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Sulpiride is a new neuroleptic which does not produce extrapyramidal side effects in humans nor catalepsy in experimental animals. Sulpiride in rat striatum and nucleus accumbens homogenates fails to block adenylate cyclase activation induced by both dopamine and apomorphine. Moreover the in vivo cyclic adenosine monophosphate accumulation induced by apomorphine in the striatum of rats is not blocked by sulpiride as haloperidol and other classic neuroleptic do. Sulpiride appears to be unique in respect to other neuroleptic since according to the experiments reported in this paper it does not block dopamine receptors either in vitro or in vivo.

Levels of radioactive caffeine and metabolites, after intra muscular injection of 1-methyl 14 C caffeine to pregnant rats, have been measured in maternal and fetal brains and livers at various time intervals. Caffeine and metabolites diffuse into fetal tissues and accumulate in fetal brain.

Summary Sodium gamma-hydroxybutyrate (Na-GHB), a well-known anesthetic agent, does not alter brain serotonin levels in rats. However, at anesthetic doses (14.4 mmoles/Kg. i.p.) an increased level of 5-hydroxyindolacetic acid has been observed. This increase is potentiated by the administration of probenecid. Using smaller, non-anesthetic doses (4.8 mmoles/Kg. i.p.) of the drugs, an increased (almost 100%) turnover of serotonin has been demonstrated. These results underline the need to measure turnover rates versus concentrations of the control mediators in the investigation of the mode of action of centrally acting drugs.

A method is presented for separating and estimating the endogenous concentrations of DM, HVA, and DOPAC in neural tissue. The procedure involves solvent extraction and batch adsorption and elution of catechols from alumina. Because of its simplicity, many samples can be processed in a day.

Many butyric acid congeners were screened for their behavioural effect and for their influence on brain amines. Among the compounds examined, all butyric acid derivatives endowed with depressant action on the CNS, and only those endowed with such action, were capable of increasing selectively brain DA. Brain NE and serotonin were not influenced. Besides -OH and -BL, the following compounds were found to be active: 1,4-BD, α-OH-butyric acid, -BL- -carboxylic acid and succinate. 1,4-BD was studied in detail in rats and in rabbits. The effect of this compound shows close similiarities to that of -OH. There is a direct correlation between the degree of sedation produced by this compound an the accumulation of DA in the brain. This is particularly evident in rabbits: the anaesthetic effect occurs after a delay of about two hours, as does the rise in brain DA. The DA levels return to normal when the animals are awake. The newly-formed DA is localized in the pallidum and in the striatum. The mechanism by which the above compounds, and specifically 1,4-BD, produce the change in brain DA is not clear: 1,4-BD, like -OH, does not inhibit MAO either in vivo or in vitro. The fact that 1,4-BD produces its effect after a long delay suggests that it acts through an active metabolite.

Summary New synthetic derivatives of natural cyclic nucleotides have been tested for their metabolic (blood glucose and plasma corticosterone) and cardiovascular (heart rate and blood pressure) effects in the rat. A clear cut specificity of the effects emerges from the comparison between the different series of substituted nucleotides (N 6 , 2′O-8-and 2-substitutions). A long lasting effect on plasma steroid levels has been demonstrated with the compound 6-(3′4′-dimethoxyphenyl-)ethyl-amino-3′,5′-PuMP + , at doses and times where there is no effect on the cardiovascular parameters or blood glucose levels.

— γ-Hydroxybutyrate (γ-OH) produces a selective accumulation of brain DA not only in normal animals but also in reserpinized animals. This is especially evident after the administration of DOPA; while in parallel experiments γ-OH does not influence significantly the amount of 5-HT present in brain after 5-HTP treatment. γ-OH does not raise DA in rats after inhibition of tyrosine hydroxylase. The accumulation of brain DA is not due to inhibition of MAO or COMT activity.

Nel topo geneticamente nano, che presenta una selettiva carenza di ormone somatotropo (GH) e nel ratto ipofisectomizzato, i livelli cerebrali di 1-triptofano (TP) e di acido 5-idrossi-indolacetico (5-HIAA) sono considerevolmente piu elevati che nei controlli, mentre i livelli cerebrali di serotonina (5-HT) sono praticamente immodificati. La somministrazione di GH riduce i livelli di TP e 5-HIAA e non modifica i livelli di 5-HT sia nel topo nano che nel ratto ipofisectomizzato. Questi risultati dimostrano che la carenza di GH e un fattore importante nel determinare le alterazioni del metabolismo della 5-HT presenti in entrambi i modelli sperimentali.

