Psychotropic agents in functional gastrointestinal disorders

Functional gastrointestinal disorders (FGIDs) are common conditions diagnosed by established symptom-based criteria. Dysregulation of the brain-gut axis is emerging as the primary pathophysiologic mechanism for FGIDs; this opens avenues for newer treatment modalities. Psychotropic agents act on a variety of neurotransmitter receptors in the brain-gut regulatory pathways that target serotonergic, dopaminergic, opioidergic, and noradrenergic receptor sites. The role of psychotropic agents, especially tricyclic antidepressants is fairly well established in the management of FGIDs and benefit from the newer serotonin norepinephrine reuptake inhibitors is promising. Selective serotonin reuptake inhibitors may provide benefit by reducing symptom anxiety and achieve global symptom relief. In spite of expanding research in evaluating these potential agents, there remains an unmet need in pharmacological management of these disorders, especially at the severe end of their spectrum where options for combined treatments or augmentation need to be developed. In addition, the understanding and management of these disorders hinges on a multidisciplinary biopsychosocial approach, which itself can be a challenging strategy.     

Relationship Between Glycine Transporter 1 Inhibition as Measured with Positron Emission Tomography and Changes in Cognitive Performances in Nonhuman Primates

Several lines of evidence suggest that schizophrenia is associated with deficits in glutamatergic transmission at the N-methyl-d-aspartate (NMDA) receptors. Glycine is a NMDA receptor co-agonist, and extracellular levels of glycine are regulated in the forebrain by the glycine type-1 transporters (GlyT-1). GlyT-1 inhibitors elevate extracellular glycine and thus potentiate NMDA transmission. This mechanism represents a promising new avenue for the treatment of schizophrenia. Here, the recently introduced positron emission tomography radiotracer [11C]GSK931145 was used to quantify the relationship between occupancy of GlyT-1 by a GlyT-1 inhibitor, Org 25935, and its impact on spatial working memory performances in rhesus monkeys. The effect of Org 25935 on working memory was assessed both in control conditions and during a state of relative NMDA hypofunction induced by ketamine administration, at a dose selected for each animal to reduce task performance by about 50%. Under control conditions, Org 25935 had no effect on working memory at GlyT-1 occupancies lower than 75% and significantly impaired working memory at occupancies higher than 75%. Under ketamine conditions, Org 25935 reversed the deficit in working memory induced by ketamine and did so optimally in the 40–70% GlyT-1 occupancy range. The results confirm the efficacy of this mechanism to correct working memory deficits associated with NMDA hypofunction. These data also suggest the existence of an inverted-U dose–response curve in the potential therapeutic effect of this class of compounds.     

Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release.

Pharmacological manipulation of N-methyl-D-aspartate (NMDA) receptors may be critical for the treatment of many neurological and psychiatric disorders. Metabotropic glutamate (mGlu5) receptors are abundant in corticolimbic circuitry, where they modulate NMDA receptor-mediated signal transduction. Therefore, pharmacological manipulation of mGlu5 receptor may provide a treatment strategy for cognitive disorders that are associated with NMDA receptor dysfunction. We sought to determine whether the recently described molecular and cellular interactions between NMDA and mGlu5 receptors coregulate higher order behaviors. We examined the interaction of the selective mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and the use-dependent NMDA antagonist MK-801, on locomotion, stereotypy, working memory, instrumental learning, and corticolimbic dopamine release. MPEP, at 10 mg/kg, but not 3 mg/kg, impaired working memory and instrumental learning, transiently increased dopamine release in prefrontal cortex and nucleus accumbens, and augmented the effect of MK-801 on cortical dopamine release, locomotion, and stereotypy. Pretreatment with 3 mg/kg of MPEP enhanced the detrimental effects of MK-801 on cognition. These results demonstrate that an mGlu5 receptor antagonist can potentiate the motoric, cognitive, and dopaminergic effects of an NMDA receptor antagonist. Thus, mGlu5 receptors appear to play a major role in regulating NMDA receptor-dependent cognitive functions such as learning and working memory. By extension, these results suggest that pharmacological potentiation of mGlu5 receptors may ameliorate the cognitive and other behavioral abnormalities associated with NMDA receptor deficiency.     

