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

<p>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.</p><p>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.</p><p>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.</p><h3>List of scientific papers</h3><p>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.</p><p>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. <br><a href="https://pubmed.ncbi.nlm.nih.gov/11927184">https://pubmed.ncbi.nlm.nih.gov/11927184</a><br><br></p><p>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. <br><a href="https://pubmed.ncbi.nlm.nih.gov/10931533">https://pubmed.ncbi.nlm.nih.gov/10931533</a><br><br></p><p>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]</p><p>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]</p>