Nicotine effects in adolescence and adulthood on cognition and α₄β₂-nicotinic receptors in the neonatal ventral hippocampal lesion rat model of schizophrenia.
BACKGROUND
Nicotine use in schizophrenia has traditionally been explained as "self-medication" of cognitive and/or nicotinic acetylcholinergic receptor (nAChR) abnormalities.


OBJECTIVE
We test this hypothesis in a neurodevelopmental rat model of schizophrenia that shows increased addiction behaviors including enhanced nicotine reinforcement and drug-seeking.


METHODS
Nicotine transdermal patch (5 mg/kg/day vs. placebo × 10 days in adolescence or adulthood) effects on subsequent radial-arm maze learning (15 sessions) and frontal-cortical-striatal nAChR densities (α4β2; [3H]-epibatidine binding) were examined in neonatal ventral hippocampal lesion (NVHL) and SHAM-operated rats.


RESULTS
NVHL cognitive deficits were not differentially affected by nicotine history compared to SHAMs. Nicotine history produced minimal cognitive effects while increasing food-reward consumption on the maze, compounding with NVHL-induced overconsumption. Acute nicotine (0.5 mg/kg) delivered before the final maze sessions produced modest improvements in maze performance in rats with nicotine patch histories only, but not differentially so in NVHLs. Consistent with in vivo neuroimaging of β2 nAChR binding in schizophrenia smokers vs. non-smokers and healthy controls, adult NVHLs showed 12% reductions in nAChR binding in MPFC (p < 0.05) but not ventral striatum (<5% changes, p > .40), whereas nicotine history elevated nAChRs across both regions (>30%, p < 0.001) without interacting with NVHLs. Adolescent vs. adult nicotine exposure did not alter nAChRs differentially.


CONCLUSIONS
Although replicating nicotine-induced upregulation of nAChRs in human smokers and demonstrating NVHL validity in terms of schizophrenia-associated nAChR density patterns, these findings do not support hypotheses explaining increased nicotine use in schizophrenia as reflecting illness-specific effects of nicotine to therapeutically alter cognition or nAChR densities.
Laboratory for Translational Neuroscience of Dual Diagnosis & Development, Suite 314D, 320 West 16th Street, Indianapolis, IN, 46202, USA, berg.fieler@gmail.com.
Sarah A
SA
Berg
Alena M
AM
Sentir
Richard L
RL
Bell
Eric A
EA
Engleman
R Andrew
RA
Chambers
D000279:Administration, Cutaneous; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D009538:Nicotine / Q000008:administration & dosage* / Q000378:metabolism*; D011247:Pregnancy; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism*; D016896:Treatment Outcome
D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine