Limits...
Pharmacological blockade of serotonin 5-HT₇ receptor reverses working memory deficits in rats by normalizing cortical glutamate neurotransmission.

Bonaventure P, Aluisio L, Shoblock J, Boggs JD, Fraser IC, Lord B, Lovenberg TW, Galici R - PLoS ONE (2011)

Bottom Line: The effect of SB-269970 was evaluated in the delayed non-matching to position task alone or in combination with MK-801, a non-competitive NMDA receptor antagonist, and, in separate experiments, with scopolamine, a non-selective muscarinic antagonist.SB-269970 (10 mg/kg) significantly reversed the deficits induced by MK-801 (0.1 mg/kg) but augmented the deficit induced by scopolamine (0.06 mg/kg).These results indicate that 5-HT₇ receptor antagonists might reverse cognitive deficits associated with NMDA receptor hypofunction by selectively normalizing glutamatergic neurotransmission.

View Article: PubMed Central - PubMed

Affiliation: Johnson & Johnson Pharmaceutical Research and Development, L.L.C., San Diego, California, United States of America. Pbonave1@its.jnj.com

ABSTRACT
The role of 5-HT₇ receptor has been demonstrated in various animal models of mood disorders; however its function in cognition remains largely speculative. This study evaluates the effects of SB-269970, a selective 5-HT₇ antagonist, in a translational model of working memory deficit and investigates whether it modulates cortical glutamate and/or dopamine neurotransmission in rats. The effect of SB-269970 was evaluated in the delayed non-matching to position task alone or in combination with MK-801, a non-competitive NMDA receptor antagonist, and, in separate experiments, with scopolamine, a non-selective muscarinic antagonist. SB-269970 (10 mg/kg) significantly reversed the deficits induced by MK-801 (0.1 mg/kg) but augmented the deficit induced by scopolamine (0.06 mg/kg). The ability of SB-269970 to modulate MK-801-induced glutamate and dopamine extracellular levels was separately evaluated using biosensor technology and microdialysis in the prefrontal cortex of freely moving rats. SB-269970 normalized MK-801 -induced glutamate but not dopamine extracellular levels in the prefrontal cortex. Rat plasma and brain concentrations of MK-801 were not affected by co-administration of SB-269970, arguing for a pharmacodynamic rather than a pharmacokinetic mechanism. These results indicate that 5-HT₇ receptor antagonists might reverse cognitive deficits associated with NMDA receptor hypofunction by selectively normalizing glutamatergic neurotransmission.

Show MeSH

Related in: MedlinePlus

Effects of SB-269970 on scopolamine-induced DNMTP deficits.SB-269970 (10 mg/kg) and scopolamine (0.06 mg/kg), or their vehicles, were administered 10 and 30 min, respectively, before the beginning of the session (N = 6 per group). SB-269970 augmented the deficit caused by scopolamine (*p<0.05, main effect). For statistical details see the result section.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3119073&req=5

pone-0020210-g002: Effects of SB-269970 on scopolamine-induced DNMTP deficits.SB-269970 (10 mg/kg) and scopolamine (0.06 mg/kg), or their vehicles, were administered 10 and 30 min, respectively, before the beginning of the session (N = 6 per group). SB-269970 augmented the deficit caused by scopolamine (*p<0.05, main effect). For statistical details see the result section.

Mentions: The effect of SB-269970 (10 mg/kg, IP) on scopolamine (0.06 mg/kg, IP) -induced deficits was evaluated in the DNMTP task (Fig. 2). A two-way repeated measures ANOVA (delay x treatment group), with repeated measures on delay, detected a main effect of delay (F(4, 25) = 2.79, p = 0.048) and group (F(3, 75) = 37.29, p = 0.000005), but no interaction (F(12, 75) = 0.88, p = 0.57). Duncan's post-hoc tests on group revealed that scopolamine worsened performance in both the vehicle-pretreated and SB-269970- pretreated groups (p<0.00006 comparing vehicle + vehicle to vehicle + scopolamine and p<0.00005 comparing vehicle + vehicle to SB-269970 + scopolamine). SB-269970 had no effect on its own (p = 0.83, comparing vehicle + vehicle to SB-269970 + vehicle), but augmented the deficit caused by scopolamine (p<0.0003 comparing vehicle + scopolamine to SB-269970 + scopolamine). There was no difference in the number of trials completed in each session among treatment groups (F(3,15) = 2.65, p = 0.086).


