A 68930 and dihydrexidine inhibit locomotor activity and d-amphetamine-induced hyperactivity in rats: A role of inhibitory dopamine d1/5 receptors in the prefrontal cortex?

R. Isacson, B. Kull, Claes R Wahlestedt, P. Salmi

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

The behavioral and biochemical effects of the full dopamine D 1/5 receptor agonists, dihydrexidine and (1R,3S)-1-aminomethyl-5,6- dihydroxy-3-phenylisochroman HCl (A 68930), were examined in rats. Both A 68930 (0-4.6 mg kg-1, s.c.) and dihydrexidine (0-8.0 mg kg-1, s.c.) caused a dose-dependent suppression of locomotor activity, as assessed in an open-field. This locomotor suppression was dose-dependently antagonized by the selective dopamine D1/5 receptor antagonist R(+)-7-chloro-8- hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl (SCH 23390; 0-5.0 μg kg-1, s.c.), but not by the selective dopamine D 2/3 receptor antagonist raclopride (0-25.0 μg kg-1, s.c.). Furthermore, A 68930 and dihydrexidine did not cause any locomotor activity in habituated rats that displayed a very low base-line activity. Neither did A 68930 nor dihydrexidine produce any excessive stereotypies that could possibly interfere with and mask ambulatory activity. In fact, both A 68930 and dihydrexidine potently blocked hyperactivity produced by d-amphetamine (0-4.0 mg kg-1, s.c.). Such findings traditionally would be interpreted as a sign of potential antipsychotic properties of A 68930 and dihydrexidine. Examination of neuronal activation, as indexed by the immediate early gene c-fos, showed that A 68930 and dihydrexidine caused a highly significant expression of c-fos in the medial prefrontal cortex. This c-fos expression was sensitive to treatment with SCH 23390, but not with raclopride. The effects of A 68930 and dihydrexidine on c-fos expression in caudate putamen or nucleus accumbens were less marked, or undetectable. The results indicate that stimulation of dopamine D1/5 receptors, possibly in the medial prefrontal cortex, is associated with inhibitory actions on locomotor activity and d-amphetamine-induced hyperactivity. Assuming an important role of prefrontal dopamine D1/5 receptors in schizophrenia, such inhibitory actions of dopamine D1/5 receptor stimulation on psychomotor activation mya have interesting clinical implications in the treatment of schizophrenia.

Original languageEnglish
Pages (from-to)33-42
Number of pages10
JournalNeuroscience
Volume124
Issue number1
DOIs
StatePublished - Feb 19 2004
Externally publishedYes

Fingerprint

A 68930
Dopamine D1 Receptors
Dextroamphetamine
Locomotion
Prefrontal Cortex
Raclopride
Dopamine
Schizophrenia
Mya
Immediate-Early Genes
dihydrexidine
Putamen
Nucleus Accumbens
Masks
Antipsychotic Agents

Keywords

  • d-amphetamine
  • Dopamine D receptor
  • Immediate early gene
  • Locomotion
  • Rat

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

@article{56afe2d0845941d38bb211fac0845b56,
title = "A 68930 and dihydrexidine inhibit locomotor activity and d-amphetamine-induced hyperactivity in rats: A role of inhibitory dopamine d1/5 receptors in the prefrontal cortex?",
abstract = "The behavioral and biochemical effects of the full dopamine D 1/5 receptor agonists, dihydrexidine and (1R,3S)-1-aminomethyl-5,6- dihydroxy-3-phenylisochroman HCl (A 68930), were examined in rats. Both A 68930 (0-4.6 mg kg-1, s.c.) and dihydrexidine (0-8.0 mg kg-1, s.c.) caused a dose-dependent suppression of locomotor activity, as assessed in an open-field. This locomotor suppression was dose-dependently antagonized by the selective dopamine D1/5 receptor antagonist R(+)-7-chloro-8- hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl (SCH 23390; 0-5.0 μg kg-1, s.c.), but not by the selective dopamine D 2/3 receptor antagonist raclopride (0-25.0 μg kg-1, s.c.). Furthermore, A 68930 and dihydrexidine did not cause any locomotor activity in habituated rats that displayed a very low base-line activity. Neither did A 68930 nor dihydrexidine produce any excessive stereotypies that could possibly interfere with and mask ambulatory activity. In fact, both A 68930 and dihydrexidine potently blocked hyperactivity produced by d-amphetamine (0-4.0 mg kg-1, s.c.). Such findings traditionally would be interpreted as a sign of potential antipsychotic properties of A 68930 and dihydrexidine. Examination of neuronal activation, as indexed by the immediate early gene c-fos, showed that A 68930 and dihydrexidine caused a highly significant expression of c-fos in the medial prefrontal cortex. This c-fos expression was sensitive to treatment with SCH 23390, but not with raclopride. The effects of A 68930 and dihydrexidine on c-fos expression in caudate putamen or nucleus accumbens were less marked, or undetectable. The results indicate that stimulation of dopamine D1/5 receptors, possibly in the medial prefrontal cortex, is associated with inhibitory actions on locomotor activity and d-amphetamine-induced hyperactivity. Assuming an important role of prefrontal dopamine D1/5 receptors in schizophrenia, such inhibitory actions of dopamine D1/5 receptor stimulation on psychomotor activation mya have interesting clinical implications in the treatment of schizophrenia.",
keywords = "d-amphetamine, Dopamine D receptor, Immediate early gene, Locomotion, Rat",
author = "R. Isacson and B. Kull and Wahlestedt, {Claes R} and P. Salmi",
year = "2004",
month = "2",
day = "19",
doi = "10.1016/j.neuroscience.2003.11.016",
language = "English",
volume = "124",
pages = "33--42",
journal = "Neuroscience",
issn = "0306-4522",
publisher = "Elsevier Limited",
number = "1",

}

TY - JOUR

T1 - A 68930 and dihydrexidine inhibit locomotor activity and d-amphetamine-induced hyperactivity in rats

T2 - A role of inhibitory dopamine d1/5 receptors in the prefrontal cortex?

