Type I and type II positive allosteric modulators of α7 nicotinic acetylcholine receptors induce antidepressant-like activity in mice by a mechanism involving receptor potentiation but not neurotransmitter reuptake inhibition. Correlation with mTOR intracellular pathway activation
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Type I and type II positive allosteric modulators of α7 nicotinic acetylcholine receptors induce antidepressant-like activity in mice by a mechanism involving receptor potentiation but not neurotransmitter reuptake inhibition. Correlation with mTOR intracellular pathway activation. / Targowska-Duda, Katarzyna M.; Budzynska, Barbara; Michalak, Agnieszka; Wnorowski, Artur; Loland, Claus J.; Maj, Maciej; Manetti, Dina; Romanelli, Maria Novella; Jozwiak, Krzysztof; Biala, Grazyna; Arias, Hugo R.
In: European Neuropsychopharmacology, Vol. 52, 2021, p. 31-47.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Type I and type II positive allosteric modulators of α7 nicotinic acetylcholine receptors induce antidepressant-like activity in mice by a mechanism involving receptor potentiation but not neurotransmitter reuptake inhibition. Correlation with mTOR intracellular pathway activation
AU - Targowska-Duda, Katarzyna M.
AU - Budzynska, Barbara
AU - Michalak, Agnieszka
AU - Wnorowski, Artur
AU - Loland, Claus J.
AU - Maj, Maciej
AU - Manetti, Dina
AU - Romanelli, Maria Novella
AU - Jozwiak, Krzysztof
AU - Biala, Grazyna
AU - Arias, Hugo R.
N1 - Publisher Copyright: © 2021 Elsevier B.V. and ECNP
PY - 2021
Y1 - 2021
N2 - The aim of this study is to determine whether type I and type II positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptors (nAChRs) induce antidepressant-like activity in mice after acute, subchronic, and chronic treatments, and to assess whether α7-PAMs inhibit neurotransmitter transporters and activate mTOR (mammalian target of rapamycin) and/or ERK (extracellular signal-regulated protein kinases) signaling. The forced swim (FST) and tail suspension (TST) test results indicated that NS-1738 (type I PAM), PNU-120596 and PAM-2 (type II PAMs) induce antidepressant-like activity after subchronic treatment, whereas PAM-2 was also active after chronic treatment. Methyllycaconitine (α7-antagonist) inhibited the observed effects, highlighting the involvement of α7 nAChRs in this process. Drug interaction studies showed synergism between PAM-2 and bupropion (antidepressant), but not between PAM-2 and DMXBA (α7-agonist). The studied PAMs showed no high affinity (< 1 µM) for the human dopamine, serotonin, and noradrenaline transporters, suggesting that transporter inhibition is not the underlying mechanism for the observed activity. To assess whether mTOR and ERK signaling pathways are involved in the activity of α7-PAMs, the phosphorylation status of key signaling nodes was determined in prefrontal cortex and hippocampus from mice chronically treated with PAM-2. In conclusion, the antidepressant-like activity of type I and type II PAMs is mediated by a mechanism involving α7 potentiation but not α7 desensitization or neurotransmitter transporter blockade, and is correlated with activation of both mTOR and ERK signaling pathways. These results support the view that α7-PAMs might be clinically used to ameliorate depression disorders.
AB - The aim of this study is to determine whether type I and type II positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptors (nAChRs) induce antidepressant-like activity in mice after acute, subchronic, and chronic treatments, and to assess whether α7-PAMs inhibit neurotransmitter transporters and activate mTOR (mammalian target of rapamycin) and/or ERK (extracellular signal-regulated protein kinases) signaling. The forced swim (FST) and tail suspension (TST) test results indicated that NS-1738 (type I PAM), PNU-120596 and PAM-2 (type II PAMs) induce antidepressant-like activity after subchronic treatment, whereas PAM-2 was also active after chronic treatment. Methyllycaconitine (α7-antagonist) inhibited the observed effects, highlighting the involvement of α7 nAChRs in this process. Drug interaction studies showed synergism between PAM-2 and bupropion (antidepressant), but not between PAM-2 and DMXBA (α7-agonist). The studied PAMs showed no high affinity (< 1 µM) for the human dopamine, serotonin, and noradrenaline transporters, suggesting that transporter inhibition is not the underlying mechanism for the observed activity. To assess whether mTOR and ERK signaling pathways are involved in the activity of α7-PAMs, the phosphorylation status of key signaling nodes was determined in prefrontal cortex and hippocampus from mice chronically treated with PAM-2. In conclusion, the antidepressant-like activity of type I and type II PAMs is mediated by a mechanism involving α7 potentiation but not α7 desensitization or neurotransmitter transporter blockade, and is correlated with activation of both mTOR and ERK signaling pathways. These results support the view that α7-PAMs might be clinically used to ameliorate depression disorders.
KW - 3-furan-2-yl-N-p-tolyl-acrylamide
KW - antidepressant-like activity
KW - mTOR phosphorylation
KW - Positive allosteric modulator
KW - α7 Nicotinic acetylcholine receptor
U2 - 10.1016/j.euroneuro.2021.06.006
DO - 10.1016/j.euroneuro.2021.06.006
M3 - Journal article
C2 - 34237657
AN - SCOPUS:85109129762
VL - 52
SP - 31
EP - 47
JO - European Neuropsychopharmacology
JF - European Neuropsychopharmacology
SN - 0924-977X
ER -
ID: 276330152