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Drug-induced release of biogenic amines from synaptosomes and blood platelets of guinea-pigs.

Synaptosomes from guinea-pig brain were compared with blood platelets (partly from previous experiments) regarding the action of imipramine, the benzoquinolizine derivative Ro 4-1284, tyramine and p-chlormethamphetamine (PCMA) on the contents of stored radio-labelled 5-hydroxytryptamine (5HT), dopamine (DA) and noradrenaline (NA). Normal and reserpinized preparations were used in order to differentiate between granular and extragranular (reserpine-resistant) sites. Imipramine, in concentrations greater than those inhibiting 5HT- and NA-uptake released the three amines from granular and extragranular sites and showed the same order of potency in synaptosomes as in platelets. The drug Ro 4-1284 acted on the granular amines only, but its action on NA was less potent in synaptosomes than in platelets. Tyramine and PCMA also caused an exclusive release of granular amines in synaptosomes, whereas in platelets the drugs released extragranular 5HT (and DA) as well as the granular amines. Tyramine was more potent in synaptosomes than in platelets, and PCMA showed a preferential effect on 5HT in synaptosomes but not in platelets. It is concluded that, regarding the action of monoamine-releasing drugs, platelets are only partial models for synaptosomes. However, they may be superior to synaptosomes in predicting the pattern of amine release in brain in vivo as seen with Ro 4-1284.

2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗

The effect of the selective reversible acetylcholinesterase inhibitor E2020 on extracellular acetylcholine and biogenic amine levels in rat cortex.

E2020 is a piperidine cholinesterase inhibitor (ChEI) which is structurally distinct from other compounds presently under study for treatment of Alzheimer's disease. We studied the effect of this compound on acetylcholine (ACh), norepinephrine (NE), dopamine (DA) and serotonin (5-HT; 5-hydroxytryptamine) by means of transcortical microdialysis in the cortex of awake rats with no ChEI in the probe. We also compared the inhibition of brain cholinesterase (ChE) by two different approaches. Following 0.5 and 2.0 mg/kg s.c. administration, the increase in ACh was 200% (30 min) and 2100% (1 hr), respectively. The maximal ChE inhibition at 30 min was 35.5% (2.0 mg/kg) and 15.6% (0.5 mg/kg) when measured as ACh hydrolysis in the diluted homogenate. After the 2.0 mg/kg dose, phosphorylation by DFP was completely blocked at 30 min. After 0.5 mg/kg, ChE phosphorylation was maximally inhibited at 30 min (56%) and declined thereafter to negligible levels by 3 hr. In addition, E2020 increased extracellular levels of catecholamines in cortex in agreement with our previous findings with carbamate ChEI. Following 2.0 mg/kg, both NE (100%) and DA (80%) were elevated, whereas after 0.5 mg/kg only NE (50%) was affected. Neither dose affected extracellular 5-HT. Thus, E2020, which inhibits brain ChE by a novel, reversible mechanism, elevates extracellular ACh in a comparable manner to other centrally-active ChEI, and this elevation of ACh is associated with stimulation of catecholamine release.

Acetylcholine↗

Uptake of tritium-labelled biogenic amines by the prostomium of the polychaete Nereis virens (Sars) (Annelida).

The uptake of tritium-labelled 5-HT, noradrenaline, 5-hydroxytrytophan, DOPA and dopamine by the cerebral ganglion and prostomial nervous system of the polychaete Nereis virens has been examined using radioautography at the level of the light microscope. Pronounced uptake of (3)H-5HT occurred in the antennal, palpal, tegumentary and nuchal nerves as well as in ganglionic nuclei 13, 14, 15, 16, 17, 20, 24 and 25, the mid-brain neuropile, the neurosecretory neuropil and the infracerebral organ; (3)H-NA uptake was observed in small cells in the prostomial epidermis, and the infracerebral organ; (3)H-dopamine only in one of two common types of epidermal mucus cells. Prostomial muscles labelled generally with (3)H-NA and at specific sites with (3)H-5HT. These observations support the concept of an efferent serotonergic system originating in several cerebral ganglionic nuclei and serving prostomial muscle and epidermis. Evidence for an afferent adrenergic system is less substantial. The role of dopamine remains obscure.

5-Hydroxytryptophan↗

Electrophysiological studies on neuronal transmission in the frog's photosensory pineal organ. The effect of amino acids and biogenic amines.