AU - Isacson, R.

AU - Kull, B.

AU - Wahlestedt, Claes R

AU - Salmi, P.

PY - 2004/2/19

Y1 - 2004/2/19

N2 - The behavioral and biochemical effects of the full dopamine D 1/5 receptor agonists, dihydrexidine and (1R,3S)-1-aminomethyl-5,6- dihydroxy-3-phenylisochroman HCl (A 68930), were examined in rats. Both A 68930 (0-4.6 mg kg-1, s.c.) and dihydrexidine (0-8.0 mg kg-1, s.c.) caused a dose-dependent suppression of locomotor activity, as assessed in an open-field. This locomotor suppression was dose-dependently antagonized by the selective dopamine D1/5 receptor antagonist R(+)-7-chloro-8- hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl (SCH 23390; 0-5.0 μg kg-1, s.c.), but not by the selective dopamine D 2/3 receptor antagonist raclopride (0-25.0 μg kg-1, s.c.). Furthermore, A 68930 and dihydrexidine did not cause any locomotor activity in habituated rats that displayed a very low base-line activity. Neither did A 68930 nor dihydrexidine produce any excessive stereotypies that could possibly interfere with and mask ambulatory activity. In fact, both A 68930 and dihydrexidine potently blocked hyperactivity produced by d-amphetamine (0-4.0 mg kg-1, s.c.). Such findings traditionally would be interpreted as a sign of potential antipsychotic properties of A 68930 and dihydrexidine. Examination of neuronal activation, as indexed by the immediate early gene c-fos, showed that A 68930 and dihydrexidine caused a highly significant expression of c-fos in the medial prefrontal cortex. This c-fos expression was sensitive to treatment with SCH 23390, but not with raclopride. The effects of A 68930 and dihydrexidine on c-fos expression in caudate putamen or nucleus accumbens were less marked, or undetectable. The results indicate that stimulation of dopamine D1/5 receptors, possibly in the medial prefrontal cortex, is associated with inhibitory actions on locomotor activity and d-amphetamine-induced hyperactivity. Assuming an important role of prefrontal dopamine D1/5 receptors in schizophrenia, such inhibitory actions of dopamine D1/5 receptor stimulation on psychomotor activation mya have interesting clinical implications in the treatment of schizophrenia.

AB - The behavioral and biochemical effects of the full dopamine D 1/5 receptor agonists, dihydrexidine and (1R,3S)-1-aminomethyl-5,6- dihydroxy-3-phenylisochroman HCl (A 68930), were examined in rats. Both A 68930 (0-4.6 mg kg-1, s.c.) and dihydrexidine (0-8.0 mg kg-1, s.c.) caused a dose-dependent suppression of locomotor activity, as assessed in an open-field. This locomotor suppression was dose-dependently antagonized by the selective dopamine D1/5 receptor antagonist R(+)-7-chloro-8- hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl (SCH 23390; 0-5.0 μg kg-1, s.c.), but not by the selective dopamine D 2/3 receptor antagonist raclopride (0-25.0 μg kg-1, s.c.). Furthermore, A 68930 and dihydrexidine did not cause any locomotor activity in habituated rats that displayed a very low base-line activity. Neither did A 68930 nor dihydrexidine produce any excessive stereotypies that could possibly interfere with and mask ambulatory activity. In fact, both A 68930 and dihydrexidine potently blocked hyperactivity produced by d-amphetamine (0-4.0 mg kg-1, s.c.). Such findings traditionally would be interpreted as a sign of potential antipsychotic properties of A 68930 and dihydrexidine. Examination of neuronal activation, as indexed by the immediate early gene c-fos, showed that A 68930 and dihydrexidine caused a highly significant expression of c-fos in the medial prefrontal cortex. This c-fos expression was sensitive to treatment with SCH 23390, but not with raclopride. The effects of A 68930 and dihydrexidine on c-fos expression in caudate putamen or nucleus accumbens were less marked, or undetectable. The results indicate that stimulation of dopamine D1/5 receptors, possibly in the medial prefrontal cortex, is associated with inhibitory actions on locomotor activity and d-amphetamine-induced hyperactivity. Assuming an important role of prefrontal dopamine D1/5 receptors in schizophrenia, such inhibitory actions of dopamine D1/5 receptor stimulation on psychomotor activation mya have interesting clinical implications in the treatment of schizophrenia.

KW - d-amphetamine

KW - Dopamine D receptor

KW - Immediate early gene

KW - Locomotion

KW - Rat

UR - http://www.scopus.com/inward/record.url?scp=0442307957&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0442307957&partnerID=8YFLogxK

U2 - 10.1016/j.neuroscience.2003.11.016

DO - 10.1016/j.neuroscience.2003.11.016

M3 - Article

C2 - 14960337

AN - SCOPUS:0442307957

VL - 124

SP - 33

EP - 42

JO - Neuroscience

JF - Neuroscience

SN - 0306-4522

IS - 1

ER -