Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil

  title={Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil},
  author={Philip Seeman and H C Guan and H{\'e}l{\`e}ne Hirbec},
Although it is commonly stated that phencyclidine is an antagonist at ionotropic glutamate receptors, there has been little measure of its potency on other receptors in brain tissue. Although we previously reported that phencyclidine stimulated cloned‐dopamine D2Long and D2Short receptors, others reported that phencyclidine did not stimulate D2 receptors in homogenates of rat brain striatum. This study, therefore, examined whether phencyclidine and other hallucinogens and psychostimulants could… 

Cannabidiol is a partial agonist at dopamine D2High receptors, predicting its antipsychotic clinical dose

  • P. Seeman
  • Psychology, Biology
    Translational psychiatry
  • 2016
It was found that cannabidiol inhibited the binding of radio-domperidone with dissociation constants in the same biphasic manner as a dopamine partial agonist antipsychotic drug such as aripiprazole.

Dopamine D2 receptors as treatment targets in schizophrenia.

  • P. Seeman
  • Psychology, Medicine
    Clinical schizophrenia & related psychoses
  • 2010
Animal models of psychosis show that a variety of risk factors, genetic and nongenetic, are associated with behavioral supersensitivity to dopamine, reflected in elevated levels of dopamine D2High receptors, and long-term use of traditional antipsychotics can further enhance dopamine supersensitivity in patients.

Exposure to Nicotine Produces an Increase in Dopamine D2High Receptors: A Possible Mechanism for Dopamine Hypersensitivity

It is suggested that nicotine-induced elevation in D2High levels could be participating in hypersensitivity to dopamine following nicotine exposure, as indicated by lower D2 high levels in rats after a prolonged withdrawal period.

d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology

The LSD-induced psychosis is a useful model to test the therapeutic efficacy of potential novel antipsychotic drugs, particularly drugs with dual serotonergic and dopaminergic (DA) mechanism or acting on TAAR1 receptors.

Salvinorin A Produces Cerebrovasodilation through Activation of Nitric Oxide Synthase, &kgr; Receptor, and Adenosine Triphosphate–sensitive Potassium Channel

Although naloxone, norbinaltorphimine, and glibenclamide abolished salvinorin A–induced cerebrovasodilation, this response was unchanged by iberiotoxin and sulpiride.

Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens

Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A

Salvinorin A has therapeutic potential as a treatment for pain, mood and personality disorders, substance abuse, and gastrointestinal disturbances, and suggests that nonalkaloids are potential scaffolds for drug development for aminergic G-protein coupled receptors.



Modafinil inhibits rat midbrain dopaminergic neurons through D2-like receptors

Dopaminergic D1 and D2 Receptors Are Essential for the Arousal Effect of Modafinil

Findings strongly indicate that dopaminergic D1R and D2R are essential for the wakefulness induced by modafinil.

Dopamine D2 receptor-mediated G protein activation assessed by agonist-stimulated [35S]guanosine 5′-O-(γ-thiotriphosphate) binding in rat striatal membranes

Dopamine displaces [3H]domperidone from high‐affinity sites of the dopamine D2 receptor, but not [3H]raclopride or [3H]spiperone in isotonic medium: Implications for human positron emission tomography

3H]domperidone labels D2High sites in the presence of isotonic NaCl in either striatum or cloned D2Long receptors, yielding a dopamine dissociation constant (1.75 nM) in agreement with that found with [3H], suggesting that [3 H]domPeridone has better access to the D2 receptor from the cytoplasmic aspect of the cell membrane.

Phencyclidine- and Dizocilpine-Induced Hyperlocomotion Are Differentially Mediated

Different mechanisms of action may account for the motor stimulatory effects of PCP and dizocilpine, which may differ in the way they act on “regulatory” NMDA receptors controlling neuronal activity in midbrain neurons.

The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist.

Neurophysiological studies in vitro, using a rat cortical-slice preparation, demonstrated a potent, selective, and noncompetitive antagonistic action of MK-801 on depolarizing responses to N-Me-D-Asp but not to kainate or quisqualate, providing an explanation for the mechanism of action ofMK-801 as an anticonvulsant.

Dopamine D2 receptor binding sites for agonists. A tetrahedral model.

A tetrahedral model is proposed; this has two sites for agonist attachment, the extremities of the sites being separated by 8 A, and their functional groups directed between 15 degrees and 30 degrees off the orthogonal from the receptor surface.

The human dopamine D2(Longer) receptor has a high-affinity state and inhibits adenylyl cyclase.