Chronic treatment with first or second generation antipsychotics in rodents: Effects on high affinity nicotinic and muscarinic acetylcholine receptors in the brain

A. V. Terry, D. A. Gearhart, S. P. Mahadik, S. Warsi, J. L. Waller

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Several postmortem and neuroimaging studies suggest that central nicotinic and muscarinic acetylcholine receptors are important in both the pathophysiology and pharmacotherapy of schizophrenia. However, while antipsychotic drugs are routinely used in the therapeutics of schizophrenia, little is known about their effects on the densities of these receptors when they are administered for extended periods of time (a common practice in the clinical setting). In the present study in rats, the residual effects of prior chronic exposure to representative first generation antipsychotics and second generation antipsychotics on the densities of high affinity nicotinic acetylcholine receptors and muscarinic acetylcholine receptor in the brain were investigated. Test subjects were treated with the first generation antipsychotics, haloperidol (2.0 mg/kg/day) or chlorpromazine (10.0 mg/kg/day) or the second generation antipsychotics, risperidone (2.5 mg/kg/day) or olanzapine (10.0 mg/kg/day) in drinking water for periods of 90 or 180 days, given a drug-free washout period (i.e. returned to normal drinking water) for two weeks and then killed. Quantitative receptor autoradiography was subsequently performed using 16 μm sagittal slices of whole brain incubated with [3H]-epibatidine, [3H]-pirenzepine or [3H]-AFDX-384 to measure high affinity nicotinic acetylcholine receptors, M1 and M2 muscarinic acetylcholine receptors, respectively. The most notable experimental result was a moderate, but significant (P<0.01) increase in [3H]-AFDX-384 binding sites in a number of brain regions (including cortex, hippocampus, subiculum, substantia innominata, and thalamus) associated with prior exposure to olanzapine for 90, but not 180 days. Olanzapine was also associated with a significantly higher density of [3H]-pirenzepine binding sites in cortex lamina I after 90 days of prior drug exposure. These data indicate that chronic treatment with a commonly used second generation antipsychotic, olanzapine is associated with modest increases in M2 muscarinic acetylcholine receptors in memory-related brain regions that may eventually abate with longer periods of chronic drug exposure.

Original languageEnglish (US)
Pages (from-to)1277-1287
Number of pages11
JournalNeuroscience
Volume140
Issue number4
DOIs
StatePublished - Jun 28 2006

Fingerprint

olanzapine
Nicotinic Receptors
Muscarinic Receptors
Antipsychotic Agents
Rodentia
Brain
Pirenzepine
epibatidine
Drinking Water
Hippocampus
Schizophrenia
Therapeutics
Substantia Innominata
Binding Sites
Pharmaceutical Preparations
Risperidone
Chlorpromazine
Haloperidol
Autoradiography
Thalamus

Keywords

  • chlorpromazine
  • cognition
  • haloperidol
  • olanzapine
  • risperidone
  • schizophrenia

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Chronic treatment with first or second generation antipsychotics in rodents : Effects on high affinity nicotinic and muscarinic acetylcholine receptors in the brain. / Terry, A. V.; Gearhart, D. A.; Mahadik, S. P.; Warsi, S.; Waller, J. L.

In: Neuroscience, Vol. 140, No. 4, 28.06.2006, p. 1277-1287.

Research output: Contribution to journalArticle

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