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Acute ketamine induces hippocampal synaptic depression and spatial memory impairment through dopamine D1/D5 receptors

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Abstract

Rationale

Subanesthetic doses of ketamine have been reported to induce psychotic states that may mimic positive and negative symptoms as well as cognitive and memory deficits similar to those observed in schizophrenia. The cognitive and memory deficits are persistent, and their underlying cellular mechanisms remain unclear.

Objectives

We sought to investigate the roles of dopamine D1/D5 receptors and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in hippocampal synaptic transmission and spatial memory impairment induced by ketamine.

Methods

We examined the effects of subanesthetic ketamine on hippocampal synaptic transmission in freely moving rats. Spatial memory was tested with the Morris water maze. Pretreatment with the D1/D5 receptors antagonist SCH23390 or the AMPA receptors endocytosis interfering peptide Tat-GluR23Y was conducted to examine their capacities to reverse ketamine-induced electrophysiological and behavioral alterations. A series of behavioral observations, including locomotion, prepulse inhibition, and social interaction, were also conducted after ketamine treatment.

Results

Ketamine induced synaptic depression lasting at least 4 h at hippocampal Schaffer collateral-CA1 synapses in freely moving rats and long-term spatial memory impairment. Both the effects were blocked by either SCH23390 or Tat-GluR23Y. Ketamine also elicited transient behavioral changes lasting less than 90 min, such as hyperlocomotion and prepulse inhibition deficits. These changes were ameliorated by SCH23390 but not by Tat-GluR23Y. Rats treated with ketamine showed social withdrawal that was also attenuated by either SCH23390 or Tat-GluR23Y.

Conclusions

Our results indicate that hippocampal synaptic depression is involved in ketamine-induced memory impairment, and this is modulated by D1/D5 receptors activation and AMPA receptors endocytosis.

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Acknowledgments

This work was supported by 973 program from the Ministry of Science and Technology of China (2013CB835103 to L.X., 2009CB941302 to L.X. and 2009CB522006 to J.C.), the Strategic Priority Research Program of the Chinese Academy of Science (XDB02020200 to L.X.), and The National Science Foundation of China (31100775 to Q.-X. Z.) and NSFC-Yunnan Joint Grant (U1032605 to L.X.) and NSFC-CIHR Joint Grant (81161120536 to L.X.).

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Authors and Affiliations

  1. Key Laboratory of Animal Models and Human Disease Mechanisms, and Laboratory of Learning and Memory, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China

    Ting-Ting Duan, Ji-Wei Tan, Qiang Yuan, Jun Cao, Qi-Xin Zhou & Lin Xu

  2. School of Life Sciences, University of Science and Technology of China, Hefei, 230026, China

    Ting-Ting Duan

  3. University of Chinese Academy of Sciences, Beijing, 100049, China

    Ji-Wei Tan

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  1. Ting-Ting Duan
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  2. Ji-Wei Tan
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  4. Jun Cao
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  6. Lin Xu
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Correspondence to Qi-Xin Zhou or Lin Xu.

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Fig.1

Electrophysiological recording of basal synaptic transmission. a Synaptic transmission at Schaffer collateral-CA1 synapses was recorded stably for at least 24 h in freely moving rats (n = 5). b, c Tat-GluR2 peptides and D1/D5 receptors antagonist did not affect basal synaptic transmission in the hippocampal CA1 region in freely moving rats. After 40 min of stable baseline recording, rats were injected b Tat-GluR23S peptide (3 μmol/kg, i.p., n = 5), Tat-GluR23Y peptide (3 μmol/kg, i.p., n = 5), or c SCH23390 (0.1 mg/kg, n = 5 and 0.25 mg/kg, n = 5; i.p.). The impact of these drugs on fEPSPs was monitored for 2 or 3 h. SCH, SCH23390 (JPEG 37 kb)

High resolution image (TIFF 231 kb)

Fig.2

Effects of different treatments on swim speed in the Morris water maze. During the probe test, the impact of eight different treatments on swim speed was examined: saline + saline (i.p., n = 19); SCH23390 + saline (0.1 mg/kg, i.p., n = 10); Tat-GluR23S peptide + saline (3 μmol/kg, i.p., n = 10) and Tat-GluR23Y peptide + saline (3 μmol/kg, i.p., n = 9); saline + ketamine (30 mg/kg, i.p., n = 10); SCH23390 + ketamine (0.1 mg/kg, i.p., n = 12); Tat-GluR23S peptide + ketamine (3 μmol/kg, i.p., n = 13) and Tat-GluR23Y peptide + ketamine (3 μmol/kg, i.p., n = 14). No drug effect on swim speed during the retrieval phase was detected. Data represent the mean ± the SEM. Sal saline, Ket ketamine, SCH SCH23390 (JPEG 27 kb)

High resolution image (TIFF 269 kb)

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Duan, TT., Tan, JW., Yuan, Q. et al. Acute ketamine induces hippocampal synaptic depression and spatial memory impairment through dopamine D1/D5 receptors. Psychopharmacology 228, 451–461 (2013). https://doi.org/10.1007/s00213-013-3048-2

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