The distribution of noradrenaline between the residue and high-speed supernatant of adipose tissue homogenates in rats, guinea-pigs and cats has been examined. Most of the noradrenaline is in the supernatant fraction; little is in the 100,000 g fraction.

Recent investigations suggest a role for cyclic GMP in cerebellum as an important factor involved in the regulation of Purkinje cells activity. Since the formation of synapses in cerebellar Purkinje cell body of rat is complete only after the first 15 days of life, cGMP levels have been measured during development. Young adult and three day old rats have been used. The animals were killed by a beam of focused microwave radiation on the skull for 3 seconds. In the new born rat cerebellum the levels of cGMP are much lower than in adult animals. Harmaline, a potent and selective activator of the climbing fibers, a pathway which activates the onset of burst discharges in the Purkinje cells when injected in adult rats,induces, as it has been-previously shown, a 5 fold increase of the level of cerebellar cGMP. In contrast in new born rats harmaline does not increase cGMP concentrations. Moreover diazepam, which has been shown to decrease cerebellar cGMP levels in adult rats, does not appear to have such effect in new borns. On the other hand guanylate-cyclase activity is significantly higher in the new born rats in comparison with adults. Furthermore Harmaline injection in adult animals induces a stimulation of cerebellar guanylate-cyclase, as measured in vitro .

Summary The influence of clofibrate (CPIB) on free and total tryptophan concentrations in rat serum and on brain concentrations of tryptophan, 5-hydroxytryptamine (5HT), and 5-hydroxyindolacetic acid (5HIAA) has been established. A single dose of CPIB administered orally caused a pronounced fall of total tryptophan, and a significant increase of free tryptophan in serum. Under the same experimental condition increases of brain tryptophan and 5HIAA concentrations were observed, with no change in brain 5HT. Similar modifications were observed after repeated administrations of the drug. From these results it may be inferred that CPIB increases brain 5HT synthesis by displacement of protein bound tryptophan in serum and thus by increasing in brain the availability of the substrate to tryptophan-hydroxylase.

The effect of clofibrate on free and bound tryptophan levels was tested in 8 volunteers, 5 of whom were hospitalised. Comparing the effects of the drug, administered for 5 days, with those of a placebo, given for 5 further days, after an interval of 2 days, it was observed that clofibrate lowered total plasma tryptophan by 50–70% in all subjects. The decrease is in the bound fraction and probably reflects a displacement due to the high protein binding affinity of the drug. At the same time plasma free tryptophan values increase significantly. These data confirm our previous observations in the rat, demonstrating a decrease of bound plasma tryptophan and an increase of brain tryptophan and 5-HIAA levels, and supporting the hypothesis that clofibrate increased the availability of tryptophan to brain tryptophan hydroxylase, thus stimulating serotonin synthesis.

— Gamma-hydroxybutyrate administration produces a marked selective increase of brain dopamine in different animal species. Following γ-hydroxybutyrate administration, dopamine accumulated in the basal ganglia of the rat and in the caudate nucleus of the rabbit at a rate which greatly exceeded the normal synthesis rate of the amine in these species. Dopamine accumulation was prevented by α-methyltyrosine. These data indicate that γ-hydroxybutyrate stimulates dopamine synthesis. In addition, γ-hydroxybutyrate increased the homovanillic acid level in the rat basal ganglia to a maximum of about 300 per cent of the normal level indicating that γ-hydroxybutyrate inhibits neither monoamine oxidase nor catechol O-methyltransferase in vivo. The possible mechanisms of dopamine accumulation following γ-hydroxybutyrate administration are discussed.

THERE is some doubt about the role of brain serotonin in aggression. In mice made aggressive by prolonged isolation, there is a decrease in brain serotonin turnover1, while increased aggressiveness has been noted in cats2 and rats3 given p-chlorophenylalanine (PCPA), which inhibits serotonin synthesis4, although the experiments with cats2 were not confirmed later5. Dominguez and Longo6 reported that PCPA attenuates irritability and viciousness in rats with septal lesions, and Welch and Welch7 observed decreased aggressiveness in isolated mice given PCPA. The explanation for these contradictory results may be that different models of aggression are not mediated through the same areas of the brain or by the same biochemical mechanisms.