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

Sammanfattning: 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.