C6H6
Bluelighter
- Joined
- Jan 29, 2005
- Messages
- 607
I just learned that there is a recently identified trace amine receptor which might have a role in the effects of drugs of abuse and thought I post two interesting abstracts:
J Pharmacol Exp Ther. 2005 Mar 11; [Epub ahead of print]
PRIMATE TRACE AMINE RECEPTOR 1 MODULATION BY THE DOPAMINE TRANSPORTER.
Miller GM, Verrico CD, Jassen AK, Konar M, Yang H, Panas HN, Bahn M, Johnson RS, Madras BK.
Harvard Medical School/New England Primate Research Center.
Recently identified trace amine receptors are potential direct targets for drugs of abuse, including amphetamine and MDMA. We cloned full-length rhesus monkey trace amine receptor 1 (rhTA1) that was 96% homologous to human TA1. The trace amines tyramine, beta-phenylethylamine (PEA) and the monoamine transporter substrates, (+)-, (-)-amphetamine and (+)-, (-)-MDMA (methylenedioxymethamphetamine), stimulated cAMP accumulation in rhTA1-expressing cell lines, as measured by a CRE-luciferase assay. The dopamine transport inhibitor cocaine did not stimulate cAMP accumulation in rhTA1 cells, but blocked [(3)H]PEA transport mediated by the dopamine transporter. Cotransfection with the human dopamine transporter, a conduit for intracellular entry of the trace amines and amphetamines, enhanced PEA-, amphetamine-, and MDMA-mediated rhTA1 receptor activation, but diminished tyramine activation of rhTA1. As TA1 (EGFP-rhTA1 chimera) was largely intracellular, conceivably the dopamine transporter can facilitate access of specific agonists to intracellular TA1. The physiological relevance of this finding was supported by detection of rhTA1 mRNA in rhesus monkey substantia nigra, implying that TA1 may be co-localized with the dopamine transporter in dopamine neurons. In summary, primate TA1 receptors are direct targets of trace amines, amphetamine, and MDMA. These receptors could also be indirect targets of amphetamine, MDMA and cocaine, through modification of monoamine or trace amine transport via monoamine transporters. Conceivably, rhTA1 receptors may be located on pre- or post-synaptic membranes. Interference with the carrier function of monoamine transporters with a consequent rise of extracellular levels of trace amines could activate these receptors. The cloning of a highly homologous TA1 from rhesus monkey and demonstration that rhTA1 receptors are activated by drugs of abuse, indicates that nonhuman primates may serve to model physiological and pharmacological TA1-mediated responses in humans.
PMID: 15764732
Med Hypotheses. 2005;64(5):930-7.
Endogenous psychoactive tryptamines reconsidered: an anxiolytic role for dimethyltryptamine.
Jacob MS, Presti DE.
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3200, USA.
The presence of the potent hallucinogenic psychoactive chemical N,N-dimethyltryptamine (DMT) in the human body has puzzled scientists for decades. Endogenous DMT was investigated in the 1960s and 1970s and it was proposed that DMT was involved in psychosis and schizophrenia. This hypothesis developed from comparisons of the blood and urine of schizophrenic and control subjects. However, much of this research proved inconclusive and conventional thinking has since held that trace levels of DMT, and other endogenous psychoactive tryptamines, are insignificant metabolic byproducts. The recent discovery of a G-protein-coupled, human trace amine receptor has triggered a reappraisal of the role of compounds present in limited concentrations in biological systems. Interestingly enough, DMT and other psychoactive tryptamine hallucinogens elicit a robust response at the trace amine receptor. While it is currently accepted that serotonin 5-HT(2A) receptors play a pivotal role in the activity of hallucinogenic/psychedelic compounds, we propose that the effects induced by exogenous DMT administration, especially at low doses, are due in part to activity at the trace amine receptor. Furthermore, we suggest that endogenous DMT interacts with the TA receptor to produce a calm and relaxed mental state, which may suppress, rather than promote, symptoms of psychosis. This hypothesis may help explain the inconsistency in the early analysis of endogenous DMT in humans. Finally, we propose that amphetamine action at the TA receptor may contribute to the calming effects of amphetamine and related drugs, especially at low doses.
