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University of Newcastle Winter Meeting December 2004 |
PCP and ketamine lack functional activity at serotonin 5-HT2A and 5-HT2C receptors as well as dopamine D2 and D3 receptors Nisha Patel, Jennie Heath & Martyn Wood. Psychiatry Centre of |
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Print abstractAlterations in both glutamatergic and dopaminergic systems are believed to underlie schizophrenia. The NMDA (N-methyl D-aspartate) receptor antagonists PCP (phencyclidine) and ketamine both induce a number of symptoms associated with schizophrenia in healthy volunteers and have, therefore, been used to generate preclinical models of disease (Meltzer et al., 1976). Recently, Kapur et al., 2002 employed a radioligand approach to demonstrate that both PCP and ketamine interact with the high affinity state of dopamine D2 and serotonin 5-HT2 receptors. Furthermore, [35S]GTPγS binding studies have suggested that these compounds act as partial agonists at the dopamine D2 receptor.
The present study focussed on re-evaluating these findings by investigating the functional activity of PCP and ketamine at serotonin 5-HT2A and 5-HT2C receptors using the FLIPR (Jerman et al.,2001) and at dopamine D2 and D3 receptors using microphysiometry (Boyfield et al.,1996).
5-HT caused a concentration dependent increase in intracellular calcium induced by 5-HT in SH-SY5Y-5-HT2A and SH-SY5Y-5-HT2C cells with pEC50 values of 8.54±0.07 (n=3) and 8.51±0.01 (n=4), respectively. In contrast, PCP and ketamine (up to 100 µM) displayed no agonist like activity in either untreated or butyrate treated cells.
Spiperone inhibited the intracellular rise in calcium induced by 5-HT (100 nM) mediated activation of
5-HT 2A and 5-HT2C receptors with pIC50 values of 8.06±0.04 (n=3) and 6.08±0.02 (n=4), respectively, in untreated cells. Neither PCP nor ketamine (up to 100 µM) antagonised the response induced by 100 nM 5-HT in either butyrate treated or untreated cells.
The dopamine receptor agonist quinpirole produced concentration dependent increases in extracellular acidification rates in both CHO-hD2 and CHO-hD3 cells with pEC50 values of 7.57 (n=2) and 8.54 (n=2), respectively. In contrast, both PCP and ketamine (up to 100 µM) did not affect basal acidification rates in either cell line.
The current study has failed to confirm the findings of Kapur et al. (2002) that suggest that PCP and ketamine display partial agonist like activity at the dopamine D2 receptor. Furthermore, this study demonstrates that both PCP and ketamine (up to 100 µM) lack functional activity at dopamine D2 and
D3 receptors as well as at serotonin 5-HT2A and 5-HT2C receptors even when receptor expression was increased using sodium butyrate treatment.
Boyfield I. et al (1996) Biochem Soc Trans. 24 (1):57S.
Jerman J.C. et al (2001) European Journal of Pharmacology. 414:23-30.
Kapur S. et al (2002) Molecular Psychiatry. 7:837-844.
Meltzer H.Y et al (1976) Schizophrenia Bulletin. 2(1):19-76.