Inhibitory effects of trace amines on rat midbrain dopaminergic neurons
Introduction
Trace amines are present in low concentrations in neuronal tissue where they are packaged and released along with traditional amines (Boulton, 1976, Durden and Philips, 1980, Parker and Cubeddu, 1988). They have been considered to be “false transmitters”, which displace active biogenic amines from their stores and are also believed to act on transporters in an amphetamine-like manner (Janssen et al., 1999, Mundorf et al., 1999, Parker and Cubeddu, 1988, Raiteri et al., 1978), thus, increasing the extracellular concentration of dopamine (DA) (Bailey et al., 1987). In addition, they have been thought as “modulators” of the neurotransmission mediated by catecholamines and serotonin (Boulton, 1991).
The recent identification of a novel family of G-protein coupled trace amine receptors linked to cAMP production in expression systems (Borowsky et al., 2001, Bunzow et al., 2001), has revealed new insights into the mechanism by which trace amines function.
It is known that the blockade of catecholamine catabolism leads to the accumulation of trace amines in the central nervous system (Boulton, 1991, Dyck et al., 1982, Holschneider et al., 2001). Moreover, antipsychotics, antidepressants, psychostimulants and drugs interfering with amine storage, alter the concentration of trace amines in the brain (Boulton et al., 1977, Boulton, 1991, Juorio, 1983, Juorio and Danielson, 1978, Juorio et al., 1991a, Greenshaw et al., 1985, Sardar and Juorio, 1987). The role of trace amines in the dopaminergic midbrain is of great interest due to the established role of these neurons in schizophrenia, drug abuse, attention deficit hyperactive disorders (ADHD) and Parkinson’s disease.
Some lines of evidence have already suggested that trace amines affect mental and motor activity by interacting with the dopaminergic system. Previous extracellular electrophysiological studies in vivo (β-PEA) (Barroso and Rodriguez, 1996) and in vitro (TYR) (Pinnock, 1983) have reported an inhibitory effect of two trace amines, β-phenylethylamine (β-PEA) and tyramine (TYR), on the firing rate of the dopaminergic neurons. However, nothing is known of the mechanism of this action of trace amines. Trace amines colocalise with dopamine in dopaminergic cells (Juorio et al., 1991b), can be released with DA (Jones et al., 1983), increase the release of DA (Raiteri et al., 1978) and induce homolateral turning in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal dopamine system (Barroso and Rodriguez, 1996).
Since trace amines appear to be co-released with DA and may further stimulate DA release, we hypothesised that exogenous trace amines inhibit dopamine neurons by increasing DA release and the activation of the well characterised inhibitory D2 autoreceptors. We further hypothesised that stimulation of DA release by trace amines was a result of activation of the dopamine transporter (DAT). We have thus examined the inhibitory effects of two trace amines on the spontaneous discharge and membrane potential of dopaminergic neurons in ventral midbrain slices. We investigated the sensitivity of this response to antagonism of the D2 autoreceptor, blockade of DAT and depletion of vesicular dopamine.
A preliminary account of this work has been previously presented in abstract form (Mercuri et al., 2002).
Section snippets
Brain slice preparation and electrophysiological recordings
Intracellular recordings with sharp microelectrodes were made from midbrain substantia nigra (SN) and ventral tegmental area (VTA) dopaminergic neurons in horizontal slices (250–300 μm thick) prepared from 21- to 35-day-old male Wistar rats (150–300 g) (as described in Mercuri et al., 1995). Animals used in this study were treated in strict accordance with the approved experimental procedures of the Comitato Etico of the Tor Vergata University. Briefly, the animals were anaesthetised with
Results
Data in this study were obtained from 55 intracellularly recorded “principal” neurons in the SNc and 22 in the VTA that were identified as dopaminergic according to electrophysiological and pharmacological criteria (see Methods). All neurons fired spontaneous action potentials at a mean rate of 1.2 Hz (range 0.9–2.8 Hz) and had a relatively long lasting spike (>1.2 ms).
Discussion
Our intracellular experiments confirm the findings of previous extracellular studies (Rodriguez and Barroso, 1995, Pinnock, 1983) showing an inhibitory action of β-PEA and TYR on the DAergic cells in the ventral mesencephalon. The main finding reported here is that this action of trace amines is mediated by indirect activation of the D2 autoreceptors caused by an increase in dopamine release.
The electrophysiological effects of stimulating the recently cloned trace amine receptors has not yet
Acknowledgements
We thank Dr. C. Peter Bengtson for his comments on the manuscript. This work was supported by CNR (Biomolecole Per La Salute Umana) and MURST (Cofin) grants to N. B. Mercuri.
References (40)
- et al.
Action of beta-phenylethylamine and related amines on nigrostriatal dopamine neurotransmission
Eur. J. Pharmacol.
(1996) - et al.
The dopamine-containing neuron: maestro or simple musician in the orchestra of addiction?
Trends Pharmacol. Sci.
(2003) Phenylethylaminergic modulation of catecholaminergic neurotransmission
Prog. Neuropsychopharmacol. Biol. Psychiatr.
(1991)- et al.
Trace amine receptors as targets for novel therapeutics: legend, myth and fact
Curr. Opin. Pharmacol.
(2003) Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia
Neuroscience
(1991)- et al.
Behavioral and neurochemical effects of deprenyl and beta-phenylethylamine in Wistar rats
Brain Res. Bull.
(1985) - et al.
Biochemical, behavioral, physiologic, and neurodevelopmental changes in mice deficient in monoamine oxidase A or B
Brain Res. Bull.
(2001) The effect of some decarboxylase inhibitors on striatal tyramines in the mouse
Neuropharmacology
(1983)- et al.
Effect of haloperidol and d-amphetamine on cerebral tyramine and octopamine levels
Eur. J. Pharmacol.
(1978) - et al.
The effects of some neuroleptics and d-amphetamine on striatal 2-phenylethylamine in the mouse
Gen. Pharmacol.
(1991)
Electrophysiological pharmacology of the autoreceptor-mediated responses of dopaminergic cells to antiparkinsonian drugs
Trends Pharmacol. Sci.
Phenylethylamine and schizophrenia
Prog. Neuropsychopharmacol. Biol. Psychiatr.
Sensitivity of compacta neurones in the rat substantia nigra slice to dopamine agonists
Eur. J. Pharmacol.
Beta-phenylethylamine regulation of dopaminergic nigrostriatal cell activity
Brain Res.
The regional distribution of p-tyramine and m-tyramine in the rat corpus striatum and the effect of monoamine oxidase inhibition
Prog. Neuropsychopharmacol. Biol. Psychiatr.
In vivo release of endogenous dopamine, 5-hydroxytryptamine and some of their metabolites from rat caudate nucleus by phenylethylamine
Neurochem. Res.
Trace amines: identification of a family of mammalian G protein-coupled receptors
Proc. Natl. Acad. Sci. USA
Identification, distribution, metabolism, and function of meta and para tyramine, phenylethylamine and tryptamine in brain
Adv. Biochem. Psychopharmacol.
The effects of reserpine and 6-hydroxydopamine on the concentrations of some arylakylamines in rat brain
Br. J. Pharmacol.
Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor
Mol. Pharmacol.
Cited by (0)
- 1
The two first authors equally contributed to this work.