Daniel X. Freedman

Studies on 5-hydroxyindole metabolism in autistic and other mentally retarded children*

Summary Aspects of 5-hydroxyindole metabolism have been studied in some groups of mentally retarded children. Six of 23 children with the diagnosis of infantile autism had consistently elevated blood 5-HT levels. The mean level of blood 5-HT of other severely retarded children was higher than that of the mildly retarded group. No specific clinical signs could be found in these children.

The effect of ethyl alcohol on man's electroencephalographic sleep cycle

Abstract This study indicates that 1 g of ethyl alcohol per kg of body weight administered before sleep exerts a systematic effect on EEG sleep patterns. In three human subjects over 13 consecutive nights (4 control, 5 alcohol, and 4 recovery nights), the most consistent pattern of change from night to night was seen in stage I REM. On the first night of alcohol the mean REM time dropped from the mean control value and over the next four consecutive nights on ethyl alcohol increased steadily to a peak value on the fifth night of alcohol. In four recovery nights REM time dropped back to control levels. This change in REM occurs in the first half of the night, when CSF alcohol levels are at their maximum concentration, and during the second half of the night. Latency or time to the first REM is constant in control and post-alcohol nights but varies unsystematically during nights of alcohol administration. Stages III and IV remain constant while stage II “absorbs” the shifts demonstrated in stage I.

Studies in audiogenic seizure susceptibility

A genetically heterogeneous (HS) group of mice and a highly inbred strain of mice (C57BL/6) were both shown to become highly susceptible to audiogenic seizures after exposure to acoustic stimulation (priming). In heterogeneous mice the optimal age for priming was 18 days with a test-retest interval of 48 hours. The optimal test-retest interval in C57BL/6 mice primed at 20 days of age was 8 days. One second of priming was found effective in enhancing seizure susceptibility. Drugs known to alter steady state levels of biogenic amines and to change responses of mice genetically predisposed to audiogenic seizures were found to be effective in altering seizure susceptibility from priming, but not effective in altering the priming itself.

Chemically-induced alterations in the behavioral effects of LSD-25

Abstract When LSD-25 is administered to rats trained to press a bar for food, a dose-dependent period of no responding occurs. After pretreatment with reserpine, tetrabenazine, or tranylcypromine and after recovery from behavioral effects of these compounds, the response to ED 90 or threshold doses of LSD-25 was markedly enhanced. Such effects were correlated with a change in levels of brain serotonin and norepinephrine; i.e., they occurred 5 hr after tetrabenazine when the amines were only 12% to 14% below normal. Fifteen mg benzquinamide/kg affected neither the LSD-25 response nor the levels of amines, whereas 30 μg chlorpromazine/kg attenuated the effect of 130 μg LSD-25/kg. The relationship of these findings to mechanisms regulating brain amines is discussed.

The relative potencies of psychotomimetic drugs

Abstract The behavioral effects of several indole and catechl derivatives, some of which have psychotomimetic properties in man, were compared in a situation in which hungry rats were trained to press a bar for food on a simple schedule of reinforcement (FR 30). It was found that 1) the amount of disruption each drug induces is proportional to dose, i.e., the amount given i.p. immediately before the test session. 2) d-LSD is about 10 times more potent than I-LSD, BOL, psilocybin and d-amphetamine and 100 times more potent than mescaline. 3) Among the psychotomimetic drugs, the order of potency in the animal behavior test parallels that found in man. 4) A compound related to mescaline (3–4 dimethoxy-phenylethylamine) which occurs in the urine of schizophrenic patients had no behavioral effects.

Drug-induced Changes in the Subcellular Distribution of Serotonin in Rat Brain with Special Reference to the Action of Reserpine

Publisher Summary The mode of action of reserpine (and tetrabenazine) on 5-hydroxytryptamine (5-HT) in the brain is more complex than a simple shift of the amine from a bound to an unbound form. It is felt that other agents, which influence the metabolism of monoamines in the brain, may have multiple sites of action on the subcellular level, and studies of their influence on the subcellular distribution of the amines may reveal similar complexities in their action. It is well known, for example, that α-methyldihydroxyphenylalanine not only inhibits the decarboxylase, but also leads to a release of 5-HT. Certain inhibitors of monoamine not only inhibit that enzyme, but also exert an action on the storage granule, which is manifested in an antagonism to the 5-HT releasing action of reserpine.

