Intracellular Modulation of NMDA Receptor Function by Antipsychotic Drugs

Abstract

The present study deals with the functional interaction of antipsychotic drugs and NMDA receptors. We show that both the conventional antipsychotic drug haloperidol and the atypical antipsychotic drug clozapine mediate gene expression via intracellular regulation of NMDA receptors, albeit to different extents. Data obtained in primary striatal culture demonstrate that the intraneuronal signal transduction pathway activated by haloperidol, the cAMP pathway, leads to phosphorylation of the NR1 subtype of the NMDA receptor at (897)Ser. Haloperidol treatment is likewise shown to increase (897)Ser-NR1 phosphorylation in rats in vivo. Mutation of (896)Ser and (897)Ser to alanine, which prevents phosphorylation at both sites, inhibits cAMP-mediated gene expression. We conclude that antipsychotic drugs have the ability to modulate NMDA receptor function by an intraneuronal signal transduction mechanism. This facilitation of NMDA activity is necessary for antipsychotic drug-mediated gene expression and may contribute to the therapeutic benefits as well as side effects of antipsychotic drug treatment.

The Transcription Factor NGFI-B (Nur77) and Retinoids Play a Critical Role in Acute Neuroleptic-Induced Extrapyramidal Effect and Striatal Neuropeptide Gene Expression

“…Other signaling pathways such as those implicating phospholipase C, intracellular calcium stores and protein kinase C (PKC) might also be involved (see Hernandez-Lopez et al, 2000). In addition, modulation of NGFI-B expression might also be indirect through modulation of glutamate neurotransmission by neuroleptic drugs (Leveque et al, 2000). Additional investigations are needed in order to identify the cellular The present results also indicate that retinoids might be involved in behavioral and biochemical effects of neuroleptics.…”

Striatal proenkephalin gene induction: coordinated regulation by cyclic AMP and calcium pathways

“…Primary striatal cultures were obtained as previously described [18]. The pENKAT12, Δ80 and −772 constructs were obtained from Michael Comb.…”

“…No differences in gene regulation pattern have been observed between pENKAT12 and longer constructs, however, pENKAT12 was most responsive [14]. Enkephalin constructs were transfected into primary striatal cultures using Ca 2+ transfection [25], as described previously [18]. RNA was extracted and analyzed as described previously [18].…”

“…Enkephalin constructs were transfected into primary striatal cultures using Ca 2+ transfection [25], as described previously [18]. RNA was extracted and analyzed as described previously [18].…”

Striatal dopamine–NMDA receptor interactions in the modulation of glutamate release in the substantia nigra pars reticulata in vivo: opposite role for D1 and D2 receptors

“…Indeed, blockade of D 2 receptors on glutamatergic terminals may potentiate the stimulus-evoked GLU release (Peris et al 1988;Cepeda et al 2001) while blockade of postsynaptic D 2 receptors may increase excitability of GABAergic (Cepeda et al 2001;Harsing and Zigmond 1997), possibly striatopallidal (Hernandez-Lopez et al 2000) neurons. D 2 antagonists may also directly enhance NMDA channel conductance through phosphorylation of the NR1 subunit (Leveque et al 2000), possibly via a DARPP-32 involving pathway (Blank et al 1997). It is noteworthy that, in the presence of raclopride, an increase in NMDA concentration up to 10 lM led to extinction of the NMDA effect.…”