Tetrabenazine-induced depletion of brain monoamines: mechanism by which desmethylimipramine protects cortical norepinephrine.

Pretreatment of rats with desmethylimipramine (DMI) (5 mg/kg) significantly antagonized the tetrabenazine (TBZ)-induced (3 mg/kg) depletion of cortical norepinephrine (NE) in rats. This protective effect of DMI was fully blocked by the specific alpha 2-adrenergic antagonist, RX 781094. The doses of DMI which antagonized the depleting effects of TBZ caused rapid, maximal reductions in cortical dihydroxyphenylalanine (DOPA) accumulation, effects which were also blocked by RX 781094. Like DMI, the alpha 2-adrenergic agonist, clonidine (50 micrograms/kg) decreased cortical DOPA accumulation and rapidly prevented the TBZ-evoked loss of NE in this brain region. On the other hand, doses of RX 781094 (0.5-2.0 mg/kg) which accelerated cortical DOPA synthesis, enhanced significantly the depleting effects of a threshold dose of TBZ (0.6 mg/kg). These findings suggest that DMI reduces the rate of TBZ-induced depletion of cortical NE by lowering NE turnover through the indirect stimulation of alpha 2-adrenoceptors.

Effects of methiothepin and lysergic acid diethylamide on serotonin release in vitro and serotonin synthesis in vivo: possible relation to serotonin autoreceptor function.

An in vitro system characterizing the presynaptic serotonin (5-HT) autoreceptor which controls the release of 5-HT from rat brain slices is described. Using this system, methiothepin (1-10 microM) demonstrated 5-HT autoreceptor antagonist activity by enhancing 5-HT release, while several recognized postsynaptic 5-HT receptor antagonists were inactive: mianserin, cinanserin, cyproheptadine, methysergide. The activity of methiothepin was highest in hypothalamic slices and lowest in striatal slices and was inhibited by the autoreceptor agonists lysergic acid diethylamide (LSD) and 5-methoxytryptamine (5-MT). The reversal of the methiothepin-enhanced 5-HT release from hypothalamic slices by LSD was not influenced by 0.3 microM tetrodotoxin. The peripheral administration of LSD to rats has been shown to reduce 5-HT synthesis and release by a mechanism thought to involve, in part, an autoreceptor-mediated reduction in impulse flow of 5-HT neurons. In the present experiments, intraperitoneal injection of methiothepin antagonized the LSD-induced reduction in hypothalamic 5-HT synthesis (5-hydroxytryptophan accumulation) while exerting no influence by itself. Conversely, compounds which were not active as 5-HT autoreceptor antagonists in vitro (i.e., cyproheptadine, methysergide, cinanserin) did not influence the effect of LSD on 5-HT synthesis. Further, the reduction in 5-hydroxytryptophan (5-HTP) accumulation by LSD showed regional differences in inhibition by methiothepin (hypothalamus greater than cortex greater than striatum) which paralleled the autoreceptor antagonist activity of methiothepin in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Tetrabenazine-induced depletion of brain monoamines: characterization and interaction with selected antidepressants.

The peripheral administration of tetrabenazine (TBZ) induces rapid depletion of brain regional concentrations of norepinephrine (NE), dopamine (DA) and serotonin (5-HT). With respect to both dosage and time, striatal DA was most sensitive to the effects of TBZ while hypothalamic NE was least affected. Pretreatment with the monoamine oxidase (MAO)-inhibitor, clorgyline (1-6 mg/kg) dose-dependently prevented the reduction of all three monoamines for up to 60 min after TBZ (3 mg/kg). The TBZ-induced depletion of cortical NE was also significantly antagonized by desmethylimipramine (DMI) but was of shorter duration (up to 30 min after TBZ). DMI, however, did not influence the effect of TBZ on striatal DA or hypothalamic 5-HT. The protective effects of both clorgyline and DMI were also evident under the conditions of the behavioral TBZ test utilizing high doses of TBZ (20 mg/kg).

Deanol affects choline metabolism in peripheral tissues of mice.

Administration of 2-dimethylaminoethanol (deanol) to mice induced an increase in both the concentration and the rate of turnover of free choline in blood. Treatment with deanol also caused an increase in the concentration of choline in kidneys, and markedly inhibited the rates of oxidation and phosphorylation of intravenously administered [3H-methyl]choline. In the liver, deanol inhibited the rate of phosphorylation of [3H-methyl]choline, but did not inhibit its rate of oxidation or cause an increase in the level of free choline. These findings suggest that deanol increases the choline concentration in blood by inhibition of its metabolism in tissues. Deanol may ultimately produce its central cholinergic effects by inhibition of choline metabolism in peripheral tissues, causing free choline choline to accumulate in blood, enter the brain, and stimulate cholinergic receptors.