The effect of ethyl alcohol on electroencephalographic sleep cycles in cats

EEGs taken from four sleeping cats for three control and four alcohol consecutive nights show that if 1 gm ethanol/kg body weight is administered 15 min. prior to sleep, Stage 1 REM time decreases from control values the first two alcohol nights but returns to control levels on the third and fourth alcohol nights. This pattern of change in REM time is the same as that found in humans. The REM time pattern is effected by a change in length rather than in numbers of REM periods. These data support the use of cats in establishing a mechanism for REM sleep which can be extrapolated to humans.

The effect of central nervous system lesions on brain monoamines and behavior

Lesions were made bilaterally in the lateral hypothalamus in ten rats and in the posteromedial hypothalamic midbrain transition in ten rats. A control group of ten rats had electrodes passed and withdran without any current. The groups of rats were given 12 min of escape conditioning in an operant conditioning situation. The telencephalon was analyzed for 5-hydroxytryptamine (5-HT) and norepinephrine (NE). Brain stems were examined microscopically for lesion site. There was a significant correlation between: (1) low 5-HT and NE in the telencephalon and both lesions, and (2) between prolongation of the escape latency and low 5-HT and NE in telencephalon with a significant difference from control rats, (P <0·001, differences in 5-HT and NE) (P <0·01, difference in escape latency).

Retention of 5-hydroxytryptamine by subcellular fractions of rat brain homogenates

Abstract After their incubation with 14C-labeled amine, microsomal fractions of rat brain homogenates in vitro retained up to 12 times the concentration of 5-HT-14C (on the basis of their protein content) found in the corresponding mitochondrial fractions. This difference was maintained over the range of concentrations, 100–4,000 mμg of 5-HT-14C per ml of medium. No clear evidence of saturation was seen even when the highest concentration of amine was used. While lowering the temperature of a 30-min incubation to 4° significantly reduced the retention when compared with that at 37°, similar treatment, when the duration of incubation was 10 min, failed to alter the magnitude of retention. Retention was increased (at 37°) when the duration of incubation was 30 or 60 min; however, significant retention took place even when the time of incubation was zero (i.e. when the microsomal fractions were mixed briefly with the labeled amine and immediately subjected to analysis). Microsomal fractions retained up to 12.7 times the concentration of 5-HT-14C in the medium; the corresponding figure for 5-HTP-14C was 3.3. It was found that microsomal as well as mitochondrial fractions of both rat and guinea pig brains contained significant amounts of endogenous 5-HT; in the case of guinea pig brains, the concentration of amine (in terms of the wet weight of fractions) in the microsomal was always higher than in the mitochondrial fractions. The physiological significance of retention of 5-HT by microsomal particles is not clear but may represent, in vitro, the process of binding of 5-HT synthesized in the brain, without the limitations on the process normally set in vivo by the presence of the cell membrane.

Factors influencing the uptake of noradrenaline by subcellular particles in homogenates of rat brain

Abstract A preparation of granules obtained from rat brain by differential centrifugation has been investigated for characteristics of release and uptake of catecholamines. Activation and fluorescence spectra obtained from chromatographically isolated extracts of such granules indicated that noradrenaline is the predominant endogenous catecholamine. The rate of release of this endogenous noradrenaline varied directly with temperature of incubation. When the brain granules were incubated with exogenously added noradrenaline, uptake varied directly with the external concentration of the amine, with partial saturation appearing at concentrations beyond 200 mμg noradrenaline/ml incubation medium. Partial depletion of noradrenaline from brain granules by incubation at 37° did not alter the capacity of the granules to take up exogenous noradrenaline. Greater actual uptake of exogenous noradrenaline by the granules occurred at 37° than at 4°, even though total uptake was less at 37°. Administration of reserpine to the rats markedly decreased endogenous levels of noradrenaline in the brain granules. Although granules from reserpine-treated animals continued to demonstrate an uptake of exogenous noradrenaline, the total quantity taken up was markedly below that in control preparations. Neither dinitrophenol nor iodoacetic acid altered the uptake of exogenous noradrenaline by the brain granules.