Novel mechanism of action of antipsychotic drugs : effects on neuropeptides in rat brain

Schizophrenic patients have been reported to have lower concentrations of neurotensin (NT)-like immunoreactivity (-LI) in their cerebrospinal fluid (CSF) that normalize after treatment with antipsychotic drugs. Schizophrenic patients also had higher CSF concentrations of neuropeptide Y (NPY)-LI compared to controls, thus involvement of NPY in the disease has also been suggested. In animal studies, intricate brain region specific interrelationships between NT and NPY and the dopamine (DA)-ergic system have been found. Consequently, in this series of experiments we studied effects of antipsychotic drugs and d-amphetamine, as well as their combination on NT and NPY in rat brain. Neurotensin-LI and NPY-LI were determined by radioimmunoassay (RIA) in microdialysates collected from freely moving animals and in tissues obtained from brain regions.

The most salient findings are: 1. Acute and chronic treatments with DA receptor antagonists affect NT-LI and NPY-LI in rat brain regions. Thus, haloperidol and risperidone decreased basal extracellular levels of NT-LI in ventral striatum (vSTR) but increased tissue concentrations in the same brain regions. In contrast, olanzapine increased basal extracellular levels of NT- LI in vSTR. Haloperidol and risperidone decreased the basal extracellular levels of NPY-LI in the vSTR. In contrast, olanzapine increased NPY-LI both in the basal extracellular concentrations from vSTR and in the striatal tissue; 2. Psychostimulants also have an effect on NT-LI and NPY-LI in rat brain regions. Thus, damphetamine increased NT-LI both in the extracellular concentrations in vSTR and in the striatal tissue. D-amphetamine, also increased NT-LI both in the extracellular concentrations in medial prefrontal cortex and in the frontal cortex tissue.

In parallel to increased NT-LI concentrations, NPYLI concentrations in vSTR were also elevated following d-amphetamine. In the frontal cortex, damphetamine increased NPY-LI in the outflow but had no apparent effects on tissue levels; 3. Pretreatment with drugs antagonizing DA-D1 and DA-D2 receptors abolishes effects of psychostimulants. Thus, pretreatment with SCH 23390 and raclopride as well as haloperidol, risperidone or olanzapine antagonized the stimulatory effect of d-amphetamine on extracellular NT-LI and NPY-LI levels and also on brain tissue concentrations. Thus, these results indicate that NT and NPY play a role in the therapeutic actions of antipsychotic drugs and possible also in the pathophysiology of schizophrenia.

List of scientific papers

I. Gruber SHM, Nomikos GG, Mathe AA (2002). D-amphetamine induced increase in neurotensin and neuropeptide Y outflow in the ventral striatum is mediated via stimulation of dopamine D1 and D2/3 receptors. J Neuroscience Research.

II. Gruber SH, Nomikos GG, Mathe AA (2002). Effects of haloperidol and risperidone on neurotensin levels in brain regions and neurotensin efflux in the ventral striatum of the rat. Neuropsychopharmacology. 26(5): 595-604.
https://pubmed.ncbi.nlm.nih.gov/11927184

III. Gruber SH, Mathe AA (2000). Effects of typical and atypical antipsychotics on neuropeptide Y in rat brain tissue and microdialysates from ventral striatum. J Neurosci Res. 61(4): 458-63.
https://pubmed.ncbi.nlm.nih.gov/10931533

IV. Gruber SHM, Nomikos GG, Mathe AA (2002). Effects of acute and subchronic d-amphetamine on striatal concentrations of neurotensin and neuropeptide Y in rats treated with antipsychotic drugs. [Submitted]

V. Gruber SHM, Husum H, Angelucci F, Nomikos GG, Mathe AA (2002). Effect of olanzapine on neurotensin and neuropeptide Y content, extracellular concentrations and preproNPY mRNA levels in rat brain regions. [Manuscript]