The cognitive effects of modulating the glycine site of the NMDA receptor with high-dose glycine in healthy controls

N-methyl-D-aspartate (NMDA) receptors play an important role in learning and memory. Targeting the glycine modulatory site of the NMDA receptor has been suggested as a therapeutic strategy to improve cognition, although findings have not been convincing. We used the Cognitive Drug Research computerised assessment system to examine the effects of high-dose glycine on a number of cognitive processes in healthy young subjects. The study was a randomised placebo controlled repeated measures design in which each subject received acute placebo or glycine (0.8 g/kg) orally, with treatment conditions separated by a 5-day washout period. No significant effects of glycine were found on measures of working memory, declarative memory, attention or perceptual processing. These findings, together with those of previous studies, cast doubt over the ability of acute high-dose glycine to improve cognitive function in healthy subjects and suggest that the optimum dose of glycine for improving cognition may vary between different populations, possibly due to differences in endogenous glycine levels and the functional status of NMDA receptors.     

The GABA-glutamate connection in schizophrenia: which is the proximate cause?

Schizophrenia is a chronic, disabling psychiatric disorder that genetic studies have shown to be highly heritable. Although the dopamine hypothesis has dominated the thinking about the cause of schizophrenia for 40 years, post-mortem and genetic studies have provided little support for it. Rather, post-mortem studies point to hypofunction of subsets of GABAergic interneurons in the prefrontal cortex and the hippocampus. Furthermore, clinical pharmacologic, post-mortem and genetic studies have provided compelling evidence of hypofunction of a subpopulation of NMDA receptors in schizophrenia. In support of this inference, agents that directly or indirectly activate the glycine modulatory site on the NMDA receptor (the Glycine B receptor) reduce symptoms in chronic schizophrenia, especially negative symptoms and cognitive impairments. Electrophysiologic and pharmacologic studies suggest that the vulnerable NMDA receptors in schizophrenia may be concentrated on cortico-limbic GABAergic interneurons, thereby linking these two neuropathologic features of the disorder.     

Antischizophrenic activity independent of dopamine D2 blockade

Currently, the drug therapy of schizophrenia consists of blockade of central dopamine D2 receptors. There is, however, an urgent medical need for alternative, more effective treatments. Clinical and preclinical literature suggests that stimulation of AMPA-type glutamate receptors may be involved in positive symptoms of schizophrenia, whereas hypofunctionality of NMDA-type glutamate receptors may be involved in negative symptoms and cognitive deficits. Several pharmacological approaches are conceivable to prevent stimulation of AMPA receptors (AMPA receptor blockade, metabotropic glutamate receptors (mGlu(2) receptor) stimulation or lamotrigine-like Na(+)/Ca(2+) channel blockade). Similarly, several pharmacological principles are conceivable to enhance neurotransmission at NMDA receptors (catechol-o-methyl transferase inhibition, glycine uptake blockade, glutathione suppletion and others). In this review, the possible pharmacological approaches and their respective advantages and disadvantages are discussed.     

The NMDA/D1 receptor complex as a new target in drug development

Dopamine and glutamate have been shown to extensively interact in the striatum, nucleus accumbens, hippocampus and prefrontal cortex, to regulate different physiological functions, including locomotor activity, positive reinforcement, attention and working memory. Although dysfunctions of dopamine transmission have long been identified as critical determinants of neurological and neuropsychiatric disorders, such as Parkinson's disease and schizophrenia, there is now increasing evidence that concurrent alterations of dopamine and glutamate function may play a central role in the pathophysiology of these diseases. Thus, defining the characteristics of dopamine-glutamate interactions may be crucial to identify alternative molecular targets for the development of novel pharmacological tools. At the postsynaptic level, interactions between the dopamine D1 and the glutamate NMDA receptors appear to be particularly relevant. Different mechanisms are involved in this interactions: 1) D1R-dependent, second messenger-mediated phosphorylation of NMDAR subunits; 2) coordinated regulation of receptor trafficking at synaptic sites; 3) formation of an heteromeric D1/NMDA receptor complex. In this paper we review the molecular mechanisms, functional implications and pharmacological significance of D1R/NMDAR interaction via direct protein-protein oligomerization.     

The experimental pharmacotherapy of benzodiazepine withdrawal.

