PMID- 19146909
OWN - NLM
STAT- MEDLINE
DCOM- 20090602
LR  - 20211020
IS  - 0278-5846 (Print)
IS  - 0278-5846 (Linking)
VI  - 33
IP  - 2
DP  - 2009 Mar 17
TI  - Chronic underactivity of medial frontal cortical beta2-containing nicotinic 
      receptors increases clozapine-induced working memory impairment in female rats.
PG  - 296-302
LID - 10.1016/j.pnpbp.2008.12.003 [doi]
AB  - Nicotinic receptor decreases in the frontal cortex and hippocampus are important 
      mediators of cognitive impairment in both schizophrenia and Alzheimer's disease. 
      Drug treatments for these diseases should take into account the impacts of 
      compromised brain function on drug response. This study investigated the impact 
      of compromised nicotinic receptor activity in the frontal cortex in rats on 
      memory function. Since both Alzheimer's disease and schizophrenia can involve 
      psychosis, antipsychotic drugs are often given. The impacts of antipsychotic 
      drugs on cognitive function have been found to be quite variable. It is the 
      hypothesis of this and previous studies that the cognitive effects of 
      antispychotic drugs on cognitive function depend on the integrity of brain 
      systems involved in cognition. Previously in studies of the hippocampus, we found 
      that chronic inhibition of beta2-containing nicotinic receptors with 
      dihydro-beta-erythrodine (DHbetaE) impaired working memory and that this effect 
      was attenuated by the antipsychotic drug clozapine. In contrast, chronic 
      hippocampal alpha7 nicotinic receptor blockade with methyllycaconitine (MLA) 
      potentiated the clozapine-induced memory impairment which is seen in rats without 
      compromised nicotinic receptor activity. The current study determined medial 
      frontal cortical alpha7 and beta2-containing nicotinic receptor involvement in 
      memory and the interactions with antipsychotic drug therapy with clozapine. 
      Chronic DHbetaE and MLA infusion effects and interactions with systemic clozapine 
      were assessed in female rats tested for memory on the radial-arm maze. 
      Antipsychotic drug interactions with chronic systemic nicotine were investigated 
      because nicotinic procognitive treatment has been proposed. The same local 
      infusion DHbetaE dose that impaired memory with hippocampal infusion did not 
      impair memory when infused in the medial frontal cortex. Frontal DHbetaE infusion 
      potentiated clozapine-induced memory impairment, whereas previously the memory 
      impairment caused by hippocampal DHbetaE infusion was attenuated by clozapine. 
      Frontal cortical MLA infusions at a dose that previously was found to potentiate 
      the clozapine-induced memory impairment with hippocampal infusion had no 
      significant effect when infused into the medial frontal cortex. The location and 
      subtype of nicotinic receptor underactivity are critical determinates for 
      clozapine effects on memory. Patients with hippocampal beta2-containing nicotinic 
      receptor loss may be well treated with clozapine therapy, while those with 
      frontal cortical beta2-containing receptor loss may have a potentiated memory 
      impairment caused by clozapine.
FAU - Levin, Edward D
AU  - Levin ED
AD  - Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, 
      Durham, NC 27710, USA. edlevin@duke.edu
FAU - Perkins, Abigail
AU  - Perkins A
FAU - Brotherton, Terrell
AU  - Brotherton T
FAU - Qazi, Melissa
AU  - Qazi M
FAU - Berez, Chantal
AU  - Berez C
FAU - Montalvo-Ortiz, Janitza
AU  - Montalvo-Ortiz J
FAU - Davis, Kasey
AU  - Davis K
FAU - Williams, Paul
AU  - Williams P
FAU - Christopher, N Channelle
AU  - Christopher NC
LA  - eng
GR  - R01 MH064494/MH/NIMH NIH HHS/United States
GR  - R01 MH064494-05/MH/NIMH NIH HHS/United States
GR  - MH64494/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20081224
PL  - England
TA  - Prog Neuropsychopharmacol Biol Psychiatry
JT  - Progress in neuro-psychopharmacology & biological psychiatry
JID - 8211617
RN  - 0 (Antipsychotic Agents)
RN  - 0 (Chrna7 protein, rat)
RN  - 0 (Nicotinic Antagonists)
RN  - 0 (Receptors, Nicotinic)
RN  - 0 (alpha7 Nicotinic Acetylcholine Receptor)
RN  - 0 (nicotinic receptor alpha4beta2)
RN  - 0 (nicotinic receptor beta2)
RN  - 21019-30-7 (methyllycaconitine)
RN  - 23255-54-1 (Dihydro-beta-Erythroidine)
RN  - J60AR2IKIC (Clozapine)
RN  - X8YN71D5WC (Aconitine)
SB  - IM
MH  - Aconitine/analogs & derivatives/pharmacology
MH  - Animals
MH  - Antipsychotic Agents/administration & dosage/*pharmacology
MH  - Cerebral Cortex/*drug effects/*metabolism
MH  - Chronic Disease
MH  - Clozapine/administration & dosage/*pharmacology
MH  - Dihydro-beta-Erythroidine/pharmacology
MH  - Female
MH  - Maze Learning/drug effects
MH  - Memory Disorders/*chemically induced/*psychology
MH  - Memory, Short-Term/*drug effects
MH  - Microinjections
MH  - Nicotinic Antagonists/pharmacology
MH  - Prefrontal Cortex/drug effects/*physiology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, Nicotinic/*drug effects
MH  - alpha7 Nicotinic Acetylcholine Receptor
PMC - PMC2684503
MID - NIHMS102913
EDAT- 2009/01/17 09:00
MHDA- 2009/06/03 09:00
PMCR- 2010/03/17
CRDT- 2009/01/17 09:00
PHST- 2008/10/12 00:00 [received]
PHST- 2008/12/04 00:00 [revised]
PHST- 2008/12/05 00:00 [accepted]
PHST- 2009/01/17 09:00 [entrez]
PHST- 2009/01/17 09:00 [pubmed]
PHST- 2009/06/03 09:00 [medline]
PHST- 2010/03/17 00:00 [pmc-release]
AID - S0278-5846(08)00372-2 [pii]
AID - 10.1016/j.pnpbp.2008.12.003 [doi]
PST - ppublish
SO  - Prog Neuropsychopharmacol Biol Psychiatry. 2009 Mar 17;33(2):296-302. doi: 
      10.1016/j.pnpbp.2008.12.003. Epub 2008 Dec 24.