Dopamine is not Required for the Hyperlocomotor Response to NMDA Receptor Antagonists

Abstract

N-methyl-D-aspartate (NMDA) receptor antagonists can elicit symptoms in humans that resemble those seen in schizophrenic patients. Rodents manifest locomotor and stereotypic behaviors when treated with NMDA receptor antagonists such as phencyclidine (PCP) or dizocilpine maleate (MK-801); these behaviors are usually associated with an activated dopamine system. However, recent evidence suggests that increased glutamatergic transmission mediates the effects of these NMDA receptor antagonists. The role of dopamine in PCP-and MK-801-induced behavior (eg hyperlocomotion) remains unclear. We used dopamine-deficient (DD) mice in which tyrosine hydroxylase is selectively inactivated in dopaminergic neurons to determine whether dopamine is required for the locomotor and molecular effects of PCP and MK-801. DD mice showed a similar increase in locomotor activity and c-fos mRNA induction in the striatum in response to these NMDA receptor antagonists as control mice. Restoration of dopamine signaling in DD mice enhanced their locomotor response to PCP and MK-801. Administration of LY379268, a group II metabotropic glutamate receptor agonist that inhibits glutamate release, blocked PCP-and MK-801-induced hyperlocomotion in both DD and control mice. These results suggest that glutamate, rather than dopamine, is required for the locomotor and molecular effects of NMDA receptor antagonists, but that glutamate and dopamine can act cooperatively.

Relative Prenatal and Postnatal Maternal Contributions to Schizophrenia-Related Neurochemical Dysfunction after In Utero Immune Challenge

“…It has therefore been suggested that blockade of NMDA receptors may lead to inhibition of the corticostriatal glutamatergic pathway and eventually result in excessive activation of cortical and subcortical structures, thereby stimulating locomotor activity (Carlsson et al, 2001). However, the different views on the neuronal substrates underlying MK-801-induced stimulation of locomotor activity are not mutually exclusive (Chartoff et al, 2005). Our immunohistochemical analyses of the NMDA-receptor subunit NR1 did not reveal any significant changes as a function of the prenatal and postnatal manipulations (Table 3).…”

“…In contrast, MK-801-induced hyperlocomotor activity can also occur in the absence of endogenous dopamine (Carlsson and Carlsson, 1989;Chartoff et al, 2005). It has therefore been suggested that blockade of NMDA receptors may lead to inhibition of the corticostriatal glutamatergic pathway and eventually result in excessive activation of cortical and subcortical structures, thereby stimulating locomotor activity (Carlsson et al, 2001).…”

The role of serotonin in the NMDA receptor antagonist models of psychosis and cognitive impairment

“…Thus, NMDAR antagonists induce hyperlocomotion in catecholamine-depleted animals (Carlsson and Carlsson 1989;Swanson and Schoepp 2002). PCP and MK-801 produced hyperlocomotion in genetically DA-deficient mice that was not significantly antagonized by the D 2 antagonist, haloperidol, nor the D 1 antagonist, SCH 23390 (Chartoff et al 2005). The limited importance of nucleus accumbens dopaminergic activity for NMDAR antagonistinduced locomotion is also supported by the finding that DA depletion via local administration of 6-OH-DA, attenuates, but does not prevent, PCP-induced hyperlocomotion (Steinpreis and Salamone 1993).…”

Addiction-Related Alterations in D1 and D2 Dopamine Receptor Behavioral Responses Following Chronic Cocaine Self-Administration

“…The psychomotor and reinstating effects of MK-801 are thought to occur independent of dopamine release and dopamine receptor activation (Druhan et al, 1996;Wise et al, 1996;De Vries et al, 1998;Chartoff et al, 2005). Similar to D 2 receptor challenge, animals in both low and high intake groups displayed robust locomotor sensitization to MK-801 challenge following chronic cocaine self-administration.…”