Chronic clozapine selectively decreases prefrontal cortex dopamine as shown by simultaneous cortical, accumbens, and striatal microdialysis in freely moving rats

doi:10.1016/0091-3057(95)00144-L

Pharmacology Biochemistry and Behavior

Volume 52, Issue 3, November 1995, Pages 581-589

https://doi.org/10.1016/0091-3057(95)00144-L Get rights and content

Abstract

We used microdialysis to study the acute and chronic effects of clozapine on the metabolism of dopamine (DA) in terminal areas of the mesocortical, mesolimbic, and nigrostriatal systems simultaneously. In the acute experiment, groups of four rats received the following doses: 0 (vehicle), 10, 20, and 40 mg/kg of clozapine subcutaneously, which resulted in a dose-related increase in extracellular DA, 3,4-dihydroxyphenalacetic acid (DOPAC), and homovanillic acid (HVA) in the prefrontal cortex (PFC). In the nucleus accumbens (NAC) and striatum (STR), no significant changes were observed at any dose. In the chronic experiment, six rats received 20 mg/kg of clozapine and a control group received vehicle daily for 30 days. After 30 days of treatment, DA, DOPAC, and HVA were significantly lower in the PFC, and unchanged in the NAC or STR. The 30th clozapine injection failed to increase DA, DOPAC, or HVA in any of the three regions. We conclude that clozapine acted selectively on the mesocortical system, and that this may underlie clozapine's therapeutic, antipsychotic effect.