Tissue choline studied using a simple chemical assay.

An enzymatic-radioisotopic assay was used to measure free choline in unextracted tissue. The lowest concentration of free choline in any tissue studied was present in human cerebrospinal fluid (mean, 5.7 microM; range, 1.8 + 31.2 microM). A postmortem increase in concentration of free choline occurred in blood (0.2 nmol/min.ml), kidney (13 nmol/min.g) and liver (22 nmol/min.g) of mice. The concentration of free choline in these tissues was estimated by extrapolation to be 5, 77, and 29 nmol/g (or ml), respectively. Several treatments were found to increase the concentration of free choline. For example, intraperitoneal administration of choline or 2-amino-2-methyl-propanol (a choline oxidase inhibitor) induced an increase in the level of choline i blood, kidneys, liver, and brain of mice, and administration of 2-dimethylaminoethanol (deanol) caused an increase in kidney and liver choline. The level of choline in blood was increased when rats were treated orally with either antibiotics or esters of choline such as phosphorylcholine, glycerylphosphorylcholine, laroylcholine, or propionylcholine. The results show that the concentration of free choline may be regulated by intestinal metabolism, availability of esterified precursors, and activity of enzymes that metabolize choline.

Stereospecific antidopaminergic and anticholinergic actions of the enantiomers of (+/-)-1-cyclopropylmethyl-4-(3-trifluoromethylthio-5H-dibenzo[a,d]cyclohepten-5-ylidene) piperidine (CTC), a derivative of cyproheptadine.

(+/-)-CTC, a cyproheptadine derivative, possesses both antidopaminergic and anticholinergic activities which can be resolved, respectively, into its component (-)- and (+)-enantiomers. Both in vivo (antagonism of apomorphine-induced stereotypy, elevation of striatal homovanillic acid) and in vitro (inhibition of [3H]haloperidol binding), (-)-CTC was less active than haloperidol but more potent or equipotent compared to chlorpromazine. (+)-CTC was a more potent anticholinergic agent in vitro (inhibition of [3H]quinuclidinyl benzilate binding) than either thioridazine or clozapine, whereas in vivo (antagonism of the lethal action of physostigmine) the three compounds were similar. Comparison of the racemate with (-)-CTC in several in vivo test procedures to determine the influence of intrinsic anticholinergic activity showed that the presence of the anticholinergic (+)-enantiomer had little effect on the ability of (-)-CTC to antagonize apomorphine or elevate striatal homovanillic acid, whereas the activity of (-)-CTC was reduced in tests for postural asymmetry, avoidance and catalepsy. Stereoselectivity was also observed in terms of the alpha adrenergic blocking activity of CTC (inhibition of [3H]WB 4101 binding) which resides exclusively in the (-)-enantiomer. The ratios of (+)-CTC and (-)-CTC in terms of their anti-alpha adrenergic/antidopaminergic properties were large, suggesting a low propensity for the elicitation of orthostatic hypotension and sedation.

A 5-hydroxytryptamine-like mode of anorectic action for 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212).

The mechanism of the reduction in food consumption elicited by 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) administered systemically was investigated in the rat. (+/-)-Fenfluramine and (+)-amphetamine were included in some studies for comparative purposes. 2 Pretreatment with methergoline, a 5-hydroxytryptamine (5-HT) antagonist, reduced the magnitude of the anorectic effect of 1.5 and 3 mg/kg of MK-212, while the anti-5-HT agents, cyproheptadine and cinanserin, were likewise effective against the 3 mg/kg dose. 3 Xylamidine, an antagonist of 5-HT that penetrates poorly into the central nervous system, completely blocked the decrease in food intake caused by 5-HT administered peripherally, while not antagonizing an equianorectic dose of MK-212. 4 Reduction of brain 5-HT by intraventricular injection of 5,6-dihydroxytryptamine, intraperitoneal administration of p-chloroamphetamine or placement of a lesion in the region of the median raphé nucleus diminished the anorectic response to 3 mg/kg of MK-212. The anorectic effect of amphetamine was reduced by p-chloroamphetamine or lesion in the raphé, but not by 5,6-dihydroxytryptamine. The decrease in food consumption produced by 1.5 mg/kg of MK-212 was antagonized by prior treatment with p-chloroamphetamine, but not by 5,6-dihydroxytryptamine. 5 Haloperidol, which blocks receptors for dopamine, antagonized the anorexigenic effect of amphetamine, but was ineffective in offsetting the action of MK-212, 3 mg/kg. 6 Pretreatment with chlorimipramine to inhibit the 5-hydroxytryptaminergic uptake mechanism did not affect the anorectic response to 3 mg/kg of MK-212, whereas the response to fenfluramine was diminished. 7 The results indicate that the anorectic action of MK-212 involves a 5-HT-like component which is more evident at the higher dose level of the compound. The anorexigenic property of MK-212 may depend, at least partly, upon the integrity of 5-HT-containing neurones in the central nervous system.

