Fig. 3: Reduced evoked glutamate release by ketamine and (2 R, 6 R)-HNK is AMPAR-dependent and mediated through A1Rs. | Molecular Psychiatry

Fig. 3: Reduced evoked glutamate release by ketamine and (2 R, 6 R)-HNK is AMPAR-dependent and mediated through A1Rs.

From: Ketamine decreases neuronally released glutamate via retrograde stimulation of presynaptic adenosine A1 receptors

Fig. 3

a Reduction of KCl-evoked glutamate release in subiculum of isoflurane anesthetized mice after local application of 100 µM ketamine or (2 R, 6 R)-HNK was occluded by co-application of NBQX (10 µM). Number of animals per group: N = 10 vehicle; N = 8 ketamine; N = 8 HNK; N = 7 NBQX; N = 10 NBQX/ketamine; N = 5 NBQX/HNK. Statistical significance was assessed by two-way ANOVA followed by Fisher’s LSD; interaction F (2, 42) = 1.12, p = 0.337; drug F = 5.74, p = 0.006; NBQX F = 116.9, p < 0.0001. *p < 0.05, **p < 0.01, ****p < 0.0001. b Co-application of DPCPX (2.5 μM) occluded both ketamine and (2 R, 6 R)-HNK induced reduction of KCl-evoked glutamate release in dorsal subiculum of isoflurane anesthetized mice. Number of animals per group: N = 9 vehicle; N = 9 ketamine; N = 9 HNK; N = 7 DPCPX; N = 8 DPCPX/ketamine; N = 7 DPCPX/HNK. Statistical analysis was done using two-way ANOVA followed by Fisher’s LSD; interaction F (2, 43) = 1.94, p = 0.156; drug F = 4.06, p = 0.024; DPCPX F = 71.36, p < 0.0001. *p < 0.05, **p < 0.01, ****p < 0.0001. c Reduction of KCl-evoked glutamate release upon local application of 100 µM ketamine or (2 R, 6 R)-HNK into dorsal subiculum of freely moving animals was prevented by co-application of DPCPX (2.5 μM). N = 7 vehicle; N = 7 ketamine; N = 7 HNK; N = 6 DPCPX; N = 6 DPCPX/ketamine; N = 5 DPCPX/HNK treated mice. Two-way ANOVA followed by Fisher’s LSD; interaction F (2, 32) = 2.24, p = 0.123; drug F = 2.52, p = 0.096; DPCPX F = 65.96, p < 0.0001. *p < 0.05, **p < 0.01, ****p < 0.0001. d Systemic administration of both ketamine and (2 R, 6 R)-HNK (30 min; i.p. 15 mg/kg) reduced KCl-evoked glutamate release in dorsal subiculum that was prevented by 30 min pre-treatment with DPCPX (2 mg/kg). Number of animals per group: N = 9 vehicle; N = 9 ketamine; N = 7 HNK; N = 6 DPCPX; N = 6 DPCPX/ketamine; N = 5 DPCPX/HNK. Statistical significance was assessed by two-way ANOVA followed by Fisher’s LSD; interaction F (2, 36) = 2.63, p = 0.085; drug F = 4.41, p = 0.019; DPCPX F = 53.37, p < 0.0001. **p < 0.01, ****p < 0.0001. e Acute local injection of A1R agonist, CPA (2.5 μM), into dorsal subiculum of isoflurane anesthetized mice significantly reduced KCl-evoked glutamate release. N = 10 vehicle; N = 8 CPA treated mice. Statistical significance was assessed using Student’s t test. ***p < 0.001. f Local application of 100 µM ketamine or (2 R, 6 R)-HNK into subiculum of p11 knockout or wildtype mice significantly reduced KCl-evoked glutamate release (N = 5 vehicle; N = 5 ketamine; N = 5 HNK treated animals). Pretreatment of animals with DPCPX (2.5 μM) occluded the effect of both drugs (N = 6 DPCPX; N = 4 DPCPX/ketamine; N = 4 DPCPX/HNK). Two-way ANOVA followed by Fisher’s LSD; interaction F (2, 23) = 1.53; p = 0.237; drug F = 2.042, p = 0.153; DPCPX F = 36.83, p < 0.0001. *p < 0.05.

Back to article page