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Citation Excerpt :
Furthermore, unlike in the striatum, the concentration of dopamine in the cortex is likely not uniform but graded, with ‘hotspots’ of dopamine concentrations greatest near VTA-terminal release sites (Spühler and Hauri, 2013). Measurements of dopamine levels suggest basal dopamine concentrations fluctuate in the low (0.3–15) nanomolar range during tonic dopamine neuron firing (Devoto et al., 2001; Garris et al., 1993; Garris and Wightman, 1994; Hernandez and Hoebel, 1995; Hildebrand et al., 1998; Ihalainen et al., 1999; Izaki et al., 1998; Seamans and Yang, 2004), while dopamine neuron bursting could elicit transients in the cortex that approach ~1 micromolar near release sites (Garris and Wightman, 1994; Spühler and Hauri, 2013). Dopamine exerts its action by binding to dopamine receptors (D1–5), all of which are metabotropic G-protein coupled receptors (GPCRs) often broadly grouped into subgroups: D1-like (D1, D5) and D2-like (D2–4).
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In this regard, acute clozapine in the primate (1 mg/kg/day, 3 days, i.p.) is reported to reverse the PCP-induced decrease in dlPFC DA release (Elsworth et al., 2008). However, there are conflicting reports of both an increase (Youngren et al., 1994) and decrease (Hernandez & Hoebel, 1995) in rat PFC DA release following chronic clozapine (20 mg/kg/day, 21 days, p.o. and 20 mg/kg/day, 30 days, s.c. respectively). Acute clozapine (25 and 30 mg/kg, s.c.) is associated with a reduction in rat dialysate mPFC GABA (Bourdelais & Deutch, 1994) and an increase in mPFC glutamate levels (Daly & Moghaddam, 1993).
Schizophrenia disease models are necessary to elucidate underlying changes and to establish new therapeutic strategies towards a stage where drug efficacy in schizophrenia (against all classes of symptoms) can be predicted. Here we summarise the evidence for a GABA dysfunction in schizophrenia and review the functional neuroanatomy of five pathways implicated in schizophrenia, namely the mesocortical, mesolimbic, ventral striopallidal, dorsal striopallidal and perforant pathways including the role of local GABA transmission and we describe the effect of clozapine on local neurotransmitter release.
This review also evaluates psychotropic drug-induced, neurodevelopmental and environmental disease models including their compatibility with brain microdialysis. The validity of disease models including face, construct, etiological and predictive validity and how these models constitute theories about this illness is also addressed. A disease model based on the effect of the abrupt withdrawal of clozapine on GABA release is also described.
The review concludes that while no single animal model is entirely successful in reproducing schizophreniform symptomatology, a disease model based on an ability to prevent and/or reverse the abrupt clozapine discontinuation-induced changes in GABA release in brain regions implicated in schizophrenia may be useful for hypothesis testing and for in vivo screening of novel ligands not limited to a single pharmacological class.
F15063, a potential antipsychotic with dopamine D<inf>2</inf>/D<inf>3</inf> receptor antagonist, 5-HT<inf>1A</inf> receptor agonist and dopamine D<inf>4</inf> receptor partial agonist properties: Influence on neuronal firing and neurotransmitter release
2009, European Journal of Pharmacology
F15063 (N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-ethyl]-(3-cyclopenten-1-yl-benzyl)-amine) is a potential antipsychotic with dopamine D₂/D₃ receptor antagonist, 5-HT_1A receptor agonist and dopamine D₄ receptor partial agonist properties. Herein, we compared its effects on rat ventral tegmental area dopamine and dorsal raphe serotonin electrical activity with those of the dopamine D₂ receptor partial agonist/5-HT_1A receptor agonist, SSR181507. Further, we investigated the modulation of extracellular dopamine and noradrenaline in the medial prefrontal cortex and serotonin in the hippocampus of freely moving rats by F15063 using in vivo microdialysis. In the ventral tegmental area, F15063 (200–700 µg/kg, i.v.) did not alter the electrical activity of dopamine neurons whereas SSR181507 (250–1000 µg/kg, i.v.) partially inhibited it, consistent with dopamine D₂ receptor partial agonism. Both compounds reduced the inhibition of firing rate induced by the full agonist apomorphine. In the dorsal raphe, both ligands suppressed firing activity, consistent with agonism at 5-HT_1A autoreceptors, although SSR181507 (25–75 µg/kg, i.v.) was more potent than F15063 (100–300 µg/kg, i.v.). F15063 (0.63–40 mg/kg, i.p.) dose-dependently increased dopamine levels in the prefrontal cortex and decreased hippocampal 5-HT. These effects were reversed by the selective 5-HT_1A receptor antagonist WAY100635 (0.16 mg/kg, s.c.), indicating that they were mediated by 5-HT_1A receptors (at post- and pre-synaptic levels, respectively). In the medial prefrontal cortex, noradrenaline levels were moderately but significantly increased by F15063 at 2.5 mg/kg. In conclusion, whereas SSR181507 exhibits (partial) agonism at dopamine D₂ and 5-HT_1A receptors, F15063 blocks dopamine D₂-like receptors whilst activating 5-HT_1A receptors. Such a profile distinguishes F15063 from SSR181507 and currently available antipsychotic drugs.
Erratum: The principal features and mechanisms of dopamine modulation in the prefrontal cortex (Progress in Neurobiology (2004) 74 (1-58) 10.1016/j.pneurobio.2004.05.006)
2004, Progress in Neurobiology
