Phenotypic Characterization of Neuroleptic-Sensitive Neurons in the Forebrain Contrasting Targets of Haloperidol and Clozapine

Abstract

The prototypical neuroleptic haloperidol and the atypical antipsychotic clozapine induce distinctly different patterns of c-fos expression in the forebrain. While haloperidol appears to increase c-fos expression via its D2 dopamineClozapine has been termed an "atypical" antipsychotic agent in part because at therapeutic doses it fails to produce the extrapyramidal, Parkinsonian-like side effects that are associated with the use of "typical" neuroleptics such as haloperidol and chlorpromazine. While the mechanisms by which clozapine generates its unique clinical profile are not established, recent studies from several laboratories have demonstrated that, compared to typical neuroleptics, clozapine produces a rather unique regional pattern of Fos-like immunoreactive From the Divison

Induction Patterns of Transcription Factors of the Nur Family (Nurr1, Nur77, and Nor-1) by Typical and Atypical Antipsychotics in the Mouse Brain: Implication for Their Mechanism of Action

“…This is similar to what have been observed with induction of c-fos by this typical antipsychotic (Guo et al, 1998). This raises the possibility that typical antipsychotics can induce a concerted c-fos-and Nur77-dependent transcriptional activity in a subset of cells expressing enkephalin and D 2 receptors, i.e., in neurons belonging to the indirect striatal output pathway.…”

Selective Antagonism at Dopamine D3 Receptors Enhances Monoaminergic and Cholinergic Neurotransmission in the Rat Anterior Cingulate Cortex

“…However, whereas haloperidol induces c-fos expression in the dorsal striatum, clozapine, and olanzapine induce c-fos expression in the prefrontal cortex and some limbic structures (eg lateral septal nucleus, islands of Calleja). In addition, the c-fos response to clozapine in the islands of Calleja and prefrontal cortex seems to be selectively mediated by the DA D 3 receptor (Guo et al, 1998).…”

“…This association was originally suggested from the following observations: (1) Contrary to DA D 1 and D 2 receptors, DA D 3 receptors are expressed preferentially in granule cells of the islands of Calleja and in medium-sized spiny neurons of the rostral and ventromedial shell of the nucleus accumbens, regions in which the D 2 receptors are scarcely expressed (Gurevich and Joyce, 1999;Landwehrmeyer et al, 1993;Murray et al, 1994;Sokoloff et al, 1990); (2) DA D 3 receptors have been functionally associated with cognitive and emotional behavior, in line with a possible role of this receptor in the negative symptoms of schizophrenia (Gurevich and Joyce, 1999;Herroelen et al, 1994;Suzuki et al, 1998); (3) the density of DA D 3 receptors is elevated in the brains of cocaine overdose fatalities (Staley and Mash, 1996); (4) D 3 receptors are overexpressed in the ventral striatum of drug-free schizophrenic patients (Gurevich et al, 1997), and (5) in contrast with haloperidol, the majority of clozapine-induced Fos-like immunoreactive neurons in the major island of Calleja, nucleus accumbens, and lateral septal nucleus express DA D 3 receptor mRNA (Guo et al, 1998). Thus, there is increased evidence to support the role of DA D 3 receptors in the pathophysiology of schizophrenia.…”

The Dopamine D3/D2 Agonist (+)-PD-128,907 [(R-(+)-trans-3,4a,10b-Tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol)] Protects against Acute and Cocaine-Kindled Seizures in Mice: Further Evidence for the Involvement of D3 Receptors

“…A convergence of data has generated a structural framework to account for the genesis of schizophrenic symptomatology (see Lieberman et al, 1997). The ventral striatum is highly enriched in D 3 receptors (see Levant, 1997), and these D 3 receptor-containing neurons have been shown to be a potential target of the activity of atypical antipsychotic drugs (Guo et al, 1998;Robertson et al, 2004). Cocaine kindling represents a preclinical model of this sensitization-like process.…”