MK-801 increases locomotor activity without elevating extracellular dopamine levels in the nucleus accumbens

Druhan, Jonathan P.; Rajabi, Heshmat; Stewart, Jane

doi:10.1002/(sici)1098-2396(199610)24:2<135::aid-syn5>3.0.co;2-g

Cited by 65 publications

(26 citation statements)

References 66 publications

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“…However, in the present study subchronic PCP treatment substantially increased amphetamine-induced locomotor hyperactivity without altering the NAc dopamine levels, suggesting that the enhancement of activity could not be attributed to increased activity within the mesoaccumbens system. This finding is consistent with the results of both Druhan et al (1996) and Wolf et al (1994), who observed that MK-801 potentiated amphetamine-induced hyperactivity without, itself, inducing dopamine release in NAc or potentiating amphetamine-induced dopamine release. It has recently been suggested that locomotor effects of acutely administered PCP reflect its actions within PFC rather than NAc (Adams and Moghaddam, 1998;Jentsch et al, 1998b) which is consistent with an earlier work of Nabeshima et al (1983).…”

Section: Dissociation Between Behavioral Effects and Nac Dopamine Relsupporting

confidence: 92%

Subchronic Continuous Phencyclidine Administration Potentiates Amphetamine-Induced Frontal Cortex Dopamine Release

Balla

Sershen

Serra

et al. 2003

Neuropsychopharmacol

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Functional dopaminergic hyperactivity is a key feature of schizophrenia. Etiology of this dopaminergic hyperactivity, however, is unknown. We have recently demonstrated that subchronic phencyclidine (PCP) treatment in rodents induces striatal dopaminergic hyperactivity similar to that observed in schizophrenia. The present study investigates the ability of PCP to potentiate amphetamine-induced dopamine release in prefrontal cortex (PFC) and nucleus accumbens (NAc) shell. Prefrontal dopaminergic hyperactivity is postulated to underlie cognitive dysfunction in schizophrenia. In contrast, the degree of NAc involvement is unknown and recent studies have suggested that PCP-induced hyperactivity in rodents may correlate with PFC, rather than NAc, dopamine levels. Rats were treated with 5-20 mg/kg/day PCP for 3-14 days by osmotic minipump. PFC and NAc dopamine release to amphetamine challenge (1 mg/kg) was monitored by in vivo microdialysis and HPLC-EC. Doses of 10 mg/kg/day and above produced serum PCP concentrations (50-150 ng/ml) most associated with PCP psychosis in humans. PCP-treated rats showed significant, dose-dependent enhancement in amphetamine-induced dopamine release in PFC but not NAc, along with significantly enhanced locomotor activity. Enhanced response was observed following 3-day, as well as 14-day, treatment and resolved within 4 days of PCP treatment withdrawal. These findings support the concept that endogenous NMDA receptor dysfunction could account for the pattern of dopaminergic dysfunction observed in schizophrenia, and suggest that even short duration abuse of PCP-like agents may greatly potentiate behavioral effects of psychostimulants in drug abuse situations. Finally, these studies provide a model system in which to evaluate effects of potential psychotherapeutic agents.

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Section: Dissociation Between Behavioral Effects and Nac Dopamine Relsupporting

confidence: 92%

Subchronic Continuous Phencyclidine Administration Potentiates Amphetamine-Induced Frontal Cortex Dopamine Release

Balla

Sershen

Serra

et al. 2003

Neuropsychopharmacol

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“…1B). These data confirm the notion that the hyperactivity induced by pharmacological or genetic suppression of NMDA receptor function is not related to the modulation of striatal extracellular dopamine levels (10)(11)(12)(30)(31)(32)(33).…”

Section: Striatal Extracellular Levels Of Dopamine Are Not Affected Bcontrasting

confidence: 63%

Glutamatergic modulation of hyperactivity in mice lacking the dopamine transporter

Gainetdinov

Mohn

Bohn

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

152

109

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In the brain, dopamine exerts an important modulatory influence over behaviors such as emotion, cognition, and affect as well as mechanisms of reward and the control of locomotion. The dopamine transporter (DAT), which reuptakes the released neurotransmitter into presynaptic terminals, is a major determinant of the intensity and duration of the dopaminergic signal. Knockout mice lacking the dopamine transporter (DAT-KO mice) display marked changes in dopamine homeostasis that result in elevated dopaminergic tone and pronounced locomotor hyperactivity. A feature of DAT-KO mice is that their hyperactivity can be inhibited by psychostimulants and serotonergic drugs. The pharmacological effect of these drugs occurs without any observable changes in dopaminergic parameters, suggesting that other neurotransmitter systems in addition to dopamine might contribute to the control of locomotion in these mice. We report here that the hyperactivity of DAT-KO mice can be markedly further enhanced when N-methyl-D-aspartate receptor-mediated glutamatergic transmission is blocked. Conversely, drugs that enhance glutamatergic transmission, such as positive modulators of L-␣-amino-3-hydroxy-5-methylisoxazole-4-propionate glutamate receptors, suppress the hyperactivity of DAT-KO mice. Interestingly, blockade of Nmethyl-D-aspartate receptors prevented the inhibitory effects of both psychostimulant and serotonergic drugs on hyperactivity. These findings support the concept of a reciprocal functional interaction between dopamine and glutamate in the basal ganglia and suggest that agents modulating glutamatergic transmission may represent an approach to manage conditions associated with dopaminergic dysfunction. F rontostriatal circuitry is one of the most prominent brain pathways involved in the control of locomotion, affect, impulsivity, attention, and emotion (1, 2). One axis of this circuitry involves dopaminergic projections into the striatal and mesolimbic brain areas (1, 3). Dopaminergic transmission has been intensively studied and is relatively well characterized (1, 3), largely because alterations in dopaminergic tone have clear behavioral manifestations such as changes in locomotor activity. In addition to dopaminergic innervation from substantia nigra and ventral tegmental area, the basal ganglia receive dense glutamatergic input predominantly from prefrontal cortical areas, as well as from the hippocampus, periventricular thalamus, and amygdala (1, 4, 5). There is a growing appreciation for the concept that dopaminergic and glutamatergic systems intimately interact at the level of medium-sized spiny neurons in the basal ganglia to control behavior (1, 6, 7). Particularly, an interaction at the levels of receptor signaling and regulation between dopamine D1 and͞or D2-like receptors and ionotropic glutamate N-methyl-D-aspartate (NMDA) and L-␣-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors, has been put forth (7-9). Recent findings in mice with decreased NMDA receptor expression (10) confirmed and extended pr...