Mesocotical dopamine (DA) inputs to the prefrontal cortex (PFC) play a crtical role in normal cognitive process and neuropsychiatic pathologies. This DA input regulates aspects of working memory function, planning and attention, and its dysfunctions may underlie positive and negative symtoms and cognitive deficits associated with schizophrenia. Despite intense research, there is still a lack of clear understanding of the basic principles of actions of DA in the PFC. In recent years, there has been considerable efforts by many groups to understand the cellular mechanisms of DA modulation of PFC neurons. However, the results of these efforts often lead to contradictions and controversies. One principal feature of DA that is agreed by most researchers is that DA is a neuromodulator and is clearly not an excitatory or inhibitory neurotransmitter. The present article aims to identify certain principles of DA mechanisms by drawing on published, as well as unpublished data from PFC and other CNS sites to shed light on aspects of DA neuromodulation and address some of the existing controversies. Eighteen key features about DA modulation have been identified. These points directly impact on the end result of DA neuromodulation, and in some cases explain why DA does not yield identical effects under all experimental conditions. It will become apparent that DA's actions in PFC are subtle and depend on a variety of factors that can no longer be ignored. Some of these key factors include distinct bell-shaped dose–response profiles of postsynaptic DA effects, different postsynaptic responses that are contingent on the duration of DA receptor stimulation, prolonged duration effects, bidirectional effects following activation of D1 and D2 classes of receptors and membrane potential state and history dependence of subsequent DA actions. It is hoped that these factors will be borne in mind in future research and as a result a more consistent picture of DA neuromodulation in the PFC will emerge. Based on these factors, a theory is proposed for DA's action in PFC. This theory suggests that DA acts to expand or contract the breadth of information held in working memory buffers in PFC networks.
The principal features and mechanisms of dopamine modulation in the prefrontal cortex
2004, Progress in Neurobiology
Mesocotical dopamine (DA) inputs to the prefrontal cortex (PFC) play a crtical role in normal cognitive process and neuropsychiatic pathologies. This DA input regulates aspects of working memory function, planning and attention, and its dysfunctions may underlie positive and negative symtoms and cognitive deficits associated with schizophrenia. Despite intense research, there is still a lack of clear understanding of the basic principles of actions of DA in the PFC. In recent years, there has been considerable efforts by many groups to understand the cellular mechanisms of DA modulation of PFC neurons. However, the results of these efforts often lead to contradictions and controversies. One principal feature of DA that is agreed by most researchers is that DA is a neuromodulator and is clearly not an excitatory or inhibitory neurotransmitter. The present article aims to identify certain principles of DA mechanisms by drawing on published, as well as unpublished data from PFC and other CNS sites to shed light on aspects of DA neuromodulation and address some of the existing controversies. Eighteen key features about DA modulation have been identified. These points directly impact on the end result of DA neuromodulation, and in some cases explain why DA does not yield identical effects under all experimental conditions. It will become apparent that DA's actions in PFC are subtle and depend on a variety of factors that can no longer be ignored. Some of these key factors include distinct bell-shaped dose–response profiles of postsynaptic DA effects, different postsynaptic responses that are contingent on the duration of DA receptor stimulation, prolonged duration effects, bidirectional effects following activation of D1 and D2 classes of receptors and membrane potential state and history dependence of subsequent DA actions. It is hoped that these factors will be borne in mind in future research and as a result a more consistent picture of DA neuromodulation in the PFC will emerge. Based on these factors, a theory is proposed for DA's action in PFC. This theory suggests that DA acts to expand or contract the breadth of information held in working memory buffers in PFC networks.
Clozapine treatment attenuated somatic and affective signs of nicotine and amphetamine withdrawal in subsets of rats exhibiting hyposensitivity to the initial effects of clozapine
2003, Biological Psychiatry
Citation Excerpt :
Clozapine’s effects on dopamine release in the nucleus accumbens are less profound than in the prefrontal cortex (Kuroki et al 1999) and depend on clozapine dose (Melis et al 1999) and regimen of administration (Mylecharane et al 1998). Specifically, acute clozapine either increased or had no effect on nucleus accumbens dopamine release (Broderick and Piercey 1998; Hernandez and Hoebel 1995; Kuroki et al 1999; Melis et al 1999), whereas chronic clozapine either had no effect or reduced dopamine release (Hernandez and Hoebel 1995; Mylecharane et al 1998). Furthermore, adrenergic inputs to the mesolimbic dopaminergic pathway may provide a system through which increased dopamine release may occur (Grenhoff and Svensson 1989; Nutt et al 1993); however, these clozapine-induced increases in different neurotransmitter systems may not be sufficient to reverse or prevent drug withdrawal completely.
Based on the phenomenologic similarity between symptoms of drug withdrawal and the negative symptoms of schizophrenia (e.g., anhedonia), we hypothesized that treatment with clozapine may be effective against nicotine and amphetamine withdrawal.
A rate-independent discrete-trial threshold procedure was used to assess brain stimulation reward in rats prepared with electrodes in the lateral hypothalamus. Somatic signs of nicotine withdrawal were also assessed.
Clozapine administration (.75 or 1.5 mg/kg) during nicotine or amphetamine withdrawal did not affect the threshold elevations associated with drug withdrawal. The .75 mg/kg clozapine dose reversed the increased number of somatic signs of nicotine withdrawal. Ten days of clozapine treatment (3 mg/kg/b.i.d.) before exposure to nicotine prevented the threshold elevations in a subset of rats and the increases in somatic signs in all subjects. Fourteen-day pretreatment with clozapine (6 mg/kg/day) decreased the duration of amphetamine withdrawal.
Correlational analyses indicated that the ability of clozapine to prevent the affective aspects of drug withdrawal depended on low sensitivity to acute clozapine under baseline conditions. The results are consistent with the clinical situation where clozapine is partially effective against the negative symptoms of schizophrenia and more effective in some individuals than others. These results indicate that lack of sensitivity to the initial negative effects of clozapine may predict its a subsequent therapeutic response. Finally, the data suggest that there may be commonalities in the neurosubstrates mediating affective aspects of drug withdrawal and the negative symptoms of schizophrenia.

