Tricyclic antidepressants block N‐methyl‐D‐aspartate receptors: similarities to the action of zinc

Reynolds, Ian J.; Miller, Richard J.

doi:10.1111/j.1476-5381.1988.tb16552.x

Cited by 180 publications

(83 citation statements)

References 29 publications

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“…In particular, the work of Ö gren and Goldstein 36 has shown that three dopamine antagonists (haloperidol, raclopride and remoxipride) blocked locomotion elicited by low and high doses of phencyclidine. Because these three dopamine antagonists have very low affinity for the NMDA receptor, 37 with raclopride and remoxipride being highly selective for dopamine D2 receptors, 38,39 dopamine must be an important component in the phencyclidine hypoglutamate model of schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics

2005

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Although phencyclidine and ketamine are used to model a hypoglutamate theory of schizophrenia, their selectivity for NMDA receptors has been questioned. To determine the affinities of phencyclidine, ketamine, dizocilpine and LSD for the functional high-affinity state of the dopamine D2 receptor, D2 High , their dissociation constants (K i ) were obtained on [ 3 H]domperidone binding to human cloned dopamine D2 receptors. Phencyclidine had a high affinity for D2 High with a K i of 2.7 nM, in contrast to its low affinity for the NMDA receptor, with a K i of 313 nM, as labeled by [ 3 H]dizocilpine on rat striatal tissue. Ketamine also had a high affinity for D2 High with a K i of 55 nM, an affinity higher than its 3100 nM K i for the NMDA sites. Dizocilpine had a K i of 0.3 nM at D2 High , but a K d of 1.8 nM at the NMDA receptor. LSD had a K i of 2 nM at D2 High . Because the psychotomimetics had higher potency at D2 High than at the NMDA site, the psychotomimetic action of these drugs must have a major contribution from D2 agonism. Because these drugs have a combined action on both dopamine receptors and NMDA receptors, these drugs, when given in vivo, test a combined hyperdopamine and hypoglutamate theory of psychosis. Keywords: dopamine receptor; phencyclidine; domperidone; ketamine; NMDA receptors; psychotomimetics While the clinical anti-dopaminergic actions of antipsychotic drugs are compatible with the hyperdopamine hypothesis of psychosis and schizophrenia, 1,2 the psychoses caused by glutamate antagonists such as phencyclidine or ketamine suggest a hypo-glutamate component in psychosis. [3][4][5] However, phencyclidine also lowers plasma prolactin 6 and elicits rotation, 7 suggesting a direct or indirect dopaminemimetic action of phencyclidine.Although phencyclidine and ketamine are not selective for glutamate NMDA receptors, 8 the precise affinities of these drugs for dopamine D2 receptors need to be clarified in order to determine their dopaminergic and non-dopaminergic components of action. More specifically, although phencyclidine had a dissociation constant of 37 000 nM at the D2 receptor in rat striatal homogenate, 8 phencyclidine had a dissociation constant of 1.3 nM for the functional high-affinity site of the cloned D2 receptor, or the D2 High receptor. 9 This apparent discrepancy may be resolved by the recent finding that dopamine itself has a dissociation constant of 3000 nM when competing vs [ 3 H]raclopride at striatal D2 receptors, but has a dissociation constant of 1.5 nM at the D2 High receptor when the link between dopamine D1 and D2 receptors is blocked by the D1 antagonist SCH23390. 10 The link between D1 and D2 receptors arises from several sources, including the colocalization of dopamine D1 and D2 receptors in at least 50% of the medium spiny neurons in the striatum, the cooperation and mutual potentiation of D1 and D2 agonists on various behaviors, and the biochemical conversion of D2 receptors from their functional high-affinity state, D2 High , into their low-affinity state, D2 Lo...

