MK-801 does not prevent acute stimulatory effects of amphetamine or cocaine on locomotor activity or extracellular dopamine levels in rat nucleus accumbens

Wolf, Marina E.; Xue, Chang Jiang; White, Francis J.; Dahlin, S.L.

doi:10.1016/0006-8993(94)90776-5

Cited by 49 publications

(20 citation statements)

References 53 publications

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“…Lower doses of dizocilpine have no e¤ect on the reinforcing e¤ect of cocaine measured with a FR (present results) or PR (Ranaldi et al 1996) schedule of reinforcement, while a slightly higher doses of dizocilpine (0.20.3 mg / kg) decrease responding for cocaine maintained by FR (Shoab et al 1995) or PR (Ranaldi et al 1996) schedules. These Þndings are consistent with observations that higher doses of dizocilpine result in an increase in locomotor activity accompanied with motor impairment and ataxia in rodents (Carter 1994;Wolf et al 1994;Druhan et al 1996) that is not observed at doses less than 0.25 mg / kg (see Fig. 3; Kalivas and Alesdatter 1993;Stewart and Druhan 1993;Jeziorski et al 1994;Wolf et al 1994).…”

Section: Discussionsupporting

confidence: 91%

The NMDA antagonist, dizocilpine, enhances cocaine reinforcement without influencing mesoaccumbens dopamine transmission

Rc¹,

Wm²,

Pw³

1997

Psychopharmacology

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In order to assess the role of excitatory amino acids (EAAs) in the reinforcing property of cocaine, the NMDA antagonist, dizocilpine, or the AMPA antagonist, DNQX, were administered to animals previously trained to self-administer cocaine (1.0, 0.4 or 0.16 mg/kg per infusion). The highest doses of dizocilpine (0.1 mg/kg, IP) and DNQX (30 mg/kg, IP) significantly reduced operant responding for cocaine maintained on a fixed ratio schedule of reinforcement. However, whereas dizocilpine had no influence operant responding for food, DNQX significantly decreased lever pressing for this reinforcer. These results indicate that an NMDA antagonist produces a relatively selective enhancement of cocaine reinforcement, while an AMPA antagonist decreases cocaine self-administration only at a dose that also impairs responding for an alternate reinforcer. A parallel in vivo microdialysis study performed in freely moving rats tested the effects of dizocilpine alone and in combination with cocaine on extracellular dopamine in the nucleus accumbens shell. The results revealed that dizocilpine alone (0.1 mg/kg, IP) did not alter basal extracellular dopamine levels in the nucleus accumbens or spontaneous behavior. In addition, 0.1 mg/kg dizocilpine did not alter the increase in dopamine in the accumbens shell or behavioral hyperactivity produced by cocaine (15 or 30 mg/kg). Collectively, these findings suggest that dizocilpine enhances the reinforcing effect of cocaine without influencing dopamine transmission in the nucleus accumbens shell.

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Section: Discussionsupporting

confidence: 91%

The NMDA antagonist, dizocilpine, enhances cocaine reinforcement without influencing mesoaccumbens dopamine transmission

Rc¹,

Wm²,

Pw³

1997

Psychopharmacology

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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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“…The lack of an increase in extracellular DA after MK-801 injections also was not due to an insensitivity of the microdialysis assay to changes in voltage-dependent release; DA concentrations in the NAS were significantly reduced following administration of apomorphine at doses that are known to decrease firing rates of mesolimbic DA cells (Akaoka et al, 1992;Grace and Bunney, 1985). These considerations, together with other concurring findings (Rossetti et al, 1992;Segal et al, 1995;Wolf et al, 1994b), lead us to conclude that the behavioral activation produced by MK-801 does not result from changes in NAS DA transmission, and that either non-DA or extra-NAS DA neurons mediate the locomotor stimulant effects of MK-801.…”

Section: Discussionsupporting

confidence: 68%

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

Druhan

Rajabi

Stewart

1996

Synapse

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In vivo microdialysis was used in freely moving rats to determine whether the locomotor stimulant effects of dizocilpine maleate (MK-801) were related to increased dopamine (DA) release within the nucleus accumbens (N. Acc.). Each experiment began with a baseline period of at least 2 h (starting 15-20 h after insertion of concentric, removable dialysis probes), during with activity records and dialysate samples were collected every 20 min. Rats in the first experiment then were injected with MK-801 (0.125, 0.25, or 0.50 mg/kg, i.p.) or saline, and activity and extracellular levels of DA, dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were measured for a further 160 min post-injection. In a second experiment, rats were given 1.5 mg/kg d-amphetamine sulphate 40 min after receiving the same doses of MK-801, and testing was continued for 120 min. Rats in a third experiment were given low, autoreceptor-preferring doses of apomorphine hydrochloride (25 or 50 micrograms/kg, s.c.) or its vehicle 40 min after injection of 0.25 mg/kg MK-801 and then monitored for 120 min. MK-801 produced strong and consistent increases in locomotor activity that were augmented by amphetamine and greatly reduced by the low doses of apomorphine. MK-801 did not increase extracellular DA levels within the N. Acc. when given alone, and it failed to influence the changes in extracellular DA produced by d-amphetamine and apomorphine. MK-801 did produce consistent, dose-related increases in DOPAC and HVA that were probably not related to transmitter release. These results indicate that the increases in locomotor activity seen following MK-801 do not arise from a drug-induced increase in DA levels within the N. Acc.

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MK-801 does not prevent acute stimulatory effects of amphetamine or cocaine on locomotor activity or extracellular dopamine levels in rat nucleus accumbens

Cited by 49 publications

References 53 publications

The NMDA antagonist, dizocilpine, enhances cocaine reinforcement without influencing mesoaccumbens dopamine transmission

The NMDA antagonist, dizocilpine, enhances cocaine reinforcement without influencing mesoaccumbens dopamine transmission

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

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

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