A variety of putative neurotransmitter substances and their analogues were used to characterize the synaptic connections from photoreceptors to ganglion cells in the pineal organ of the frog. The effects of all agents were tested on electrophysiologically identified luminance cells of the pineal organ. L-Aspartate and L-glutamate caused a significant increase of neuronal cell firing, the effects were dose-related, reversible and reproducible. The aspartate and glutamate agonists N-methyl-D-aspartate and kainate possess a similar ability to induce neuronal excitations in the pineal organ, N-methyl-D-aspartate being more potent than kainic acid. The excitatory action of all agents persisted if the ganglion cells were isolated from other synaptic inputs by Co2+ treatment. The excitatory action of the amino acids was antagonized by D-alpha-aminoadipate (D-alpha-AA); the order of sensitivity to antagonism by D-alpha-AA was: N-methyl-D-aspartate greater than L-aspartate greater than L-glutamate approximately equal to kainate. Taurine, by far the most abundant amino acid in pineal tissues, markedly decreased the spontaneous activity in half of the neurons tested, the remaining cells being unresponsive. The indoleamine serotonin effectively depressed the maintained activity also in half of the cells tested. Acetylcholine had only small effects on pineal luminance cells. It is concluded that L-aspartate (and/or glutamate) might interact with postsynaptic receptors in the ganglion cell membrane and mimics the action of the natural photoreceptor transmitter.

2-Aminoadipic Acid↗

Determination of levels of biogenic amines and their metabolites and both forms of monoamine oxidase in prefrontal cortex of aged rats.

Levels of dopamine, noradrenaline and serotonin and their metabolites and the activities of monoamine oxidase A and B, have been determined in the prefrontal cortex of the rat during ageing. Serotonin turnover rate has been measured as 5-hydroxytryptophan accumulation rate after central decarboxylase inhibition. The major changes were an increase of dopamine and noradrenaline levels and a decrease of serotonin in aged animals compared with control animals. A decrease of the MAO-A to MAO-B ratio was found in aged rats.

Aging↗

Papaverine, drug-induced stereotypy and catalepsy and biogenic amines in the brain of the rat.

The effects of papaverine on haloperidol-induced catalepsy and apomorphine-induced stereotypy as well as brain monoamines concentrations in rats were studied. Papaverine increased cataleptogenic effect of haloperidol whilst reduced stereotypy induced by apomorphine. Slight but significant decrease in brain dopamine concentration was observed in rats treated with papaverine. The present study indicates that papaverine has influences upon dopaminergic mechanisms in the brain.

Animals↗

Ontogeny of biogenic amine systems and modification of indole levels upon adult sexual behavior in the rat.

Male, female and androgenized female rats treated on Days 9, 10 and 11 after birth with either 5-HTP or saline were tested for female sexual behavior in adulthood. It was hypothesized that such pharmacological manipulations of the developing serotonergic system in which Day 12 sex differences have been reported might have an influence on the expression of lordosis behavior. No effect of 5-HTP was found in either normal or androgenized females, even though fluormetric analysis indicated a marked increase in endogenous levels of 5-HT at Day 12. However, males treated with 5-HTP has significantly higher 5-HT levels than 5-HT treated control or androgenized females. In addition, flurometric analysis of norepinephrine, dopamine and serotonin from hypothalamus, mesencephalon and cortex was performed on male and female rats on Day 8, 10, 12 and 14 postnatally to examine the development of various transmitter systems during the early postnatal period.

Animals↗

HPLC determination of biogenic amines in discrete brain areas in food deprived rats.

Norepinephrine (NE), dopamine (DA), 5-hydroxytryptophan (5-HTP), 5-hydroxytryptamine (5-HT), and 5-hydroxyindole acetic acid (5-HIAA) levels in the lateral hypothalamus (LH), ventromedial hypothalamus (VMH), median raphe (MR) and dorsal raphe (DR) were determined in nondeprived and 48 hr food deprived rats. Simultaneous determination of these compounds was accomplished by means of high performance liquid chromatography (HPLC) with electrochemical detection. When compared with controls, food deprived animals showed significant increases in 5-HT and 5-HIAA levels in the raphe nuclei, significant increases in 5-HIAA in the LH, but no changes in either 5-HT or 5-HIAA levels in the VMH. No changes in catecholamine levels were found in any of the brain areas studied. These results show that indoles in the raphe nuclei, as well as in the LH, are affected by food deprivation. The lack of change in indole levels in the VMH indicates that specific nuclei within the hypothalamus are differentially affected by food deprivation.

Animals↗

Effects of lesions of the ventral medial tegmentum on locomotor activity, biogenic amines and responses to amphetamine in rats.

Rats subjected to electrolytic lesions of the ventral medial tegmentum (VMT) showed long-lasting increased locomotor activity in the open field compared to sham-operated controls. In addition to severe depletion of mesolimbic dopamine, the lesions also caused significant depletions of striatal dopamine, mesolimbic and striatal norepinephrine and striatal and hippocampal serotonin. Administration of d-amphetamine sulfate produced similar dose-response functions for locomotor activity in both VMT-lesioned and sham-operated rats despite the extensive depletion of dopamine in the VMT-lesioned rats. These results suggest that the mesolimbic dopamine pathway is not the sole substrate for amphetamine-stimulated locomotor activity. Electrolytic lesions of the VMT interrupt several neurotransmitter pathways which may produce complex and antagonistic effects on behavior.

Animals↗