- Email: [email protected]
Role of dopamine and NMDA receptor subunits in the induction of long term potentiation in the nucleus accumbens
Molecular Neuropsychopharmacology H3R antagonist/inverse agonists which are currently introduced in the clinical phases of development would not alter the G protein coupling of D2Rs, which are the main targets of antipsychotics.
References [1] Arrang J.M., Garbarg M., and Schwartz J.C., 1983. Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature 302, 832-7. [2] Pillot C., Ortiz J., Heron A., Ridray S., Schwartz J.C., and Arrang J.M., 2002. Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat. J Neurosci 22, 7272-80. [3] Pillot C., Heron A., Schwartz J.C., and Arrang J.M., 2003. Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, modulates the effects of methamphetamine on neuropeptide mRNA expression in rat striatum. Eur J Neurosci 17, 307-14.
~Role
of dopamine and NMDA receptor subunits in the induction of long term potentiation in the nucleus accumbens
1Karolinska Institute, Von Eulersvdg 8, Stockholm, Sweden
S.M. S c h o t a n u s 1 , K. Chergui 1.
The nucleus accumbens (NAc) is involved in the regulation of motivation and reward-related behaviors and is a major target of drugs of abuse. Neurons in NAc receive a dense glutamatergic input from the prefrontal cortex, thalamus, hippocampus and amygdala. Long-term changes in synaptic strength in the NAc following repeated exposure to psychostimulants have been proposed to play an important role in the persistence of addiction. The precise mechanisms of induction and maintenance of long term potentiation (LTP) in the NAc are however not fully elucidated. The aim of our study is to identify the role of dopamine receptors and of NMDA receptors in LTP-induction. Indeed, excitatory inputs to the NAc are modulated by dopaminergic afferents arising from the midbrain (Chergui and Lacey, 1999). Furthermore, studies in primary cell cultures from NAc have demonstrated a role for dopamine D1 receptors in externalizing glutamatergic AMPA-receptors (Wolf et al., 2004), suggesting that dopamine acting on D1 receptors may promote LTR In addition, many forms of synaptic plasticity are dependent on NMDA receptors and may be determined by the subunit composition of these receptors. NMDA receptors are composed of NR1 and NR2A-D subunits. Recent studies have suggested that the NR2A Background:
S17
subunit plays a crucial role in LTP in the hippocampus and cortex (Liu et al., 2004). In the NAc, the involvement of each NR2 subunit in the induction of LTP has not been examined. M e t h o d s : We addressed these issues by performing electrophysiological recordings of field excitatory postsynaptic potentials (fEPSPs) evoked by stimulation of glutamatergic inputs in coronal slices of mouse NAc. After a stable fEPSP baseline was obtained, a high frequency stimulation (HFS) was applied to evoke LTP and the recording was continued for at least one hour. R e s u l t s : We found that a 100Hz train stimulation (1 second duration) repeated 3 times (10 seconds interval) consistently induced LTP in NAc. We used this protocol to induce LTP in control-slices and slices treated with dopamine-receptor antagonists or with specific antagonists for NR2A or NR2B. In control slices we observed that fEPSP amplitude measured one hour following HFS was enhanced by 43-4-10%, compared to baseline values measured before HFS. Pharmacological blockade of dopamine Dl-receptors by SCH23390 (10~M) abolished LTP-induction. In contrast, LTP was still induced (32-4-10% compared to baseline) when D2-receptors were blocked by sulpiride (10~M). There was no significant difference between LTP in control slices and in the presence of sulpiride. LTP was abolished in the presence of either NR2Aor NR2B- selective antagonists, including APV (50 nM), Ro25-6981 (0.6 ~M) and Ifenprodil (3 ~M). C o n c l u s i o n : Our results show that dopamine D1 receptors are involved in the induction of LTP in the NAc but that LTP does not require D2-receptor activation. We found that, in contrast to recent observations in the hippocampus and cortex, both NR2A and NR2B subunits of the NMDA receptor play a critical role in the induction of LTP in the NAc. Our results provide additional evidence for a crucial role for dopamine and for NMDA receptors in persistent plastic changes in the mesolin~bic system.
References [1] Chergui, K., and Lacey, M.G., 1999. Modulation by dopamine Dl-l~e receptors of synaptic transmission and NMDA receptors in rat nucleus accumbens is attenuated by the protein kinase C inhibitor Ro 32-0432. Neurophammcology 38, 223-31. [2] Liu, L., Wong, T.R, Pozza, M. E, Lingenhoehl, K., Wang, Y., Sheng, M., Auberson, Y.R, and Wang, Y.T., 2004. Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science 304, 1021-4. [3] Wolf, M.E., Sun, X., Mangiavacchi, S., and Chao, S.Z., 2004. Psychomotor stimulants and neuronal plasticity. Neuropharmacology 47(Suppl 1), 61-79.
