Further Evidence that Behavioral Tests and Neuropeptide mRNA and Tissue Level Alterations Can Differentiate between Typical and Atypical Antipsychotic Drugs

Abstract

This study was designed to compare some behavioral and biochemical effects of chronic treatment with a range of antipsychotic drugs. Gene expression of enkephalinAntipsychotic drugs are sometimes referred to as "atypical" if they demonstrate the ability to produce an antipsychotic action in most patients but with significantly less extrapyramidal side effects than classical (typical) antipsychotics (Fleischhacker and Hummer 1997). Lately, this distinction between "typical" and "atypical" antipsychotics has become the focus for much research aimed at establishing the pharmacological characteristics that serve to distinguish atypical antipsychotic drugs from the typical ones (Arnt and Skarsfeldt 1998). For example, in animals, acute and chronic treatment with these compounds causes distinct behavioral changes and alterations in the expression of different genes.Alterations in the biosynthesis of synaptic proteins and their mRNAs can be used to investigate changes in neuronal activity following different neuronal stimuli (MacArthur and Eiden 1996). Haloperidol increases tissue levels of enkephalin and the expression of mRNA (Normand et al. 1987;Romano et al. 1987) in medium spiny striatal neurons which are associated with the dopamine 2 receptor (Le Moine et al. 1991) whereas clozapine, the prototypical "atypical" antipsychotic, does not induce catalepsy and does not lead to an increased enkephalin gene expression in the striatum (Mercugliano and Chesselet 1992). Consequently, antipsychotics which do not induce catalepsy appear unlikely to increase enkephalin biosynthesis (Augood et al. 1993;Mijnster et al. 1998). Therefore, both behavioral changes and a distinct pattern of gene expression may be used to predict an atypical profile for an antipsychotic compound.The prefrontal cortex is an important brain area in schizophrenia research (Knable and Weinberger 1997;O'Donnell and Grace 1998). In animals, antipsychotic treatment causes an induction of immediate early genes in various brain areas including the prefrontal cortex. In this region, acute application of haloperidol or clozapine induces a differential expression of immediate early genes (Nguyen et al. 1992;Robertson and Fibiger 1992;Deutch and Duman 1996). Therefore, a different mechanism of action was postulated for haloperidol or clozapine treatment. However, most of these experiments investigated the induction of early genes after acute treatment.Chromogranin A, chromogranin B, and secretogranin II belong to the chromogranin family which are large protein molecules found in large dense core vesicles. They are endoproteolytically processed to smaller peptides, and are released after neuronal stimulation (Huttner et al. 1991). The distribution of chromogranin B (Mahata et al. 1991;Kroesen et al. 1996), secretogranin II mRNA, and their immunoreactivity (Marksteiner et al. 1993a) have been studied in rat brains. The biosynthesis of chromogranins is regulated by different stimuli (Shen and Gundlach 1996). For example, ten days of treatment with clozapine or hal...

Inhibition of NUDEL (nuclear distribution element-like)-oligopeptidase activity by disrupted-in-schizophrenia 1

“…Inhibition of NUDEL-oligopeptidase could lead to increases in the local concentration of NT, with a possible antipsychotic effect. Interestingly, levels of NT have been shown to increase with antipsychotic treatment, as do levels of proenkephalin products (29,(32)(33)(34) that are also NUDEL-oligopeptidase substrates. The effects of known antipsychotics on NUDELoligopeptidase activity should thus be investigated as a possible explanation for their effects in the CNS.…”

Gene expression in dopamine and GABA systems in an animal model of schizophrenia: effects of antipsychotic drugs

“…Consistent with previous reports (Fox et al ., 1994; Merchant et al ., 1994; Bauer et al ., 2000; Binder et al ., 2001), proenkephalin and neurotensin mRNA levels were significantly increased after antipsychotic treatment, but the lesion did not modify expression profiles of these genes. Furthermore, the lesion alone had no effect on the expression of these neuropeptides.…”

Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs

“…124 Interestingly, altered expression of genes involved in presynaptic function has been observed in the prefrontal cortex of the postmortem brains of schizophrenics. 129 However, Bauer et al 130 failed to detect any significant changes in cortical synaptic protein levels or their encoding mRNAs after chronic haloperidol administration in rats. Furthermore, several genes involved in the presynaptic function were not altered after chronic haloperidol treatment in the prefrontal cortex of monkeys.…”