In many people, long-term benzodiazepine (BZ) use produces dependence with manifestation of withdrawal symptoms after abrupt cessation of BZ treatment. The current therapy of BZ dependence in humans utilizes gradual dose-taper to avoid withdrawal symptoms and supportive psychotherapy to help patients cope with withdrawal reactions. The failure of dose-taper in many patients has triggered intensive animal research to find additional pharmacological treatments. The present article reviews evidence from animal studies on effectiveness of pharmacological treatment for BZ dependence and withdrawal. It explores the risk-benefit profiles of putative therapies for BZ withdrawal, including drugs acting via benzodiazepine receptors, serotonergic and noradrenergic agents, cholecystokinin-B receptor antagonists, calcium channel blockers, N-methyl-D-aspartate (NMDA) antagonists, and other miscellaneous agents.     

Dopaminergic enhancement of cognitive function

The ascending dopamine system of the mammalian brain has been associated with motor, mnemonic and goal-directed or reward-related behaviour. The most progress in understanding the cortical mechanisms of dopaminergic modulation of function has been made with regards to short-term mnemonic (or working memory) function. Research in experimental animals strongly suggests that stimulation of dopamine D1 receptors in the prefrontal cortex can ameliorate spatial working memory related cognitive deficits, and may even enhance cognitive function in healthy animals. Research in humans has not been able to clearly replicate these findings, partly due to the lack of available agents that can safely be used. Low doses of dopamine D2 receptor agonists such as bromocriptine and pergolide may be able to enhance working memory and executive functions, but these effects may be dependent on the nature of the tasks used and the baseline performance levels of the subjects. Thus, the effects of dopaminergic cognitive enhancers may not be simple, or uniform across subjects. Systematic studies in humans carefully controlling task parameters are needed in order to specify the potential cognitive processes open to enhancement with dopaminergics. However, since the DA receptor subtypes in different brain regions appear to differentially influence similar functions, carefully defining the cognitive processes to be tested against potential therapeutics is an equally important goal. Studies in patients groups using selective dopaminergics are rather restricted, but show promise for designing large-scale clinical trials into the cognitive enhancing properties of potential therapeutic agents that act through the dopamine system.     

NMDA receptors as targets for drug action in neuropathic pain.

Hyperalgesia and allodynia following peripheral tissue or nerve injury are not only due to an increase in the sensitivity of primary afferent nociceptors at the site of injury but also depend on NMDA receptor-mediated central changes in synaptic excitability. Functional inhibition of NMDA receptors can be achieved through actions at different recognition sites such as the primary transmitter site (competitive), strychnine-insensitive glycine site (glycine(B)), polyamine site (NR2B selective) and phencyclidine site located inside the cationic channel. Unfortunately, most agents which completely block NMDA receptors cause numerous side effects such as memory impairment, psychotomimetic effects, ataxia and motor incoordination. There is now, however, considerable evidence that moderate affinity channel blockers, glycine(B) and NR2B selective antagonists show a much better profile in animal models than high affinity channel blockers and competitive NMDA receptor antagonists. These "therapeutically" safe NMDA receptor antagonists are also able to slow or prevent the development of opioid tolerance, indicating the utility of their combination with opioids in the treatment of chronic pain. The antinociceptive effects of NMDA receptor antagonists and opioids could be predicted to be synergistic and the presence of an NMDA receptor antagonist should block both the development of chronic pain states and inhibit the development of tolerance to the analgesic effects of morphine. Peripheral NMDA receptors offer a very attractive target for NMDA receptor antagonists that do not cross the blood brain barrier in inflammatory and visceral pain. Such agents might be predicted to be devoid of CNS side effects at doses producing powerful antinociception at peripheral NMDA receptors.     

Glutamate input to noradrenergic neurons plays an essential role in the development of morphine dependence and psychomotor sensitization

The brain's noradrenergic system is involved in the development of behaviours induced by drugs of abuse, e.g. dependence and withdrawal, and also reward or psychomotor effects. To investigate how noradrenergic system activity is controlled in the context associated with drug-induced behaviours, we generated a Cre/loxP mouse model in which the essential glutamate NMDA receptor subunit NR1 is ablated in cells expressing dopamine β-hydroxylase (Dbh). As a result, the noradrenergic cells in NR1DbhCre mice lack the NMDA receptor-dependent component of excitatory post-synaptic currents. The mutant mice displayed no obvious behavioural alterations, had unchanged noradrenaline content and mild increase in dopamine levels in the nucleus accumbens. Interestingly, NR1DbhCre animals did not develop morphine-induced psychomotor sensitization. However, when the morphine injections were preceded by treatment with RX821002, an antagonist of α2-adrenergic receptors, the development of sensitization was restored. Conversely, pretreatment with clonidine, an agonist of α2-adrenergic receptors, blocked development of sensitization in wild-type mice. We also found that while the development of tolerance to morphine was normal in mutant mice, withdrawal symptoms were attenuated. These data reveal that NMDA receptors on noradrenergic neurons regulate development of opiate dependence and psychomotor sensitization, by controlling drug-induced noradrenaline signalling.     

Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia

Several lines of evidence implicate NMDA receptor dysfunction in the cognitive deficits of schizophrenia, suggesting that pharmacological manipulation of the NMDA receptor may be a feasible therapeutic strategy for treatment of these symptoms. Although direct manipulation of regulatory sites on the NMDA receptor is the most obvious approach for pharmacological intervention, targeting the G-protein coupled metabotropic glutamate (mGlu) receptors may be a more practical strategy for long-term regulation of abnormal glutamate neurotransmission. Heterogeneous distribution, both at structural and synaptic levels, of at least eight subtypes of mGlu receptors suggests that selective pharmacological manipulation of these receptors may modulate glutamatergic neurotransmission in a regionally and functionally distinct manner. Two promising targets for improving cognitive functions are mGlu5 or mGluR2/3 receptors, which can modulate the NMDA receptor-mediated signal transduction by pre- or postsynaptic mechanisms. Preclinical studies indicate that activation of these subtypes of mGlu receptors may be an effective strategy for reversing cognitive deficits resulting form reduced NMDA receptor mediated neurotransmission.     

N-methyl-D-aspartate receptor-coupled glycineB receptors in the pathogenesis and treatment of schizophrenia: a critical review

Glutamatergic pathways, metabotropic receptors, and ionotropic alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA), kainate and N-methyl-D-aspartate (NMDA) receptors are all implicated in the etiology and management of schizophrenia. As concerns NMDA receptors, open channel blockers (OCBs) such as phencyclidine (PCP) elicit psychotic symptoms in human subjects. This observation underpins biochemical studies indicating that a deficit in activity at NMDA receptors may be associated with psychotic states. Inasmuch as agonists at the NMDA recognition site are excitotoxic, drugs acting via the co-agonist, glycine(B) (GLY(B)) site are more promising clinical candidates as antipsychotic agents. Glycine (GLY) itself, a further endogenous agonist, D-Serine, and inhibitors of GLY reuptake are active in certain experimental models predictive of antipsychotic properties. Further, in controlled clinical trials, GLY and D-Serine enhance the ability of conventional neuroleptics such as haloperidol to improve cognitive and negative symptoms. Their actions are mimicked by the partial agonist, D-cycloserine (DCS). However, these agents exert little effect alone and may interfere with therapeutic actions of the atypical antipsychotic, clozapine. An important issue in the interpretation of drug actions at GLY(B) sites is their degree of occupation by endogenous GLY and D-Serine - although they are unlikely to be saturated. Further, distinct "subtypes" of GLY(B) site-bearing NMDA receptor may fulfill differential roles in psychotic states Finally, blockade of certain populations of NMDA receptor may be of use in the management of schizophrenia. This article reviews the complex role of GLY(B) sites/NMDA receptors and their endogenous ligands in the pathogenesis and treatment of psychotic states.     

The pharmacology of human working memory

Experimental studies conducted primarily on non-human primates have begun to address the anatomical and neurochemical correlates of working memory. There is an associated growing body of experimental literature investigating whether modulating key neurotransmitters can facilitate working memory in humans. This paper reviews evidence that acute modulation of dopamine in particular, but also noradrenaline, acetylcholine and serotonin may influence working-memory performance in humans. Differences in neurochemical specificity with regard to stages of working memory, type of working memory (spatial or non-spatial) and cortical effects are also discussed. This evidence has contributed to neuropharmacological understanding of working memory in humans. The important therapeutic consequences of a better understanding of facilitation of working memory is discussed in reference to schizophrenia, Parkinson's disease and Alzheimer's disease.     

