Chronic exposure to typical or atypical antipsychotics in rodents: temporal effects on central alpha7 nicotinic acetylcholine receptors.
A decrease in alpha7 nicotinic acetylcholine receptors in the hippocampus has been hypothesized to contribute to alterations in auditory gating and other behavioral impairments in schizophrenia. However, while both typical and atypical neuroleptics are routinely used in the therapeutics of schizophrenia, little is known about their effects on auditory gating or alpha7 nicotinic acetylcholine receptor expression particularly when they are administered for extended periods of time (which is common in the clinical setting). In the present study in normal rats, the residual effects of prior chronic treatment (90 or 180 days) with representative typical and atypical neuroleptics (oral haloperidol, 2.0 mg/kg/day; chlorpromazine, 10.0 mg/kg/day, risperidone, 2.5 mg/kg/day; or olanzapine, 10.0 mg/kg/day) on prepulse inhibition of the auditory gating response were investigated. The densities of alpha7 nicotinic acetylcholine receptors were subsequently measured using [125I]-alpha-bungarotoxin autoradiography. The results indicated that none of the compounds significantly altered the startle amplitude or prepulse inhibition response either during drug treatment (day 60) or after 90 or 180 days of treatment (i.e. during a drug free washout). However, prior exposure to chlorpromazine, risperidone and olanzapine for 90 days resulted in modest but significant (P<0.01) decreases in [125I]-alpha-bungarotoxin binding sites in some brain regions (e.g. posterior cortical amygdala). After 180 days of treatment, decreases in [(125I]-alpha-bungarotoxin binding ranging from approximately 12% (lateral dentate gyrus) up to 24% (e.g. CA1 hippocampal region) were evident in the risperidone group in 13 of the 36 regions analyzed while decreases associated with the other neuroleptics agents were still present, but not statistically significant. These data indicate that the commonly used atypical neuroleptic, risperidone is associated with time dependent and persistent negative effects on an important biological substrate of memory (i.e. the alpha7 nicotinic receptor), but that the magnitude of the deficits was not sufficient to impair auditory gating.
Terry
A V
AV
Program in Clinical and Experimental Therapeutics, University of Georgia, College of Pharmacy (Augusta Campus), Medical College of Georgia, Augusta, GA 30912, USA. aterry@mail.mcg.edu
Gearhart
D A
DA
Mahadik
S P
SP
Warsi
S
S
Davis
L W
LW
Waller
J L
JL
D000161:Acoustic Stimulation; D000818:Animals; D014150:Antipsychotic Agents / Q000097:blood / Q000494:pharmacology*; D001345:Autoradiography; D001923:Brain Chemistry / Q000187:drug effects*; D002038:Bungarotoxins / Q000493:pharmacokinetics; D003720:Densitometry; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013216:Reflex, Startle / Q000187:drug effects; D013997:Time Factors; D064569:alpha7 Nicotinic Acetylcholine Receptor
D014150:Antipsychotic Agents; D002038:Bungarotoxins; C579165:Chrna7 protein, rat; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor