or alcoholism (2), over 28 of children under 18 yr of age are exposed to alcohol abuse or dependence in the home (3), and the overall economic cost...

Mechanisms Of Methamphetamine Toxicity

As discussed above, increases in the extracellular concentrations of both DA and glutamate within the striatum appear to contribute to MA-induced damage to dopaminergic nerve terminals. Many of the manipulations used to identify the role of DA in mediating MA-induced damage also modify MA-induced changes in the extracellular concentrations of glutamate. These findings suggest that the release of both DA and glutamate are obligatory in the MA toxicity cascade (9,10,33,34). For example, D2...

The Role Of Glutamate Receptor Subtypes In Opiate Withdrawal

Glutamate receptors have been divided into two broad categories iontotropic and metabotropic. Iontotropic glutamate receptors contain cation-specific ion channels as a component of their protein complex, whereas metabotropic glutamate receptors are coupled to G-proteins and modulate intracel-lular second-messenger systems. Iontotropic receptors are divided into three main subtypes N-methyl-d-aspartate (NMDA), acid (AMPA), and kainate. Eight different clones for metabotropic glutamate (mGlu)...

AMPA Receptors

AMPA receptor antagonists may modulate AMPA receptor function by acting at the glutamate recognition site competitive antagonists or at a distinct allosteric regulatory site for 2,3-benzodi-azepines negative allosteric modulators . In addition, CA2 -permeable AMPA receptors can be antagonized by a diverse group of cationic channel blockers, including polyamines, spider and wasp toxins such as Joro spider toxin JSTX , and IEM-1460. Recent and detailed reviews of AMPA-receptor structure,...

Dcgiv

Antagonists LY 341495 ADBD LY 307452 ADED LY 310225 abused substances cf. ref. 160 . Detailed reviews of the biochemistry, physiology, and pharmacology of the burgeoning field of mGluRs are available 160-166 . Although rapid progress has been made in the discovery of selective ligands for the eight mGluRs, the pharmacology of mGluRs is not fully developed see Table 6 . Although there are some compounds that have varying degrees of selectivity for each of the three groups of mGluRs, selectivity...