Progress in the preparation and testing of glycine transporter type-1 (GlyT1) inhibitors

Clinically utilized antipsychotic agents share as a common mechanism the ability to antagonize dopamine D2 receptors and it is widely assumed that this activity contributes to their efficacy against the positive symptoms of schizophrenia. The efficacy of currently marketed antipsychotic agents on the negative and cognitive symptoms of this disease, however, is not optimal. One alternate hypothesis to the "dopamine hypothesis" of schizophrenia derives from the observation that antagonists of NMDA receptor activity better mimic the symptomatology of schizophrenia in its entirety than do dopamine agonists. Findings from this line of research have led to the NMDA receptor hypofunction (or glutamate dysfunction) hypothesis of schizophrenia, which complements existing research implicating dopamine dysfunction in the disease. According to the NMDA receptor hypofunction hypothesis, any treatment that enhances NMDA receptor activity may prove useful for the treatment of the complex symptoms that define schizophrenia. This idea is now supported by numerous clinical studies that have reported an efficacious response following treatment with activators of the NMDA receptor co-agonist glycineB site. One area of study, aimed at potentiating the NMDA receptor via activation of the glycineB site is small molecule blockade of the glycine reuptake transporter type 1 (GlyT1). Broadly, these efforts have focused on derivatives of the substrate inhibitor, sarcosine, and non-sarcosine based GlyT1 inhibitors. Accordingly, the following review discusses the development of both sarcosine and non-sarcosine based GlyT1 inhibitors and their current status as putative treatments for schizophrenia and other disorders associated with NMDA receptor hypoactivity.     

Presynaptic regulation of the release of catecholamines

During norepinephrine release elecited by the arrival of nerve impulses, the neurotransmitter interacts with specific receptors (alpha1-, beta1-, beta2-adrenoceptors) located in the membrane of the postsynaptic cell to trigger the response of the effector organ. Until a few years ago, it was thought that the role of noradrenergic nerve terminals in neurotransmission is concerned exclusively with the synthesis, storage, release, and inactivation of norepinephrine and there were no indications that receptors might also be present in the presynaptic membrane. During the last decade, evidence has accumulated in favour of the view that, in addition to the classical postsynaptic adrenoceptors that mediate the responses of the effector organ, there are also receptors located on the noradrenergic nerve terminals. These presynaptic recptors are involved in the modulation of the calcium-dependent, action-potential-evoked release of norepinephrine in the peripheral as well as in the central nervous system. Presynaptic inhibitory alpha-adrenoceptors are involved in the regulation of the release of norepinephrine through a negative feedback mechanism mediated by the neuron's own transmitter. Alpha-Adrenoceptor agonists inhibit the release of norepinephrine during nerve stimulation, while alpha-adrenoceptor blocking agents enhance the stimulation-evoked release of the neurotransmitter. These results have been obtained both i vitro and in vivo. There are pharmacological differences between the postsynaptic alpha-adrenoceptors that mediate the response of the effector organ and the presynaptic inhibitory alpha-adrenoceptors that modulate the release of norepinephrine during nerve stimulation. The subclassification of alpha-adrenoceptors into alpha1- and alpha2-types is bases on differences in relative affinities for a range of alpha-adrenoceptor agoinst and antagonist durgs. The term alpha1-adrenceptor is used for a receptor that is preferentially stimulated by phenylephrine and blocked by prazosin, whereas alpha2-adrenoceptor is reserved for those preferentially stimulated by guanabenz or clonidine and blocked by rauwolscine or yohimbine. The presynaptic inhibitory alpha-adrenoceptors in the peripheral and in the central nervous system have the pharmacological characteristics of the alpha2-adrenoceptors. Presynaptic inhibiotry autoreceptors appear to be involved in the modulation of the release of dopamine and of epinephrine in the central nervous system. A short negative feedback mechanism similar to that for norepinephrine appears to regulate the stimulation-evoked release of dopamine and epinephrine in central neurons. In addition to presynaptic autoreceptors through which the transmitter can modulate its own release, a real mosaic of receptors in present on noradrenergic nerve endings...     

Inhaled drugs of abuse enhance serotonin-3 receptor function

Despite the prevalence of their use, little is currently known of the molecular mechanisms of action of inhaled drugs of abuse. Recent studies have shown effects on NMDA, GABA(A) and glycine receptors in vitro, suggesting that inhalants may exert at least some of their pharmacological effects on ligand-gated ion channels. Enhancement of serotonin-3 receptor function has been shown to play a role in the reinforcing properties of drugs of abuse. We tested the hypothesis that the commonly abused inhaled agents 1,1,1-trichloroethane, trichloroethylene, and toluene enhance serotonin-3 receptor function. All three inhalants significantly and reversibly potentiated, in a dose-dependent manner, serotonin-activated currents mediated by mouse serotonin-3A receptors expressed in Xenopus oocytes. Our findings add the serotonin-3 receptor to the growing list of molecular targets commonly affected by both inhalants and classic CNS depressants such as ethanol and the volatile anesthetics.     

