Changes in [3H]-ouabain and [3H]-neurotensin binding to rat cerebral cortex membranes after administration of antipsychotic drugs haloperidol and clozapine

Peptides. 2017 Mar:89:82-89. doi: 10.1016/j.peptides.2016.08.009. Epub 2016 Aug 30.

Abstract

Evidences indicate the relationship between neurotensinergic and dopaminergic systems. Neurotensin inhibits synaptosomal membrane Na+, K+-ATPase activity, an effect blocked by SR 48692, antagonist for high affinity neurotensin receptor (NTS1) type. Assays of high affinity [3H]-ouabain binding (to analyze K+ site of Na+, K+-ATPase) show that in vitro addition of neurotensin decreases binding. Herein potential interaction between NTS1 receptor, dopaminergic D2 receptor and Na+, K+-ATPase was studied. To test the involvement of dopaminergic D2 receptors in [3H]-ouabain binding inhibition by neurotensin, Wistar rats were administered i.p.with antipsychotic drugs haloperidol (2mg/kg) and clozapine (3, 10 and 30mg/kg). Animals were sacrificed 18h later, cerebral cortices harvested, membrane fractions prepared and high affinity [3H]-ouabain binding assayed in the absence or presence of neurotensin at a 10 micromolar concentration. No differences versus controls for basal binding or for binding inhibition by neurotensin were recorded, except after 10mg/kg clozapine. Rats were administered with neurotensin (3, 10y 30μg, i.c.v.) and 60min later, animals were sacrificed, cerebral cortices harvested and processed to obtain membrane fractions for high affinity [3H]-ouabain binding assays. Results showed a slight but statistically significant decrease in binding with the 30μg neurotensin dose. To analyze the interaction between dopaminergic D2 and NTS1 receptors, [3H]-neurotensin binding to cortical membranes from rats injected with haloperidol (2mg/kg, i.p.) or clozapine (10mg/kg) was assayed. Saturation curves and Scatchard transformation showed that the only statistically significant change occurred in Bmax after haloperidol administration. Hill number was close to the unit in all cases. Results indicated that typical and atypical antipsychotic drugs differentially modulate the interaction between neurotensin and Na+, K+-ATPase. At the same time, support the notion of an interaction among dopaminergic and neurotensinergic systems and Na+, K+-ATPase at central synapses.

Keywords: Antipsychotic agents; CNS; Cerebral cortex; Clozapine; Dopamine; Haloperidol; K(+)-ATPase inhibition; Na(+); Neurotensin; [(3)H]-Neurotensin binding; [(3)H]-Ouabain binding.

MeSH terms

  • Animals
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / metabolism
  • Clozapine / administration & dosage
  • Dopamine / metabolism
  • Haloperidol / administration & dosage
  • Neurotensin / chemistry
  • Neurotensin / metabolism
  • Ouabain / chemistry
  • Ouabain / metabolism
  • Protein Binding / drug effects
  • Pyrazoles / administration & dosage
  • Quinolines / administration & dosage
  • Rats
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Neurotensin / metabolism*
  • Sodium-Potassium-Exchanging ATPase / metabolism*
  • Synaptosomes / drug effects
  • Synaptosomes / metabolism

Substances

  • Pyrazoles
  • Quinolines
  • Receptors, Dopamine D2
  • Receptors, Neurotensin
  • neurotensin type 1 receptor
  • SR 48692
  • Neurotensin
  • Ouabain
  • Sodium-Potassium-Exchanging ATPase
  • Clozapine
  • Haloperidol
  • Dopamine