Journal Article

In Vitro and In Vivo Characterization of the Alkaloid Nuciferine

Stout, Kristen A., Urban, Daniel J., Giguere, Patrick M., Gannon, Brenda M., McCorvy, John D., Webster, Kevin A., Fantegrossi, William E., Doak, Allison K., Hyatt, William S., Farrell, Martilias S., Park, Su Mi, Porter, Joseph H., Shoichet, Brian K., Huang, Xi-Ping, Bernstein, Alison I., Rodriguiz, Ramona M., Wetsel, William C., Roth, Bryan L., Norwood, Andrew P., White, Kate L., Miller, Gary W., Gray, Bradley W.

2016

Overview

The sacred lotus (Nelumbo nucifera) contains many phytochemicals and has a history of human use. To determine which compounds may be responsible for reported psychotropic effects, we used in silico predictions of the identified phytochemicals. Nuciferine, an alkaloid component of Nelumbo nucifera and Nymphaea caerulea, had a predicted molecular profile similar to antipsychotic compounds. Our study characterizes nuciferine using in vitro and in vivo pharmacological assays. Nuciferine was first characterized in silico using the similarity ensemble approach, and was followed by further characterization and validation using the Psychoactive Drug Screening Program of the National Institute of Mental Health. Nuciferine was then tested in vivo in the head-twitch response, pre-pulse inhibition, hyperlocomotor activity, and drug discrimination paradigms. Nuciferine shares a receptor profile similar to aripiprazole-like antipsychotic drugs. Nuciferine was an antagonist at 5-HT2A, 5-HT2C, and 5-HT2B, an inverse agonist at 5-HT7, a partial agonist at D2, D5 and 5-HT6, an agonist at 5-HT1A and D4 receptors, and inhibited the dopamine transporter. In rodent models relevant to antipsychotic drug action, nuciferine blocked head-twitch responses and discriminative stimulus effects of a 5-HT2A agonist, substituted for clozapine discriminative stimulus, enhanced amphetamine induced locomotor activity, inhibited phencyclidine (PCP)-induced locomotor activity, and rescued PCP-induced disruption of prepulse inhibition without induction of catalepsy. The molecular profile of nuciferine was similar but not identical to that shared with several approved antipsychotic drugs suggesting that nuciferine has atypical antipsychotic-like actions.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Alkaloids / Amphetamines / Animal models / Animals / Antipsychotic Agents - chemistry / Antipsychotic Agents - pharmacology / Antipsychotics / Aporphines - chemistry / Aporphines - pharmacology / Aripiprazole / Behavior, Animal - drug effects / Behavioral sciences / Biology / Biology and Life Sciences / Catalepsy / Chemistry / Clozapine / Departments / Dopamine / Dopamine D2 receptors / Dopamine D4 receptors / Dopamine D5 receptors / Dopamine transporter / Drug abuse / Drug discrimination / Drug screening / Drugs / Environmental health / Health aspects / HEK293 Cells / Humans / In vivo methods and tests / Inhibition / Locomotor activity / Lotus (Nelumbo) / Medicine / Medicine and Health Sciences / Mental health / Mice / Nelumbo nucifera / Neurobiology / Neurosciences / Pharmaceuticals / Pharmacology / Phencyclidine / Physical Sciences / Phytochemicals / Plant biochemistry / Predictions / Prescription drugs / Properties / Psychiatry / Psychopharmacology / Psychotropic drugs / Public health / Receptors / Receptors, Dopamine D4 - agonists / Research and Analysis Methods / Rodents / Schizophrenia / Serotonin / Serotonin 5-HT1 Receptor Agonists - chemistry / Serotonin 5-HT1 Receptor Agonists - pharmacology / Serotonin receptors / Serotonin S1 receptors / Serotonin S2 receptors / Serotonin S6 receptors / Structure-activity relationships (Pharmacology) / Toxicology