Glutamate-based therapeutic approaches: inhibitors of glycine transport

A growing body of evidence suggests that activation of the glutamatergic system, particularly N-methyl-D-aspartate (NMDA) receptor function, may be a viable approach to the treatment of schizophrenia, and potentially other cognitive disorders. The excitotoxicity associated with direct NMDA receptor agonists limits their therapeutic potential, and the glycine modulatory site of the NMDA receptor has received growing interest as a therapeutic target. One approach to enhance NMDA receptor function is to increase the availability of the necessary co-agonist glycine at this modulatory site through inhibition of glycine reuptake from the synapse via glycine transporter-1 (GlyT1). Both preclinical and clinical evidence provide support for this approach, as do recent findings demonstrating the regulation of dopaminergic neurotransmission by GlyT1 inhibition. As a result, several groups have focused on the development of novel GlyT1 inhibitors. In addition, recent electrophysiological findings and data from transgenic mouse models suggest that GlyT1 might also play a role in terminating the actions of glycine at strychnine-sensitive glycine receptors, and therefore GlyT1 antagonists also have potential for the treatment of conditions where activation of inhibitory pathways in the central nervous system might be beneficial.     

Twenty years of dopamine research: individual differences in the response of accumbal dopamine to environmental and pharmacological challenges

Individual differences in the dopaminergic system of the nucleus accumbens of rats have extensively been reported. These individual differences have frequently been used to explain individual differences in response to environmental and pharmacological challenges. Remarkably, only little attention is paid to the factors that underlie these individual differences. This review gives an overview of the studies that have been performed in our institute during the last 20 years to investigate individual differences in accumbal dopamine release. Data are summarised demonstrating that individual differences in accumbal dopamine release are due to individual differences in: the functional reactivity of the noradrenergic system, the accumbal concentration of vesicular monoamine transporters and tyrosine hydroxylase as well as in the quantal size of the presynaptic pools of dopamine. Our data are embedded in the available literature to create a model that illustrates the putative hardware giving rise to the individual-specific release of accumbal dopamine. An important role is contributed to individual differences in the reactivity of the: hypothalamic–pituitary–adrenal axes, the reactivity of second messenger systems as well in the aminergic reactivity of the accumbens shell and core. The consequences of the individual-specific make-up and reactivity of the nucleus accumbens on the regulation of behaviour and the response to drugs of abuse will also be discussed. Apart from agents that interact with dopaminergic receptors, re-uptake or breakdown, noradrenergic agents as well as agents that interact with vesicular monoamine transporters or tyrosine hydroxylase are suggested to have therapeutic effects in subjects that are suffering from diseases in which the dopaminergic system is disturbed.     

Acute neurobehavioral effects of toluene: Involvement of dopamine and NMDA receptors

Toluene, a widely used and commonly abused organic solvent, causes a variety of behavioral disturbances in both humans and animals. In this study, the effects of toluene on locomotor activity, motor coordination, and passive avoidance learning, along with the possible mechanism underlying these toluene-induced behavioral manifestations, were investigated. Sprague–Dawley rats were tested in the open field test, rotarod test, and step-through avoidance learning task after receiving toluene (250–750 mg/kg, i.p.). Toluene dose-dependently produced locomotor hyperactivity, motor incoordination, and memory impairment. In order to determine the possible roles of dopamine and NMDA receptors in these behavioral responses to toluene, dopamine D1 receptor antagonist SCH23390, D2 receptor antagonist raclopride, D3 receptor antagonist nafadotride, or d-serine, a co-agonist at the glycine binding site of NMDA receptors, were given prior to toluene administration. SCH23390, raclopride, and nafadotride attenuated locomotor hyperactivity, but not motor incoordination and memory impairment in response to toluene, whereas d-serine reduced all the toluene-induced behavioral alterations. These findings suggest that blockade of NMDA receptors may play a critical role in acute toluene-induced locomotor hyperactivity, motor incoordination, and memory impairment, and that dopamine neurotransmission may be specifically involved in locomotor hyperactivity.