Iontophoretic studies of some trace amines in the mammalian CNS

A key feature of escape responses is the fast translation of sensory information into a coordinated motor output. In C. elegans, anterior touch initiates a backward escape response in which lateral head movements are suppressed. Here, we show that tyramine inhibits head movements and forward locomotion through the activation of a tyramine-gated chloride channel, LGC-55. lgc-55 mutant animals have defects in reversal behavior and fail to suppress head oscillations in response to anterior touch. lgc-55 is expressed in neurons and muscle cells that receive direct synaptic inputs from tyraminergic motor neurons. Therefore, tyramine can act as a classical inhibitory neurotransmitter. Activation of LGC-55 by tyramine coordinates the output of two distinct motor programs, locomotion and head movements that are critical for a C. elegans escape response.

The trace amines are a structurally related group of amines and their isomers synthesized in mammalian brain and peripheral nervous tissues. They are closely associated metabolically with the dopamine, noradrenaline and serotonin neurotransmitter systems in mammalian brain. Like dopamine, noradrenaline and serotonin the trace amines have been implicated in a vast array of human disorders of affect and cognition. The trace amines are unique as they are present in trace concentrations, exhibit high rates of metabolism and are distributed heterogeneously in mammalian brain. While some are synthesized in their parent amine neurotransmitter systems, there is also evidence to suggest other trace amines may comprise their own independent neurotransmitter systems. A substantial body of evidence suggests that the trace amines may play very significant roles in the coordination of biogenic amine-based synaptic physiology. At high concentrations, they have well-characterized presynaptic “amphetamine-like” effects on catecholamine and indolamine release, reuptake and biosynthesis; at lower concentrations, they possess postsynaptic modulatory effects that potentiate the activity of other neurotransmitters, particularly dopamine and serotonin. The trace amines also possess electrophysiological effects that are in opposition to these neurotransmitters, indicating to some researchers the existence of receptors specific for the trace amines. While binding sites or receptors for a few of the trace amines have been advanced, the absence of cloned receptor protein has impeded significant development of their detailed mechanistic roles in the coordination of catecholamine and indolamine synaptic physiology. The recent discovery and characterization of a family of mammalian G protein-coupled receptors responsive to trace amines such as β-phenylethylamine, tyramine, and octopamine, including socially ingested psychotropic drugs such as amphetamine, 3,4-methylenedioxymethamphetamine, N,N-dimethyltryptamine, and lysergic acid diethylamide, have revitalized the field of scientific studies investigating trace amine synaptic physiology, and its association with major human disorders of affect and cognition.

β-Phenylethylamine (PEA) is a trace neuroactive amine implicated in the regulation of the hypothalamic–pituitary–adrenal (HPA) response to stress. To test this hypothesis, effects of subchronic levels of PEA (50 mg/kg/day treatment for 10 days) on the corticotroph function were studied. PEA treatment induces: (i) a significant increase of corticotrophin releasing hormone (CRH) immunoreactivity in the median eminence (ME), as measured by semi-quantitative immunofluorescence labeling techniques, (ii) a significant increase in CRH mRNA levels in paraventricular nuclei, as detected by in situ hybridization, and (iii) an increase in plasma adreno-corticotrophin hormone (ACTH) and corticosterone levels in responses to stress. PEA treatment has no effect on the number of binding sites and on the dissociation constant of the glucocorticoid receptors in any structure studied. Results of the dexamethasone suppression test were similar in PEA- and saline-treated rats. Taken together, these results suggest that PEA treatment stimulated the HPA axis activity levels directly via the CRH hypothalamic neurons, without altering the negative feed back control exerted by the glucocorticoids.

• 1.

  1. PE is present in the brain in tiny quantities; it is heterogeneously distributed and present in synaptosomes.

• 2.

  2. It is synthesised from phenylalanine by L-AADC and oxidatively deaminated by MAO-B. Its turnover is remarkably fast.

• 3.

  3. Its concentration, particularly in the caudate nucleus, is affected by MAO inhibition (increased), lesion of the Substantia nigra (decreased), amine depletion (increased) and antipsychotic drugs (increased).

• 4.

  4. When iontophoresed (or injected) it amplifies the effects of DA and NA (and their agonists) but is without effect on other neurotransmitters.

• 5.

  5. It is suggested that it acts postsynaptically as a neuromodulator of catecholaminergic neurotransmission and that it is involved in the mechanism of action of Deprenyl; it is also suggested that it, or its principal metabolite PAA, may be involved in the aetiology of schizophrenia, depression and aggression as well as perhaps in other neuropsychiatric conditions.

The firing rates of single neurones in the rat cerebral cortex were recorded using multibarrel glass microelectrodes, and the response to drugs applied by microiontophoresis was investigated. A greater number of cells responded to noradrenaline (NA) (30–66 nA) than to β-phenylethylamine (PE) (30–100 nA). When responses were obtained to both, 90% of the neurones gave the same response to NA and PE. Applications of PE with small currents (0–12 nA) caused an increase in the response to NA without affecting the baseline firing rate or the response to acetylcholine, glutamate, GABA or 5-hydroxytryptamine. An increase was seen in both excitatory and inhibitory responses to NA. The enhancement lasted up to 39 minutes after the end of the PE application. Applications of NA with small currents (0–3 nA) failed to alter responses to NA. Possible mechanisms of the effect of PE on response to NA are discussed. These results provide further evidence for the hypothesis that trace amines can modulate catecholamine neurotransmission.

The effect of the invertebrate octopamine agonists chlordimeform and clonidine on the concentration and turnover of p-octopamine and m- and p-tyramine was determined in rat hypothalamus and striatum. Clonidine (0.25 mg/Kg, s.c.) did not alter the concentration of p-octopamine in the hypothalamus or p-tyramine in the striatum. Administration of chlordimeform (50 mg/Kg, i.p.) resulted in an increase in p- and m-tyramine concentrations in the striatum but not that of p-octopamine in the hypothalamus. This increase in the tyramine isomers is consistent with the ability of chlordimeform and its metabolite, demethylchlordimeform, to inhibit monoamine oxidase (MAO). The concurrent administration of chlordimeform (50 mg/Kg, i.p.) and pargyline (75 mg/Kg, i.p.) produced a significant decrease in the accumulation of octopamine in the hypothalamus but not in the striatum. In contrast, the concurrent administration of clonidine (0.25 mg/Kg, s.c.) and pargyline (75 mg/Kg, i.p.) caused a significant decrease in the accumulation of octopamine in the striatum but not hypothalamus. These results show that the turnover of octopamine in the hypothalamus and striatum is decreased by chlordimeform and clonidine, respectively. Further, clonidine is known to modulate the turnover of amines in mammalian noradrenergic nerve terminals by an action at presynaptic adrenergic receptors. These data suggest that two mechanisms, one involving presynaptic adrenergic receptors in the striatum, and the other involving as yet unidentified receptors in the hypothalamus, modulate the turnover of octopamine in the mammalian brain.