Clozapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation

Rollema, Hans; Lu, Yasong; Schmidt, Anne W.; Zorn, Stevin H.

doi:10.1016/s0014-2999(97)81951-6

Cited by 174 publications

(106 citation statements)

References 6 publications

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“…In support of this, 8-OHDPAT administration potentiated D2 receptor antagonist (sulpiride)-induced DA efflux in the PFC and NA but not the striatum (Ichikawa and Meltzer, 1999). However, while clozapine-induced increases in cortical DA were partially antagonized by WAY 100,635 administration in one study (Rollema et al, 1997), this blockade was not observed by others (Millan et al, 1998b). Evidence has been provided that combined 5-HT(2A) and D(2) receptor blockade increases cortical DA release via 5-HT1A receptor activation (Ichikawa et al, 2001).…”

Section: Mesocortical Pathwaymentioning

confidence: 69%

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

Alex

Pehek

2007

Pharmacology & Therapeutics

526

311

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The neurotransmitter dopamine (DA) has a long association with normal functions such as motor control, cognition, and reward, as well as a number of syndromes including drug abuse, schizophrenia, and Parkinson's disease. Studies show that serotonin (5-HT) acts through several 5-HT receptors in the brain to modulate DA neurons in all three major dopaminergic pathways. There are at least 14 5-HT receptor subtypes, many of which have been shown to play some role in mediating 5-HT/DA interactions. Several subtypes, including the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT3 and 5-HT4 receptors, act to facilitate DA release, while the 5-HT2C receptor mediates an inhibitory effect of 5-HT on DA release. Most 5-HT receptor subtypes only modulate DA release when 5-HT and/or DA neurons are stimulated, but the 5-HT2C receptor, characterized by high levels of constitutive activity, inhibits tonic as well as evoked DA release. This review summarizes the anatomical evidence for the presence of each 5-HT receptor subtype in dopaminergic regions of the brain and the neuropharmacological evidence demonstrating regulation of each DA pathway. The relevance of 5-HT receptor modulation of DA systems to the development of therapeutics used to treat schizophrenia, depression, and drug abuse is discussed. Lastly, areas are highlighted in which future research would be maximally beneficial to the treatment of these disorders.

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Section: Mesocortical Pathwaymentioning

confidence: 69%

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

Alex

Pehek

2007

Pharmacology & Therapeutics

526

311

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“…Several laboratories have shown that clozapine releases dopamine in frontal cortex in animal preparations, an action possibly related to its serotonin and/or noradrenergic receptor affinity (Pehek et al, 1994;Pehek, 1996;Rollema et al, 1997;Moghaddam and Bunney, 1999;Hertel et al, 1999;Youngren et al, 1999). In electrophysiologic and immediate-early gene studies, clozapine and other secondgeneration antipsychotics demonstrate limbic selectivity in that they preferentially affect dopamine neurons projecting to limbic areas (Chiodo and Bunney, 1983;White and Wang, 1983;Robertson and Fibiger, 1992).…”

Section: Discussionmentioning

confidence: 99%

Clozapine but not Haloperidol Re-establishes Normal Task-Activated rCBF Patterns in Schizophrenia within the Anterior Cingulate Cortex

Lahti

Holcomb

Weiler

et al. 2003

Neuropsychopharmacol

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Our previous work has identified that unmedicated volunteers with schizophrenia have regional cerebral blood flow (rCBF) activation patterns inappropriately related to the cognitive demand of a task in anterior cingulate cortex (ACC). Using positron emission tomography (PET) with 15 O water, we compared task-induced rCBF patterns induced by haloperidol or clozapine in individuals with schizophrenia. We hypothesized that clozapine, given its superior clinical action, would tend to normalize the abnormal task-activated response in ACC more than haloperidol. Schizophrenia volunteers (SVs) (n ¼ 6) and normal volunteers (NVs) (n ¼ 12) were trained to perform a tone discrimination task with 70-80% accuracy. They were then scanned during three task conditions: (1) Rest, (2) sensory motor control (SMC) task, and (3) decision task (DEC). SVs were initially scanned after withdrawal of all psychotropic medication and again after treatment with therapeutic doses of haloperidol (n ¼ 5) and/or clozapine (n ¼ 5). rCBF values, sampled in the grown maxima of the task-activated ACC cluster, were analyzed between groups and task conditions. Task performance was similar across the unmedicated, haloperidol-and clozapine-medicated SV groups. There was a reduction in accuracy in the haloperidol SV group compared to the NVs. Group and task conditions affected rCBF in the ACC. Clozapine, but not haloperidol, reversed the abnormal ACC rCBF pattern in unmedicated SV to normal. The clozapine-treated SV group showed a rCBF pattern similar to the NV group in that ACC activation was not observed during the control task but occurred during the decision condition. The pattern seen in the haloperidoltreated SV group was similar to the unmedicated SV group in that ACC activation was seen during the control task and no further activation was seen during the DEC. We report that clozapine, but not haloperidol, normalizes anterior cingulate rCBF patterns in schizophrenia during a cognitive task. Based on these preliminary data, we propose that this pattern may account for the superior therapeutic effect of clozapine and represents a surrogate marker of this action.

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“…On the other hand, it has been well established that 5-HT 1A receptor agonistic action results in a significant increase in ACh outflow in the brain (Izumi et al 1994;Wilkinson et al 1994). This receptor activity might be of importance for the neurobiological effects of, primarily, clozapine and ziprasidone (Rollema et al 1997(Rollema et al , 2000. Similarly, it is unequivocally recognized that ␣ 2 adrenoceptor antagonists increase ACh efflux in the brain (Tellez et al 1997;, and that ␣ 2 adrenoceptor antagonism may underlie some of the central actions of clozapine, risperidone, and to a lesser extent of olanzapine (Hertel et al 1999a,b).…”

Section: Discussionmentioning

confidence: 99%

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

Shirazi-Southall

2002

Neuropsychopharmacology

191

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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...

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Clozapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation

Cited by 174 publications

References 6 publications

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

Clozapine but not Haloperidol Re-establishes Normal Task-Activated rCBF Patterns in Schizophrenia within the Anterior Cingulate Cortex

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

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