Anorexigenic and ancillary actions of MK-212 (6-chloro-2-(1-piperazinyl)-pyrazine; CPP).

In rats allowed to eat for 2 h/day and injected i.p. 30 min before feeding, MK-212, ED50 = 1.5 mg/kg, was two times more potent as an anorexigen than fenfluramine. However, the compounds were equiactive in the rat following p.o. administration 1.5 or 3 h before the test, while fenfluramine was more potent if the interval was extended to 6 h. In cats permitted to eat for 3 h/day, the ED50 dose (mg/kg p.o.) for MK-212 determined at 0.5, 1 and 3 h after feeding was, respectively, 15, 10, and 3 times less than that of fenfluramine. Emesis and diarrhea were frequently observed ancillary effects in cats treated with fenfluramine, whereas apparent sedation and salivation were commonly detected in animals after MK-212. In rats or cats pretreated with methergoline, the decrease in food consumption elicited by MK-212 was markedly inhibited, suggesting that the mechanism of action involves a serotoninlike effect. Compared with the marked stimulant action of amphetamine, MK-212 had only a minor and inconsistent effect on motor activity in rats and mice. Similar results were obtained with fenfluramine. MK-212 was not self-administered by rats, while the self-administration of amphetamine and morphine were demonstrated using the same experimental protocol.

Central serotonin-like activity of 6-chloro-2-[1-piperazinyl]-pyrazine (CPP; MK-212).

CPP, administered systemically, elicited four distinct responses characteristic of serotonin-receptor activation in the central nervous system. The crossed extensor reflex in the acutely spinalized rat was enhanced by treatment with CPP, 1-16 mg/kg. CPP, 1.11-10 mg/kg, elicited a dose-related increase in head twitches in mice. A complex motor syndrome in rats similar to that produced by pargyline plus tryptophan (or other treatments effecting increased activation of central serotonin receptors) was produced by 1.25-5 mg/kg of CPP. An increase in twitch frequency of the mylohyoideus muscle in the urethane anesthetized rat occured after CPP at 0.1 mg/kg or less. Complete abolition of all four effects of CPP was achieved by pretreatment with the centrally acting indoleamine antagonist methergoline. The peripherally acting serotonin antagonist xylamidine was ineffective or only weakly active, depending upon the test procedure, in preventing the serotonin-like actions of CPP. These findings indicate that CPP has a serotoninmimetic action in the central nervous system.

Fenfluramine: long-term reduction in brain serotonin (5-hydroxytryptamine).

A single oral dose of 15 mg/kg of fenfluramine reduced the level of serotonin in rat brain to 48, 51 and 63% of control at 1, 15 and 30 days, respectively, after administration. 3 mg/kg p.o. of the drug caused a smaller but significant diminution in brain serotonin. At the 3 mg/kg dose level, the decreases in serotonin were, at least partially, cumulative following multiple injections spaced 24 hr apart. Brains removed 14 days after the 5th daily injection of 5 mg/kg p.o. of fenfluramine had only 60% of the concentration of serotonin found in brains from control animals. These findings demonstrate that fenfluramine has a long-lasting action on serotonin-containing neurons in brain.

Central catecholamine receptor blocking actions of BE-2254 ('heat'): comparison with chlorpromazine and haloperidol.

BE-2254, 2-[beta-(4-hydroxyphenyl)-ethylaminomethyl]-tetralone, (ED50 = 3.4 mg/kg i.p.) was about equal to chlorpromazine (ED50 = 4.4) as an antagonist of central noradrenergic receptor stimulation produced by clonidine (enhancement of the flexor reflex in spinalized rats). Haloperidol and phentolamine had essentially no effect at 9 mg/kg i.p...