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“…NMDA antagonists are reported to enhance amphetamine-induced locomotor activity following both acute (Sripada et al 1998;Druhan et al 1996; Turgeon and Roche 1999) and continuous (Jentsch et al 1998) treatment, although contrary results have also been obtained (Gandolfi et al 1992). For the present study, therefore, amphetamine-induced locomotor activity was monitored along with striatal dopamine release.…”

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confidence: 89%

Continuous Phencyclidine Treatment Induces Schizophrenia-Like Hyperreactivity of Striatal Dopamine Release

Balla

Koneru

Smiley

et al. 2001

Neuropsychopharmacology

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Schizophrenia is a widely prevalent neuropsychiatric disorder of unknown etiology. The most widely accepted neurochemical model of schizophrenia, the dopamine model, proposes that schizophrenia is associated with functional hyperactivity of brain dopaminergic systems (Stein and Wise 1971;Davis et al. 1991;Jentsch and Roth 1999). This model is supported by the observations that amphetamine and other dopaminergic agents induce psychotic symptoms that closely resemble those of schizophrenia and that currently available antipsychotic agents function primarily by blocking dopamine (D2) receptors. Mechanisms underlying dopamine dysfunction in schizophrenia, however, remain obscure.Over the past decade, increasing attention has been paid to alternative neurochemical conceptualizations of schizophrenia based upon the phencyclidine/ N -methyl-D -aspartate (PCP/NMDA) model (Javitt 1987;Javitt and Zukin 1991). This hypothesis is based upon the observation that PCP and other dissociative anesthetictype psychotomimetics (e.g., ketamine, MK-801) induce symptoms that closely resemble those of schizophrenia but differ somewhat from the symptoms induced by amphetamine (Luby et al. 1959(Luby et al. , 1962Domino and Luby 1981 Javitt and Zukin 1991;Olney and Farber 1995;Newcomer et al. 1999;Jentsch and Roth 1999).The present study investigates the degree to which continuous treatment with PCP leads to schizophrenialike disturbances in dopamine regulation. This issue has been complicated until recently by the relative paucity of information concerning endogenous dopamine levels in schizophrenia. Over the past several years, however, several studies using in vivo radioreceptor label studies have demonstrated significant striatal hyperreactivity to amphetamine-stimulated dopamine release in schizophrenia (Laruelle et al. 1996(Laruelle et al. , 1999Breier et al. 1997;Abi-Dargham et al. 1998). Enhanced striatal dopamine levels were also observed following ketamine administration in normal volunteers (Breier et al. 1998), supporting a potential role for NMDA receptors in dopamine hyperactivity in schizophrenia. Similar effects of acute administration of NMDA antagonists are observed in rodents (Hiramatsu et al. 1989;Lillrank et al. 1994;Yonezawa et al. 1995).Given that schizophrenia is a chronic condition potentially arising from persistent dysfunction of NMDA receptor-mediated neurotransmission, continuous PCP administration provides a superior dosing paradigm than does acute administration (Sams-Dodd 1999;Jentsch et al. 1998). Further, continuous administration permits amphetamine-induced effects to be measured against a constant background PCP level. For the present study, rats were treated chronically with PCP, and dopamine response to amphetamine was measured in striatum using in vivo microdialysis to investigate the degree to which continuous PCP treatment leads to enhanced responsiveness to amphetamine challenge. PCP was administered by osmotic minipump to maintain as constant a level of PCP as possible, in order to model a persis...

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MK-801 increases locomotor activity without elevating extracellular dopamine levels in the nucleus accumbens

Cited by 65 publications

References 66 publications

Subchronic Continuous Phencyclidine Administration Potentiates Amphetamine-Induced Frontal Cortex Dopamine Release

Subchronic Continuous Phencyclidine Administration Potentiates Amphetamine-Induced Frontal Cortex Dopamine Release

Glutamatergic modulation of hyperactivity in mice lacking the dopamine transporter

Continuous Phencyclidine Treatment Induces Schizophrenia-Like Hyperreactivity of Striatal Dopamine Release

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