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Section: Discussionmentioning

confidence: 99%

Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics

2005

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“…39 In this study, the NMDA antagonist, ketamine, did not modify sensitivity to glycine, although it directly reduced NMDA receptor function through blockade of the calcium channel within the NMDA receptor complex. The tricyclic antidepressant, desipramine, which has direct NMDA receptor antagonism at therapeutic doses, 40,41 reduces the potency of glycine to displace 5,7-DCKA binding similarly to other antidepressants, and it also reduces the density of 5,7-DCKA binding sites. 39 In humans, the antidepressant activity of NMDA receptor antagonists received little rigorous evaluation.…”

Section: Glutamatergic Abnormalities In Mood Disordersmentioning

confidence: 99%

Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments

et al. 2002

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Glutamate and ␥-amino butyric acid (GABA) systems are emerging as targets for development of medications for mood disorders. There is increasing preclinical and clinical evidence that antidepressant drugs directly or indirectly reduce N-methyl-D-aspartate glutamate receptor function. Drugs that reduce glutamatergic activity or glutamate receptor-related signal transduction may also have antimanic effects. Recent studies employing magnetic resonance spectroscopy also suggest that unipolar, but not bipolar, depression is associated with reductions in cortical GABA levels. Antidepressant and mood-stabilizing treatments also appear to raise cortical GABA levels and to ameliorate GABA deficits in patients with mood disorders. The preponderance of available evidence suggests that glutamatergic and GABAergic modulation may be an important property of available antidepressant and mood-stabilizing agents. Future research will be needed to develop and evaluate new agents with specific glutamate and GABA receptor targets in the treatment of mood disorders. Molecular Psychiatry (2002) 7, S71-S80.

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“…Moreover, the antihistaminergic action of TCAs may have a general analgesic effect (Rumore and Schlichting, 1986). Recent findings have shown that antidepressants also interact with the opioidergic system (Gray et al, 1998) and that they act as NMDA-receptor antagonists (Reynolds and Miller, 1988). Antidepressants, especially selective serotonin reuptake inhibitors (SSRIs) and TCAs, are also indicated for anxiety disorders, including generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, and posttraumatic stress disorder.…”

Section: Introductionmentioning

confidence: 99%

Usefulness of Antidepressants for Improving the Neuropathic Pain-Like State and Pain-Induced Anxiety through Actions at Different Brain Sites

Matsuzawa-Yanagida

Narita

Nakajima

et al. 2007

Neuropsychopharmacol

122

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Clinically, it is well known that chronic pain induces depression, anxiety, and a reduced quality of life. There have been many reports on the relationship between pain and emotion. We previously reported that chronic pain induced anxiety with changes in opioidergic function in the central nervous system. In this study, we evaluated the anxiolytic-like effects of several types of antidepressants under a chronic neuropathic pain-like state and searched for the brain site of action where antidepressants show anxiolytic or antinociceptive effects. Sciatic nerve-ligated mice exhibited thermal hyperalgesia and tactile allodynia from days 7 to 28 after nerve ligation. At 4 weeks after ligation, these mice showed a significant anxiety-related behavior in the light-dark test and the elevated plus-maze test. Under these conditions, repeated administration of antidepressants, including the tricyclic antidepressant (TCA) imipramine, the serotonin noradrenaline reuptake inhibitor (SNRI) milnacipran, and the selective serotonin reuptake inhibitor (SSRI) paroxetine, significantly prevented the anxiety-related behaviors induced by chronic neuropathic pain. These antidepressants also produced a significant reduction in thermal hyperalgesia and tactile allodynia. Moreover, the microinjection of paroxetine into the basolateral amygdala or cingulate cortex reduced anxiety-related behavior, and microinjection into the primary somatosensory cortex significantly attenuated thermal hyperalgesia. These findings suggest that serotonergic antidepressants are effective for treating anxiety associated with chronic neuropathic pain and may be useful for treating neuropathic pain with emotional dysfunction such as anxiety. Furthermore, SSRIs show anxiolytic and antinociceptive effects by acting on different brain regions.

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Tricyclic antidepressants block N‐methyl‐D‐aspartate receptors: similarities to the action of zinc

Cited by 180 publications

References 29 publications

Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics

Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics

Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments

Usefulness of Antidepressants for Improving the Neuropathic Pain-Like State and Pain-Induced Anxiety through Actions at Different Brain Sites

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