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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.

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Related in: MedlinePlus

Effects of SB-269970 on MK-801-induced dopamine release.Results are expressed as percentage ofbaseline (mean ± S.E.M., N = 5-6 per group). SB-269970 (10 mg/kg) did not affect dopamine levels by itself, nor did it alter the effect of MK-801 (0.1 mg/kg) on dopamine levels.*p<0.001, at each time point compared to control.
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pone-0020210-g004: Effects of SB-269970 on MK-801-induced dopamine release.Results are expressed as percentage ofbaseline (mean ± S.E.M., N = 5-6 per group). SB-269970 (10 mg/kg) did not affect dopamine levels by itself, nor did it alter the effect of MK-801 (0.1 mg/kg) on dopamine levels.*p<0.001, at each time point compared to control.

Mentions: The effect of SB-269970 (10 mg/kg, IP) on MK-801 (0.1 mg/kg, IP) induced dopamine extracellular levels was evaluated in the cortex of conscious rats using microdialysis (Fig. 4.). A two-way repeated measures ANOVA revealed a main effect of group (F(3, 17) = 21.18, p = 0.00001) and time (F(11, 187) = 45.27, p = 0.00005), and an interaction (F(33, 187) = 13.89, p = 0.00005). Post-hoc tests revealed that the vehicle + MK-801 had higher dopamine levels compared to the vehicle + vehicle group from 30 – 105 min (p = 0.000004–0.000075 at those time points). SB-269970 did not affect dopamine levels by itself, nor did it alter the effect of MK-801 on dopamine levels (p>0.05 at all time points).


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 MK-801-induced dopamine release.Results are expressed as percentage ofbaseline (mean ± S.E.M., N = 5-6 per group). SB-269970 (10 mg/kg) did not affect dopamine levels by itself, nor did it alter the effect of MK-801 (0.1 mg/kg) on dopamine levels.*p<0.001, at each time point compared to control.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3119073&req=5

pone-0020210-g004: Effects of SB-269970 on MK-801-induced dopamine release.Results are expressed as percentage ofbaseline (mean ± S.E.M., N = 5-6 per group). SB-269970 (10 mg/kg) did not affect dopamine levels by itself, nor did it alter the effect of MK-801 (0.1 mg/kg) on dopamine levels.*p<0.001, at each time point compared to control.
Mentions: The effect of SB-269970 (10 mg/kg, IP) on MK-801 (0.1 mg/kg, IP) induced dopamine extracellular levels was evaluated in the cortex of conscious rats using microdialysis (Fig. 4.). A two-way repeated measures ANOVA revealed a main effect of group (F(3, 17) = 21.18, p = 0.00001) and time (F(11, 187) = 45.27, p = 0.00005), and an interaction (F(33, 187) = 13.89, p = 0.00005). Post-hoc tests revealed that the vehicle + MK-801 had higher dopamine levels compared to the vehicle + vehicle group from 30 – 105 min (p = 0.000004–0.000075 at those time points). SB-269970 did not affect dopamine levels by itself, nor did it alter the effect of MK-801 on dopamine levels (p>0.05 at all time points).

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