Eunyong Chung Hwang

Serotonin-norepinephrine interactions in the tremorolytic actions of phenoxybenzamine and trazodone.

Phenoxybenzamine (5 mg/kg IP) and trazodone (5 mg/kg IP) reduced tremors produced in mice by administration of oxotremorine (10 mg/kg), harmaline (80 mg/kg), catechol (60 mg/kg), kepone (200 mg/kg) and clonidine (100 mg/kg). Azapetine (10 mg/kg IP) in combination with L-5-hydroxytryptophan (50 mg/kg IP) reduced the tremor induced by oxotremorine, catechol, kepone and clonidine. In mice with lower thoracic spinal cord transection, phenoxybenzamine and trazodone reduced catechol-induced tremor above and below the site of transection. These findings suggest that an alpha noradrenergic-serotonergic neuronal balance in the spinal cord may modulate tremors of different etiologies.

Behavioral and biochemical actions of p-chlorophenylethylamine (p-CPEA) in mice.

Abstract p-chlorophenylethylamine (p-CPEA), a metabolite of p-chlorophenylalanine (p-CPA) induces the “serotonin syndrome” which consists of lateral head weaving, Straub tail, hindlimb abduction, tremor, hyperactivity, reciprocal fore-paw treading, salivation and piloerection. These p-CPEA-induced behavioral signs were partially prevented by pretreatment with serotonin (5-HT) uptake blockers (fluoxetine, chlorimipramine, Org 6582) and 5-HT receptor blockers (methiothepin, methysergide, cinnanserin) but not by two depletors of brain 5-HT (p-CPA, reserpine). p-CPEA (50 mg/kg) produces an initial decrease in 5-HT associated with a concurrent increase in 5-hydroxyindoleacetic acid with a maximum change at 30 minutes after injection; these early biochemical changes are prevented by pretreatment with fluoxetine (10 mg/kg). p-CPEA also competes with ( 3 H)-5-HT for 5-HT receptors. The reported paradoxical effects of p-CPA on several behavioral paradigms could be due to its decarboxylation to p-CPEA which may both stimulate 5-HT receptors and enhance 5-HT release.

Study of serotonin in neuropsychiatric disorders.

Disturbances of serotonin (S-HT) metabolism have been detected in numerous human diseases. Perhaps the best known and understood serotonin disorder is the carcinoid syndrome, caused by the rapid synthesis of S-HT by a carcinoid tumor originating from the entenochnomaffin cells in the small intestine. Platelets possess specific subcellular storage sites for 5-HT and preferentially accumulate 5-HT synthesized in the gut. Abnormalities of platelet accumulation of 5-HT are found in several hemotological disorders such as storage pool disease and Hermansky-Pudlak syndrome. There is considerable evidence that 5-HT abnormalities also may be present in a number of neuropsychiatnic diseases. However, the relationship of 5-HT to the pathogenesis of these central nervous system disorders is less well understood compared to peripheral S-HT diseases. Several techniques have been used to uncover abnormalities of 5-HT metabolism in neunopsychiatric disorders: I . Evaluation of the effect of S-HT agonists and antagonists on clinical signs and symptoms in patients with neurological and psychiatric diseases. The hypothesis that brain S-HT deficiencies play a role in the pathogenesis of a subcategory of mental depression and certain types ofmyoclonus is supported by studies with 5-HT precursors. Both tryptophan and L-5hydroxytryptophan (L-5-HTP), as well as specific S-HT uptake blockers, have been reported to improve depression and alleviate myoclonus (18,19). The methodology and specific protocols used in human pharmacological investigation are regulated and monitored by the Food and Drug Administration (FDA) (see Appendix).

Comparative effects of various serotonin releasing agents in mice.

Abstract Five serotonin (5-HT) releasers, p -chlorophenylethylamine ( p -Cl-PEA), p -methoxyphenyl-ethylamine ( p -CH 3 O-PEA), 4-methyl-alpha-ethyl-meta-tyramine (H75/12), fenfluramine and p -chloro-amphetamine ( p -CA) were compared as to their effects on mouse brain 5-HT metabolism. All 5-HT releasers had similar ed 50 values (0.34–0.70 μM) for tritiated 5-HT ([ 3 H]5-HT) release from brain synaptosomes. With the exception of H75/12, they had similar potencies for the production of the ‘serotonin syndrome,’ which probably reflect their in vivo 5-HT releasing actions. H75/12 was also the only 5-HT releaser that did not elevate brain tryptophan concentration. p -CH 3 -PEA and H75/12 did not have any long-term effects on brain 5-HT, 5-hydroxyindoleacetic acid (5-H1AA), or tryptophan hydroxylase activity, in contrast to the reported neurotoxic effects of p -CA and fenfluramine. p -Cl-PEA and p -CH 3 O-PEA were the only 5-HT releasers that increased brain 5-HT and 5-HIAA levels. Despite the structural similarities of these five 5-HT releasers, we have found considerable differences in their actions on brain 5-HT metabolism.