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¹: L. Hernandez's present address is the Laboratory of Behavioral Physiology, Medical School, Los Andes University, Mérida 5101, Venezuela.

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ArticleChronic clozapine selectively decreases prefrontal cortex dopamine as shown by simultaneous cortical, accumbens, and striatal microdialysis in freely moving rats

Abstract

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Life Sci.

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Brain Res. Bull.

Brain Res.

Neuropharmacology

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Life Sci.

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Neurosci. Lett.

Neurosci. Lett.

Life Sci.

Brain Res.

Trends Pharmacol. Sci.

Pharmacol. Biochem. Behav.

Brain Res. Bull.

Neurosci. Lett.

Brain Res.

Effect of clozapine on the turnover of dopamine in the corpus striatum and in the limbic system

J. Pharm. Pharmacol.

Evidence for different states of the D1 receptor: Clozapine and fluperlapine may preferentially label an adenylcyclase coupled-state of the D1 receptor

J. Neurochem.

Neuroleptics and extrapyramidal reactions in psychiatric patients

Chronic treatment with haloperidol or fluphenazine decanoate: Regional effects on dopamine and serotonin metabolism in primate brains

J. Pharmacol. Exp. Ther.

Mesocortical dopamine system: Lack of autoreceptors modulating dopamine synthesis

Mol. Pharmacol.

Mesocortical dopamine neurons: Unique response to antipsychotic drugs explained by the absence of terminal autoreceptors

Nature

Direct in vivo electrochemical monitoring of dopamine release in response to neuroleptic drugs

Eur. J. Pharmacol.

Regional differences in homovanillic acid concentrations after acute and chronic administration of antipsychotic drugs

J. Pharm. Pharmacol.

Regional differences in the effect of typical and atypical neuroleptics on terminal release of dopamine: In vivo microdialysis studies

Soc. Neurosci. Abstr.

Some terminal release characteristics of dopamine neurons after chronic haloperidol treatment

Soc. Neurosci. Abstr.

Dopaminergic neurons: Effect of antipsychotic drugs and amphetamine on single cell activity

J. Pharmacol. Exp. Ther.

On the use of multiple probe insertions at the same site for repeated intracerebral microdialysis experiments in the nigrostriatal dopamine system of rats

J. Neurochem.

Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain

Acta Pharmacol. Toxicol.

Typical and atypical neuroleptics: Differential effects of chronic administration on the activity of A9 and A10 midbrain dopaminergic neurons

J. Neurosci.

Possible mechanism by which repeated clozapine administration differentially affects the activity of two subpopulations of midbrain dopamine neurons

J. Neurosci.

Clozapine in the treatment of newly admitted schizophrenic patients

J. Clin. Pharmacol.

Persistent dyskinesia

Br. J. Psychiatry

Tardive dyskinesia in patients treated with major neuroleptics: A review of the literature

Am. J. Psychiatry

Article
Chronic clozapine selectively decreases prefrontal cortex dopamine as shown by simultaneous cortical, accumbens, and striatal microdialysis in freely moving rats

Evidence for different states of the D₁ receptor: Clozapine and fluperlapine may preferentially label an adenylcyclase coupled-state of the D₁ receptor