References [1] Arrang J.M., Garbarg M., and Schwartz J.C., 1983. Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature 302, 832-7. [2] Pillot C., Ortiz J., Heron A., Ridray S., Schwartz J.C., and Arrang J.M., 2002. Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat. J Neurosci 22, 7272-80. [3] Pillot C., Heron A., Schwartz J.C., and Arrang J.M., 2003. Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, modulates the effects of methamphetamine on neuropeptide mRNA expression in rat striatum. Eur J Neurosci 17, 307-14.
~Role
of dopamine and NMDA receptor subunits in the induction of long term potentiation in the nucleus accumbens
1Karolinska Institute, Von Eulersvdg 8, Stockholm, Sweden
S.M. S c h o t a n u s 1 , K. Chergui 1.
The nucleus accumbens (NAc) is involved in the regulation of motivation and reward-related behaviors and is a major target of drugs of abuse. Neurons in NAc receive a dense glutamatergic input from the prefrontal cortex, thalamus, hippocampus and amygdala. Long-term changes in synaptic strength in the NAc following repeated exposure to psychostimulants have been proposed to play an important role in the persistence of addiction. The precise mechanisms of induction and maintenance of long term potentiation (LTP) in the NAc are however not fully elucidated. The aim of our study is to identify the role of dopamine receptors and of NMDA receptors in LTP-induction. Indeed, excitatory inputs to the NAc are modulated by dopaminergic afferents arising from the midbrain (Chergui and Lacey, 1999). Furthermore, studies in primary cell cultures from NAc have demonstrated a role for dopamine D1 receptors in externalizing glutamatergic AMPA-receptors (Wolf et al., 2004), suggesting that dopamine acting on D1 receptors may promote LTR In addition, many forms of synaptic plasticity are dependent on NMDA receptors and may be determined by the subunit composition of these receptors. NMDA receptors are composed of NR1 and NR2A-D subunits. Recent studies have suggested that the NR2A Background:
S17
subunit plays a crucial role in LTP in the hippocampus and cortex (Liu et al., 2004). In the NAc, the involvement of each NR2 subunit in the induction of LTP has not been examined. M e t h o d s : We addressed these issues by performing electrophysiological recordings of field excitatory postsynaptic potentials (fEPSPs) evoked by stimulation of glutamatergic inputs in coronal slices of mouse NAc. After a stable fEPSP baseline was obtained, a high frequency stimulation (HFS) was applied to evoke LTP and the recording was continued for at least one hour. R e s u l t s : We found that a 100Hz train stimulation (1 second duration) repeated 3 times (10 seconds interval) consistently induced LTP in NAc. We used this protocol to induce LTP in control-slices and slices treated with dopamine-receptor antagonists or with specific antagonists for NR2A or NR2B. In control slices we observed that fEPSP amplitude measured one hour following HFS was enhanced by 43-4-10%, compared to baseline values measured before HFS. Pharmacological blockade of dopamine Dl-receptors by SCH23390 (10~M) abolished LTP-induction. In contrast, LTP was still induced (32-4-10% compared to baseline) when D2-receptors were blocked by sulpiride (10~M). There was no significant difference between LTP in control slices and in the presence of sulpiride. LTP was abolished in the presence of either NR2Aor NR2B- selective antagonists, including APV (50 nM), Ro25-6981 (0.6 ~M) and Ifenprodil (3 ~M). C o n c l u s i o n : Our results show that dopamine D1 receptors are involved in the induction of LTP in the NAc but that LTP does not require D2-receptor activation. We found that, in contrast to recent observations in the hippocampus and cortex, both NR2A and NR2B subunits of the NMDA receptor play a critical role in the induction of LTP in the NAc. Our results provide additional evidence for a crucial role for dopamine and for NMDA receptors in persistent plastic changes in the mesolin~bic system.
References [1] Chergui, K., and Lacey, M.G., 1999. Modulation by dopamine Dl-l~e receptors of synaptic transmission and NMDA receptors in rat nucleus accumbens is attenuated by the protein kinase C inhibitor Ro 32-0432. Neurophammcology 38, 223-31. [2] Liu, L., Wong, T.R, Pozza, M. E, Lingenhoehl, K., Wang, Y., Sheng, M., Auberson, Y.R, and Wang, Y.T., 2004. Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science 304, 1021-4. [3] Wolf, M.E., Sun, X., Mangiavacchi, S., and Chao, S.Z., 2004. Psychomotor stimulants and neuronal plasticity. Neuropharmacology 47(Suppl 1), 61-79.