Effect of antipsychotic drugs on extracellular serotonin levels in rat medial prefrontal cortex and nucleus accumbens

Junji Ichikawa; Toshihide Kuroki; Jin Dai; Herbert Y. Meltzer

doi:10.1016/S0014-2999(98)00308-2

Effect of antipsychotic drugs on extracellular serotonin levels in rat medial prefrontal cortex and nucleus accumbens

Junji Ichikawa^*, Toshihide Kuroki, Jin Dai, Herbert Y. Meltzer

^*Corresponding author for this work

Psychiatry and Behavioral Sciences

Research output: Contribution to journal › Article › peer-review

79 Scopus citations

Abstract

Amperozide, clozapine, olanzapine and risperidone are more potent serotonin (5-hydroxytryptamine, 5-HT)(2A) receptor antagonists than dopamine D₂-like receptor antagonists. Haloperidol and S(-)-sulpiride are potent or selective dopamine D₂-like receptor antagonists and lack 5-HT(2A) receptor antagonist properties. We studied the effect of these five proven antipsychotic drugs and one putative (amperozide) antipsychotic drug on extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens of awake, freely-moving rats, using in vivo microdialysis with dual probe implantation. Risperidone (1 mg/kg) and clozapine (20 mg/kg) significantly increased extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens, respectively. Amperozide (2 and 10 mg/kg) significantly increased extracellular 5-HT levels in both regions. Olanzapine (1 and 10 mg/kg), S(-)-sulpiride (10 and 25 mg/kg), haloperidol (0.1 and 1 mg/kg) and the selective 5-HT(2A) receptor antagonist MDL-100,907 (1 mg/kg) had no significant effect on extracellular 5-HT levels in either region. Thus, the ability to increase extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens by these antipsychotic drugs is not directly related to their affinity for 5-HT(2A) receptors since olanzapine and MDL-100,907 had no significant effect on extracellular 5-HT levels. A variety of mechanisms other than those involving 5-HT(2A) receptors, e.g., reuptake inhibition (amperozide) and blockade of α₂-adrenoceptors (clozapine), may contribute to the ability to increase extracellular 5-HT levels in the brain. The increase in extracellular 5-HT levels in the medial prefrontal cortex or nucleus accumbens following amperozide, clozapine, or risperidone administration may not be related to the effect on psychotic symptoms but could be related to effects on other types of psychopathology such as depression, negative symptoms, or cognition.

Original language	English (US)
Pages (from-to)	163-171
Number of pages	9
Journal	European Journal of Pharmacology
Volume	351
Issue number	2
DOIs	https://doi.org/10.1016/S0014-2999(98)00308-2
State	Published - Jun 19 1998

Funding

This work was supported in part by USPHS MH 41684, GCRC MO1RR00080 and the National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award grant, as well as grants from Elisabeth Severance Prentiss Foundation and Mr. Larry Freedman. J.I. and T.K. are recipients of a NARSAD Young Investigator Award. H.Y.M. is recipient of a USPHS Research Career Scientist Award MH 47808.

Keywords

5-HT (5-hydroxytryptamine, serotonin)
Antipsychotic drug
Cortex, medial prefrontal
MDL-100,907
Microdialysis, in vivo
Nucleus accumbens
Rat

ASJC Scopus subject areas

Pharmacology

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10.1016/S0014-2999(98)00308-2

Cite this

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title = "Effect of antipsychotic drugs on extracellular serotonin levels in rat medial prefrontal cortex and nucleus accumbens",

abstract = "Amperozide, clozapine, olanzapine and risperidone are more potent serotonin (5-hydroxytryptamine, 5-HT)(2A) receptor antagonists than dopamine D2-like receptor antagonists. Haloperidol and S(-)-sulpiride are potent or selective dopamine D2-like receptor antagonists and lack 5-HT(2A) receptor antagonist properties. We studied the effect of these five proven antipsychotic drugs and one putative (amperozide) antipsychotic drug on extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens of awake, freely-moving rats, using in vivo microdialysis with dual probe implantation. Risperidone (1 mg/kg) and clozapine (20 mg/kg) significantly increased extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens, respectively. Amperozide (2 and 10 mg/kg) significantly increased extracellular 5-HT levels in both regions. Olanzapine (1 and 10 mg/kg), S(-)-sulpiride (10 and 25 mg/kg), haloperidol (0.1 and 1 mg/kg) and the selective 5-HT(2A) receptor antagonist MDL-100,907 (1 mg/kg) had no significant effect on extracellular 5-HT levels in either region. Thus, the ability to increase extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens by these antipsychotic drugs is not directly related to their affinity for 5-HT(2A) receptors since olanzapine and MDL-100,907 had no significant effect on extracellular 5-HT levels. A variety of mechanisms other than those involving 5-HT(2A) receptors, e.g., reuptake inhibition (amperozide) and blockade of α2-adrenoceptors (clozapine), may contribute to the ability to increase extracellular 5-HT levels in the brain. The increase in extracellular 5-HT levels in the medial prefrontal cortex or nucleus accumbens following amperozide, clozapine, or risperidone administration may not be related to the effect on psychotic symptoms but could be related to effects on other types of psychopathology such as depression, negative symptoms, or cognition.",

keywords = "5-HT (5-hydroxytryptamine, serotonin), Antipsychotic drug, Cortex, medial prefrontal, MDL-100,907, Microdialysis, in vivo, Nucleus accumbens, Rat",