PMID: 15780487
J Pharmacol Exp Ther. 2005 Mar 11; [Epub ahead of print]
PRIMATE TRACE AMINE RECEPTOR 1 MODULATION BY THE DOPAMINE TRANSPORTER.
Miller GM, Verrico CD, Jassen AK, Konar M, Yang H, Panas HN, Bahn M, Johnson RS, Madras BK.
Harvard Medical School/New England Primate Research Center.
Recently identified trace amine receptors are potential direct targets for drugs of abuse, including amphetamine and MDMA. We cloned full-length rhesus monkey trace amine receptor 1 (rhTA1) that was 96% homologous to human TA1. The trace amines tyramine, beta-phenylethylamine (PEA) and the monoamine transporter substrates, (+)-, (-)-amphetamine and (+)-, (-)-MDMA (methylenedioxymethamphetamine), stimulated cAMP accumulation in rhTA1-expressing cell lines, as measured by a CRE-luciferase assay. The dopamine transport inhibitor cocaine did not stimulate cAMP accumulation in rhTA1 cells, but blocked [(3)H]PEA transport mediated by the dopamine transporter. Cotransfection with the human dopamine transporter, a conduit for intracellular entry of the trace amines and amphetamines, enhanced PEA-, amphetamine-, and MDMA-mediated rhTA1 receptor activation, but diminished tyramine activation of rhTA1. As TA1 (EGFP-rhTA1 chimera) was largely intracellular, conceivably the dopamine transporter can facilitate access of specific agonists to intracellular TA1. The physiological relevance of this finding was supported by detection of rhTA1 mRNA in rhesus monkey substantia nigra, implying that TA1 may be co-localized with the dopamine transporter in dopamine neurons. In summary, primate TA1 receptors are direct targets of trace amines, amphetamine, and MDMA. These receptors could also be indirect targets of amphetamine, MDMA and cocaine, through modification of monoamine or trace amine transport via monoamine transporters. Conceivably, rhTA1 receptors may be located on pre- or post-synaptic membranes. Interference with the carrier function of monoamine transporters with a consequent rise of extracellular levels of trace amines could activate these receptors. The cloning of a highly homologous TA1 from rhesus monkey and demonstration that rhTA1 receptors are activated by drugs of abuse, indicates that nonhuman primates may serve to model physiological and pharmacological TA1-mediated responses in humans.
PMID: 15764732
Med Hypotheses. 2005;64(5):930-7.
Endogenous psychoactive tryptamines reconsidered: an anxiolytic role for dimethyltryptamine.
Jacob MS, Presti DE.
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3200, USA.
The presence of the potent hallucinogenic psychoactive chemical N,N-dimethyltryptamine (DMT) in the human body has puzzled scientists for decades. Endogenous DMT was investigated in the 1960s and 1970s and it was proposed that DMT was involved in psychosis and schizophrenia. This hypothesis developed from comparisons of the blood and urine of schizophrenic and control subjects. However, much of this research proved inconclusive and conventional thinking has since held that trace levels of DMT, and other endogenous psychoactive tryptamines, are insignificant metabolic byproducts. The recent discovery of a G-protein-coupled, human trace amine receptor has triggered a reappraisal of the role of compounds present in limited concentrations in biological systems. Interestingly enough, DMT and other psychoactive tryptamine hallucinogens elicit a robust response at the trace amine receptor. While it is currently accepted that serotonin 5-HT(2A) receptors play a pivotal role in the activity of hallucinogenic/psychedelic compounds, we propose that the effects induced by exogenous DMT administration, especially at low doses, are due in part to activity at the trace amine receptor. Furthermore, we suggest that endogenous DMT interacts with the TA receptor to produce a calm and relaxed mental state, which may suppress, rather than promote, symptoms of psychosis. This hypothesis may help explain the inconsistency in the early analysis of endogenous DMT in humans. Finally, we propose that amphetamine action at the TA receptor may contribute to the calming effects of amphetamine and related drugs, especially at low doses.
PMID: 15780487
