TY - JOUR

T1 - Positive allosteric modulation of AMPA receptors differentially modulates the behavioural effects of citalopram in mouse models of antidepressant and anxiolytic action

AU - Fitzpatrick, Ciarán Martin

AU - Larsen, Maria

AU - Madsen, Louise

AU - Pickering, Darryl S

AU - Clausen, Rasmus Prætorius

AU - Andreasen T., Jesper

PY - 2016/6/26

Y1 - 2016/6/26

N2 - Drugs that increase monoamine neurotransmission are effective in both anxiety and depression. The therapeutic effects of monoamine-based antidepressant drugs may involve indirect effects on neurotransmission through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPAR).Thus, chronic antidepressant treatment increases AMPAR-mediated neurotransmission, and AMPAR positive allosteric modulators (APAMs) have shown antidepressant-like efficacy in rodents. Here, the effect of enhanced AMPAR neurotransmission on the antidepressant-like and anxiolytic-like actions of the selective serotonin reuptake inhibitor (SSRI) citalopram (0-10 mg/kg) was investigated in mice, using the APAM LY451646 (0-3 mg/kg). Antidepressant-like effects were assessed with the forced swim test (FST), while anxiolytic-like effects were tested with the elevated zero maze (EZM) and the marble burying test (MBT). LY451646 (3 mg/kg) increased swim distance in the FST and a sub-active dose of LY451646 (1 mg/kg) enhanced the effect of citalopram in the FST. In the EZM, LY451646 (3 mg/kg) did not show anxiogenic effects alone, but blocked the anxiolytic-like action of citalopram in the EZM, as reflected by an increase in the latency to enter the open areas and a decrease in the number of entries and time spent in the open areas in citalopram-treated mice. In the MBT, LY451646 (3 mg/kg) showed no effect alone but significantly attenuated the anxiolytic-like effect of citalopram (1.25-2.5 mg/kg) by increasing the number of marbles buried in citalopram-treated mice. These results suggest that AMPAR neurotransmission plays opposite roles in anxiety and depression, as AMPAR potentiation facilitated the antidepressant-like effects of citalopram while attenuating its anxiolytic-like effect. These findings have ramifications in the search for AMPAR-based novel anxiolytic and antidepressant treatments.

AB - Drugs that increase monoamine neurotransmission are effective in both anxiety and depression. The therapeutic effects of monoamine-based antidepressant drugs may involve indirect effects on neurotransmission through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPAR).Thus, chronic antidepressant treatment increases AMPAR-mediated neurotransmission, and AMPAR positive allosteric modulators (APAMs) have shown antidepressant-like efficacy in rodents. Here, the effect of enhanced AMPAR neurotransmission on the antidepressant-like and anxiolytic-like actions of the selective serotonin reuptake inhibitor (SSRI) citalopram (0-10 mg/kg) was investigated in mice, using the APAM LY451646 (0-3 mg/kg). Antidepressant-like effects were assessed with the forced swim test (FST), while anxiolytic-like effects were tested with the elevated zero maze (EZM) and the marble burying test (MBT). LY451646 (3 mg/kg) increased swim distance in the FST and a sub-active dose of LY451646 (1 mg/kg) enhanced the effect of citalopram in the FST. In the EZM, LY451646 (3 mg/kg) did not show anxiogenic effects alone, but blocked the anxiolytic-like action of citalopram in the EZM, as reflected by an increase in the latency to enter the open areas and a decrease in the number of entries and time spent in the open areas in citalopram-treated mice. In the MBT, LY451646 (3 mg/kg) showed no effect alone but significantly attenuated the anxiolytic-like effect of citalopram (1.25-2.5 mg/kg) by increasing the number of marbles buried in citalopram-treated mice. These results suggest that AMPAR neurotransmission plays opposite roles in anxiety and depression, as AMPAR potentiation facilitated the antidepressant-like effects of citalopram while attenuating its anxiolytic-like effect. These findings have ramifications in the search for AMPAR-based novel anxiolytic and antidepressant treatments.

U2 - 10.1097/FBP.0000000000000243

DO - 10.1097/FBP.0000000000000243

M3 - Journal article

C2 - 27341500

VL - 27

SP - 549

EP - 555

JO - Behavioural Pharmacology

JF - Behavioural Pharmacology

SN - 0955-8810

IS - 6

ER -