Pharmacological blockade of serotonin 5-HT₇ receptor reverses working memory deficits in rats by normalizing cortical glutamate neurotransmission.

Bonaventure P, Aluisio L, Shoblock J, Boggs JD, Fraser IC, Lord B, Lovenberg TW, Galici R - PLoS ONE (2011)

Effects of SB-269970 on scopolamine-induced DNMTP deficits.SB-269970 (10 mg/kg) and scopolamine (0.06 mg/kg), or their vehicles, were administered 10 and 30 min, respectively, before the beginning of the session (N = 6 per group). SB-269970 augmented the deficit caused by scopolamine (*p<0.05, main effect). For statistical details see the result section.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3119073&req=5

pone-0020210-g002: Effects of SB-269970 on scopolamine-induced DNMTP deficits.SB-269970 (10 mg/kg) and scopolamine (0.06 mg/kg), or their vehicles, were administered 10 and 30 min, respectively, before the beginning of the session (N = 6 per group). SB-269970 augmented the deficit caused by scopolamine (*p<0.05, main effect). For statistical details see the result section.
Mentions: The effect of SB-269970 (10 mg/kg, IP) on scopolamine (0.06 mg/kg, IP) -induced deficits was evaluated in the DNMTP task (Fig. 2). A two-way repeated measures ANOVA (delay x treatment group), with repeated measures on delay, detected a main effect of delay (F(4, 25) = 2.79, p = 0.048) and group (F(3, 75) = 37.29, p = 0.000005), but no interaction (F(12, 75) = 0.88, p = 0.57). Duncan's post-hoc tests on group revealed that scopolamine worsened performance in both the vehicle-pretreated and SB-269970- pretreated groups (p<0.00006 comparing vehicle + vehicle to vehicle + scopolamine and p<0.00005 comparing vehicle + vehicle to SB-269970 + scopolamine). SB-269970 had no effect on its own (p = 0.83, comparing vehicle + vehicle to SB-269970 + vehicle), but augmented the deficit caused by scopolamine (p<0.0003 comparing vehicle + scopolamine to SB-269970 + scopolamine). There was no difference in the number of trials completed in each session among treatment groups (F(3,15) = 2.65, p = 0.086).

Bottom Line: The effect of SB-269970 was evaluated in the delayed non-matching to position task alone or in combination with MK-801, a non-competitive NMDA receptor antagonist, and, in separate experiments, with scopolamine, a non-selective muscarinic antagonist.SB-269970 (10 mg/kg) significantly reversed the deficits induced by MK-801 (0.1 mg/kg) but augmented the deficit induced by scopolamine (0.06 mg/kg).These results indicate that 5-HT₇ receptor antagonists might reverse cognitive deficits associated with NMDA receptor hypofunction by selectively normalizing glutamatergic neurotransmission.

View Article: PubMed Central - PubMed

Affiliation: Johnson & Johnson Pharmaceutical Research and Development, L.L.C., San Diego, California, United States of America. Pbonave1@its.jnj.com

ABSTRACT
The role of 5-HT₇ receptor has been demonstrated in various animal models of mood disorders; however its function in cognition remains largely speculative. This study evaluates the effects of SB-269970, a selective 5-HT₇ antagonist, in a translational model of working memory deficit and investigates whether it modulates cortical glutamate and/or dopamine neurotransmission in rats. The effect of SB-269970 was evaluated in the delayed non-matching to position task alone or in combination with MK-801, a non-competitive NMDA receptor antagonist, and, in separate experiments, with scopolamine, a non-selective muscarinic antagonist. SB-269970 (10 mg/kg) significantly reversed the deficits induced by MK-801 (0.1 mg/kg) but augmented the deficit induced by scopolamine (0.06 mg/kg). The ability of SB-269970 to modulate MK-801-induced glutamate and dopamine extracellular levels was separately evaluated using biosensor technology and microdialysis in the prefrontal cortex of freely moving rats. SB-269970 normalized MK-801 -induced glutamate but not dopamine extracellular levels in the prefrontal cortex. Rat plasma and brain concentrations of MK-801 were not affected by co-administration of SB-269970, arguing for a pharmacodynamic rather than a pharmacokinetic mechanism. These results indicate that 5-HT₇ receptor antagonists might reverse cognitive deficits associated with NMDA receptor hypofunction by selectively normalizing glutamatergic neurotransmission.

Show MeSH
Related in: MedlinePlus