On the neuropeptide mRNA expression following neuropsychopharmacological treatments

Abstract

In addition to classical neurotransmitters, an increasing number of neuropeptides have been found in the brain. Although neuropeptides may play important roles especially in higher brain functions such as emotion, mood, memory, and learning, most focus has been directed upon classical neurotransmitters and their receptors. In a clinical perspective, antidepressants have a slow onset of 3 to 8 weeks. Furthermore, 30%. of depressed patients are drug resistant. Whilst the major area of research has been the manipulation and enhancement of monoaminergic transmission, attention needs to be turned to other mechanisms of action.

In this thesis, new evidence is provided regarding the regulation of mRNAs coding for neuropeptides such as neuropeptide Y (NPY), somatostatin, cholecystokinin (CCK) and substance P and their sensitivity to treatments of affective disorders, e.g., electroconvulsive therapy (ECT) and lithium but also their sensitivity to seizure-inducing excitotoxic stress such as following systemic kainic acid (KA) administration. Moreover, post- mortem schizophrenic brains are analysed with respect to neuropeptide receptor mRNA expression. The detailed effects on specific neuronal systems are discussed and the brain regions in focus are the hippocampal formation including the entorhinal cortex, striatum including nucleus accumbens, and the prefrontal cortex.

ECS and lithium produced to some extent similar effects on the studied expression of respective neuropeptide mRNA with increases in NPY mRNA levels following repeated electroconvulsive shock (ECS, a model for ECT) in hippocampus, the prefrontal cortex and nucleus accumbens. Somatostatin mRNA levels were elevated in the cortical and hippocampal areas. In contrast to NPY and somatostatin, levels of both CCK and substance P mRNAs as well as tachykinin NK1, receptor mRNA were reduced in striatal subregions after ECS. Following chronic lithium administration, increases of NPY mRNA levels were seen in most of the regions and somatostatin mRNA levels were increased in the entorhinal cortex and striatum. In contrast, CCK mRNA levels were reduced in the entorhinal cortex and striatum following lithium administration.

The changes in NFIY may reflect a response to the seizure-inducing stimuli per se, with activation of the GABA system. In addition, in light of the known interaction between somatostatin and serotonergic systems, alterations in the serotonergic transmission might be a beneficial effect of increased somatostatin following ECS. The decrease of CCK mRNA levels in the caudate-putamen following both ECS and lithium provides further support for the hypothesis of a decreased postsynaptic DAergic action in striatum following these treatments. As well as the data an CCK mRNA expression following ECS, the reported decreased levels of substance P mRNA in striatum following ECS may also indicate a downregulated postsynaptic DAergic action. The marked reduction of tachykinin NK1, receptor mRNA in nucleus accumbens following ECS, implicates that tachykinin NK1, receptor signalling in this region might be of relevance in the treatment of affective disorders.

A reduction of the levels of mRNA coding for CCKB receptor isoforms were found in the frontal cortex of schizophrenics. The reduced levels strengthens the hypothesis that CCKergic transmission in this part of the brain is involved in schizophrenia and suggests that CCKB agonist might have a future in the treatment of psychosis. When studying the effects of excitotoxic stress, substance P mRNA was increased both in allocortex and striatum. The induced seizures were attenuated by pretreatment with CP-122,721-1, a selective tachykinin NK1, receptor antagonist. The attenuation of the seizures, indicates that NK1, receptor antagonists might become therapeutically interesting not only in the treatment of affective disorders but also in the treatment of neurological insults with an excess of excitation such as following seizures.