Effects of Typical and Atypical Antipsychotics and Receptor Selective Compounds on Acetylcholine Efflux in the Hippocampus of the Rat

Abstract

Some atypical antipsychotic drugs appear to improve cognitive function in schizophrenia and since acetylcholine (ACh) is of importance in cognition, we used in vivo microdialysis to examine the effects of antipsychotics administered acutely (SC or IP) at pharmacologically comparable doses on ACh outflow in the hippocampus of the rat. The atypical antipsychotics olanzapine and clozapine produced robust increases in ACh up to 1500% and 500%, respectively. The neuroleptics haloperidol, thioridazine, and chlorpromazine, as (MDL 100,907), the 5-HT 2C (SB 242,084), the 5-HT 6 KEY WORDS : Antipsychotic; Schizophrenia; Olanzapine; Clozapine; Microdialysis; Acetylcholine Impairments in cognitive processes, such as deficits in executive function, verbal memory and attention, are prevalent in most patients with schizophrenia (Breier 1999). Some atypical antipsychotic drugs appear to improve not only the positive symptoms, but also the negative symptoms and the cognitive deficits when compared with classical neuroleptics (Kinon and Lieberman 1996;Meltzer and McGurk 1999;Remington and Kapur 2000). For example, some atypical antipsychotic drugs have been shown to improve attention, motor and executive function in schizophrenic patients (Meltzer and McGurk 1999 NO . 5 cal and clinical studies have indicated that atypical antipsychotics, such as clozapine, olanzapine and risperidone, potently inhibit serotonin 5-HT 2 receptor function and affect a variety of other receptors in the brain (Meltzer et al. 1989;Leysen et al. 1992;Bymaster et al. 1996). In particular, clozapine and olanzapine show a complex pharmacological profile, being described as "multi-acting-receptor-targeted antipsychotic agents" (MARTAs) .Acetylcholine has been shown to be an important neurotransmitter in motor function, attention and various aspects of cognition. Cholinergic synapses are prevalent in many areas of the brain, including the striatum, the prefrontal cortex and the hippocampus. Neuronal processes within the hippocampus, in particular, mediate declarative memory, and participate in cognitive mapping in both experimental animals and humans (Eichenbaum et al. 1999). It appears likely therefore that a dysfunction in cholinergic neurotransmission within the hippocampus may be responsible for the cognitive impairments often encountered in schizophrenia. In turn, the beneficial effects of some atypical antipsychotic drugs in the treatment of cognitive deficits in schizophrenia may be related to their selective action on cholinergic function in the hippocampus, as a consequence of their multireceptor pharmacological profile.Earlier in vivo microdialysis experiments have revealed a selective action of clozapine on ACh outflow in limbocortical, dopaminergic regions of the brain, such as the prefrontal cortex, as compared with classical neuroleptics (Parada et al. 1997;Moore et al. 1999). In general, antipsychotic drugs appear to either increase or have no effect on ACh efflux within the striatum, a dopaminergic region of the brain related to...

The Selective 5-HT6 Receptor Antagonist Ro4368554 Restores Memory Performance in Cholinergic and Serotonergic Models of Memory Deficiency in the Rat

“…The present data suggest that it may involve an increase in cholinergic transmission (Riemer et al, 2003;Shirazi-Southall et al, 2002). Previous behavioral studies indicated such an enhanced cholinergic neurotransmission after administration with a 5-HT 6 antagonist (Bentley et al, 1999).…”

Reversal of Clozapine Effects on Working Memory in Rats with Fimbria–Fornix Lesions

“…Thus, in the absence of the septohippocampal projection, clozapine effects in the prefrontal cortex could exert a larger influence on working memory and produce the clozapine-induced working memory improvement in lesioned animals. In support of this mechanism, clozapine has been shown to increase acetylcholine release in the hippocampus and prefrontal cortex, possibly due to presynaptic blockade of muscarinic acetylcholine receptors (Parada et al, 1997;Shirazi-Southall et al, 2002). In the prefrontal cortex, this clozapine-induced increase in acetylcholine is suggested to be related to 5-HT receptor interactions (Ichikawa et al, 2002).…”

Cholinergic Circuits and Signaling in the Pathophysiology of Schizophrenia

“…Preclinical studies have demonstrated that many antipsychotic medications cause the release of ACh in cortical (Ichikawa et al, 2002;Li et al, 2005) and hippocampal regions ( Johnson et al, 2005;Shirazi-Southall et al, 2002). While a broad range of antipsychotic medications have been shown to release cortical and hippocampal ACh, olanzapine and clozapine have been shown to be especially potent in this regard.…”