author = "Junji Ichikawa and Toshihide Kuroki and Jin Dai and Meltzer, {Herbert Y.}",

note = "Funding Information: This work was supported in part by USPHS MH 41684, GCRC MO1RR00080 and the National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award grant, as well as grants from Elisabeth Severance Prentiss Foundation and Mr. Larry Freedman. J.I. and T.K. are recipients of a NARSAD Young Investigator Award. H.Y.M. is recipient of a USPHS Research Career Scientist Award MH 47808.",

year = "1998",

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doi = "10.1016/S0014-2999(98)00308-2",

language = "English (US)",

volume = "351",

pages = "163--171",

journal = "European Journal of Pharmacology",

issn = "0014-2999",

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number = "2",

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T1 - Effect of antipsychotic drugs on extracellular serotonin levels in rat medial prefrontal cortex and nucleus accumbens

AU - Ichikawa, Junji

AU - Kuroki, Toshihide

AU - Dai, Jin

AU - Meltzer, Herbert Y.

N1 - Funding Information: This work was supported in part by USPHS MH 41684, GCRC MO1RR00080 and the National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award grant, as well as grants from Elisabeth Severance Prentiss Foundation and Mr. Larry Freedman. J.I. and T.K. are recipients of a NARSAD Young Investigator Award. H.Y.M. is recipient of a USPHS Research Career Scientist Award MH 47808.

PY - 1998/6/19

Y1 - 1998/6/19

N2 - Amperozide, clozapine, olanzapine and risperidone are more potent serotonin (5-hydroxytryptamine, 5-HT)(2A) receptor antagonists than dopamine D2-like receptor antagonists. Haloperidol and S(-)-sulpiride are potent or selective dopamine D2-like receptor antagonists and lack 5-HT(2A) receptor antagonist properties. We studied the effect of these five proven antipsychotic drugs and one putative (amperozide) antipsychotic drug on extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens of awake, freely-moving rats, using in vivo microdialysis with dual probe implantation. Risperidone (1 mg/kg) and clozapine (20 mg/kg) significantly increased extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens, respectively. Amperozide (2 and 10 mg/kg) significantly increased extracellular 5-HT levels in both regions. Olanzapine (1 and 10 mg/kg), S(-)-sulpiride (10 and 25 mg/kg), haloperidol (0.1 and 1 mg/kg) and the selective 5-HT(2A) receptor antagonist MDL-100,907 (1 mg/kg) had no significant effect on extracellular 5-HT levels in either region. Thus, the ability to increase extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens by these antipsychotic drugs is not directly related to their affinity for 5-HT(2A) receptors since olanzapine and MDL-100,907 had no significant effect on extracellular 5-HT levels. A variety of mechanisms other than those involving 5-HT(2A) receptors, e.g., reuptake inhibition (amperozide) and blockade of α2-adrenoceptors (clozapine), may contribute to the ability to increase extracellular 5-HT levels in the brain. The increase in extracellular 5-HT levels in the medial prefrontal cortex or nucleus accumbens following amperozide, clozapine, or risperidone administration may not be related to the effect on psychotic symptoms but could be related to effects on other types of psychopathology such as depression, negative symptoms, or cognition.

AB - Amperozide, clozapine, olanzapine and risperidone are more potent serotonin (5-hydroxytryptamine, 5-HT)(2A) receptor antagonists than dopamine D2-like receptor antagonists. Haloperidol and S(-)-sulpiride are potent or selective dopamine D2-like receptor antagonists and lack 5-HT(2A) receptor antagonist properties. We studied the effect of these five proven antipsychotic drugs and one putative (amperozide) antipsychotic drug on extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens of awake, freely-moving rats, using in vivo microdialysis with dual probe implantation. Risperidone (1 mg/kg) and clozapine (20 mg/kg) significantly increased extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens, respectively. Amperozide (2 and 10 mg/kg) significantly increased extracellular 5-HT levels in both regions. Olanzapine (1 and 10 mg/kg), S(-)-sulpiride (10 and 25 mg/kg), haloperidol (0.1 and 1 mg/kg) and the selective 5-HT(2A) receptor antagonist MDL-100,907 (1 mg/kg) had no significant effect on extracellular 5-HT levels in either region. Thus, the ability to increase extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens by these antipsychotic drugs is not directly related to their affinity for 5-HT(2A) receptors since olanzapine and MDL-100,907 had no significant effect on extracellular 5-HT levels. A variety of mechanisms other than those involving 5-HT(2A) receptors, e.g., reuptake inhibition (amperozide) and blockade of α2-adrenoceptors (clozapine), may contribute to the ability to increase extracellular 5-HT levels in the brain. The increase in extracellular 5-HT levels in the medial prefrontal cortex or nucleus accumbens following amperozide, clozapine, or risperidone administration may not be related to the effect on psychotic symptoms but could be related to effects on other types of psychopathology such as depression, negative symptoms, or cognition.

KW - 5-HT (5-hydroxytryptamine, serotonin)

KW - Antipsychotic drug

KW - Cortex, medial prefrontal

KW - MDL-100,907

KW - Microdialysis, in vivo

KW - Nucleus accumbens

KW - Rat

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Effect of antipsychotic drugs on extracellular serotonin levels in rat medial prefrontal cortex and nucleus accumbens

Abstract

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