The selective alpha7 nicotinic acetylcholine receptor agonist A-582941 activates immediate early genes in limbic regions of the forebrain: Differential effects in the juvenile and adult rat
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The selective alpha7 nicotinic acetylcholine receptor agonist A-582941 activates immediate early genes in limbic regions of the forebrain : Differential effects in the juvenile and adult rat. / Thomsen, M S; Mikkelsen, J D; Timmermann, D B; Peters, David Alberg; Hay-Schmidt, A; Martens, Harald Aagaard; Hansen, H H; Thomsen, Morten Skøtt.
In: Neuroscience, Vol. 154, No. 2, 23.06.2008, p. 741-53.Research output: Contribution to journal › Journal article › Research
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T1 - The selective alpha7 nicotinic acetylcholine receptor agonist A-582941 activates immediate early genes in limbic regions of the forebrain
T2 - Differential effects in the juvenile and adult rat
AU - Thomsen, M S
AU - Mikkelsen, J D
AU - Timmermann, D B
AU - Peters, David Alberg
AU - Hay-Schmidt, A
AU - Martens, Harald Aagaard
AU - Hansen, H H
AU - Thomsen, Morten Skøtt
PY - 2008/6/23
Y1 - 2008/6/23
N2 - Due to the cognitive-enhancing properties of alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists, they have attracted interest for the treatment of cognitive disturbances in schizophrenia. Schizophrenia typically presents in late adolescence or early adulthood. It is therefore important to study whether alpha7 nAChR stimulation activates brain regions involved in cognition in juvenile as well as adult individuals. Here, we compared the effects of the novel and selective alpha7 nAChR agonist 2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole (A-582941) in the juvenile and adult rat forebrain using two markers, activity-regulated cytoskeleton-associated protein (Arc) and c-Fos, to map neuronal activity. Acute administration of A-582941 (1, 3, 10 mg/kg) induced a dose-dependent increase in Arc mRNA expression in the medial prefrontal cortex (mPFC) and the ventral/lateral orbitofrontal (VO/LO) cortex of juvenile, but not adult rats. This effect was mitigated by the alpha7 nAChR antagonist methyllycaconitine. A-582941 also increased c-Fos mRNA expression in the mPFC of juvenile, but not adult rats. Furthermore, A-582941 increased the number of Arc and c-Fos immunopositive cells in the mPFC, VO/LO, and shell of the nucleus accumbens, in both juvenile and adult rats. The A-582941-induced c-Fos protein expression was significantly greater in the mPFC and VO/LO of juvenile compared with adult rats. These data indicate that A-582941-induced alpha7 nAChR stimulation activates brain regions critically involved in working memory and attention. Furthermore, this effect is more pronounced in juvenile than adult rats, indicating that the juvenile forebrain is more responsive to alpha7 nAChR stimulation. This observation may be relevant in the treatment of juvenile-onset schizophrenia.
AB - Due to the cognitive-enhancing properties of alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists, they have attracted interest for the treatment of cognitive disturbances in schizophrenia. Schizophrenia typically presents in late adolescence or early adulthood. It is therefore important to study whether alpha7 nAChR stimulation activates brain regions involved in cognition in juvenile as well as adult individuals. Here, we compared the effects of the novel and selective alpha7 nAChR agonist 2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole (A-582941) in the juvenile and adult rat forebrain using two markers, activity-regulated cytoskeleton-associated protein (Arc) and c-Fos, to map neuronal activity. Acute administration of A-582941 (1, 3, 10 mg/kg) induced a dose-dependent increase in Arc mRNA expression in the medial prefrontal cortex (mPFC) and the ventral/lateral orbitofrontal (VO/LO) cortex of juvenile, but not adult rats. This effect was mitigated by the alpha7 nAChR antagonist methyllycaconitine. A-582941 also increased c-Fos mRNA expression in the mPFC of juvenile, but not adult rats. Furthermore, A-582941 increased the number of Arc and c-Fos immunopositive cells in the mPFC, VO/LO, and shell of the nucleus accumbens, in both juvenile and adult rats. The A-582941-induced c-Fos protein expression was significantly greater in the mPFC and VO/LO of juvenile compared with adult rats. These data indicate that A-582941-induced alpha7 nAChR stimulation activates brain regions critically involved in working memory and attention. Furthermore, this effect is more pronounced in juvenile than adult rats, indicating that the juvenile forebrain is more responsive to alpha7 nAChR stimulation. This observation may be relevant in the treatment of juvenile-onset schizophrenia.
KW - Aging
KW - Animals
KW - Cytoskeletal Proteins
KW - Genes, Immediate-Early
KW - Genes, fos
KW - Immunohistochemistry
KW - In Situ Hybridization
KW - Limbic System
KW - Male
KW - Nerve Tissue Proteins
KW - Nicotinic Agonists
KW - Prefrontal Cortex
KW - Prosencephalon
KW - Pyridazines
KW - Pyrroles
KW - RNA, Messenger
KW - Rats
KW - Rats, Wistar
KW - Receptors, Nicotinic
KW - alpha7 Nicotinic Acetylcholine Receptor
U2 - 10.1016/j.neuroscience.2008.03.083
DO - 10.1016/j.neuroscience.2008.03.083
M3 - Journal article
C2 - 18495359
VL - 154
SP - 741
EP - 753
JO - Neuroscience
JF - Neuroscience
SN - 0306-4522
IS - 2
ER -
ID: 111182691