L. Vargiu

Low doses of ethanol activate dopaminergic neurons in the ventral tegmental area.

In unanesthetized rats the intravenous administration of low doses of ethanol (0.125-0.5 g/kg) produced a dose-dependent increase (30-80%) in the firing rate of dopaminergic (DA) neurons in the Ventral Tegmental Area (VTA). In agreement with previous observations, a dose range between 0.5 and 2 g/mg of ethanol was needed to produce comparable stimulant responses in DA neurons of the Substantia Nigra Pars Compacta. However, in anesthetized rats, doses of ethanol up to 1 g/kg failed to activate VTA-DA neurons. The high sensitivity of VTA-DA neurons to ethanol activation suggests that they might be involved in the reinforcing properties of the drug.

Evidence for dopamine receptors mediating sedation in the mouse brain.

APOMORPHINE, a direct stimulant of dopamine (DA) receptors, and L-dopa, the direct precursor of DA, have a biphasic action on behaviour; in low doses they decrease motor activity, while in higher doses they cause hyper-motility and sterotypy1–3.

Free tryptophan in serum controls brain tryptophan level and serotonin synthesis

Abstract Tryptophan (Try) is the only aminoacid present in plasma bound to serum proteins. The administration of Try to rats increased free and total Try in serum. Changes in free Try were much more pronounced and longer lasting than in total Try. Brain Try and 5-hydroxyindoleacetic acid (5-HIAA) underwent changes, parallel and proportional to the changes in free Try in serum. Rats fasted for 24 hours had higher concentrations of free serum tryptophan, brain tryptophan and 5-HIAA than rats fed for 2 hours. In contrast, total serum tryptophan was lower in fasted than in fed rats. These results indicate that brain tryptophan and serotonin turnover are controlled by free serum tryptophan and that free serum tryptophan levels are independent from total serum tryptophan concentrations.

Selective increase of brain dopamine induced by gamma-hydroxybutyrate

Abstract Gamma-OH produces a marked and rapid increase in brain dopamine. Changes in brain norepinephrine and serotonin are much less pronunced. The increase in dopamine is limited to the areas of the extrapyramidal system. There is a temporal correlation between behavioural changes and dopamine increase induced by Gamma-OH. The mechanism of action of Gamma-OH in producing the dopamine rise is neither a MAO inhibition nor seems to be a stimulation of the dopamine synthesis.

SELECTIVE INCREASE OF BRAIN DOPAMINE SYNTHESIS BY SULPIRIDE

—Sulpiride (5–200 mg/kg) increases brain HVA and DOPAC levels, causes no change in dopamine concentration, does not interfere with the outflow of HVA from the CNS and enhances the disappearance of brain dopamine after inhibition of tyrosine hydroxylase. The compound influences neither 5‐HT nor NE metabolism. The central action of sulpiride differs from that of classic neuroleptics in that this drug stimulates dopamine turnover without producing catalepsy.

d(CH2)5Tyr(Me)-[Orn8]vasotocin, a potent oxytocin antagonist, antagonizes penile erection and yawning induced by oxytocin and apomorphine, but not by ACTH-(1-24).

Intraventricular (i.c.v.) injection of d(CH2)5-Tyr(Me)-[Orn8]vasotocin, a potent oxytocin antagonist, antagonized in a dose-dependent manner (10-100 ng) penile erection and yawning induced by the systemic injection of apomorphine (80 micrograms/kg s.c.) or by the i.c.v. injection of oxytocin (30 ng). In contrast, the oxytocin antagonist, even at the dose of 10 micrograms, did not modify penile erection and yawning induced by the i.c.v. injection of ACTH-(1-24). These results suggest that apomorphine, but not ACTH-(1-24), induce penile erection and yawning by releasing oxytocin in some brain area.

Increase of brain tryptophan and stimulation of serotonin synthesis by salicylate

Indirect evidence indicates that the rate‐limiting step in the synthesis of brain 5‐HT is the concentration of tryptophan in brain and not, as previously considered (Green and Sawyer, 1966), tryptophan hydroxylase. In fact this enzyme has a Km for its substrate much higher than the concentration of tryptophan normally present in the mammalian brain (Jequier, Lovenberg and Sjoerdsma, 1967; Jequier, Robinson, Lovesberg and Sjoerdsma, 1969; Mcgeer, Peters and Mcgeer, 1968). Tryptophan is the only amino acid circulating in plasma which is highly bound to serum proteins (Mcmenamy and Oncley, 1958). We have previously shown that the free fraction of serum tryptophan controls the concentration of brain tryptophan and, therefore, 5‐HT synthesis as well (Tagliamonte, Biggio and Gessa, 1971d; Gessa, Biggio and Tagliamonte, 1972). Salicylate has been shown to displace tryptophan from its protein binding in plasma and to raise the free tryptophan concentration (Mcarthur and Dawkins, 1969; Smith and Lakatos, 1971). These considerations prompted us to study the effect of salicylate on tryptophan concentrations and 5‐HT metabolism in brain.

Evidence for selective and long-lasting stimulation of “regulatory” dopamine-receptors by bromocriptine (CB 154)

SummaryBromocriptine, an ergot-derivate with DA-receptor stimulating properties in vivo, produces long-lasting hypomotility in mice not accustomed to the motility cage and decreases brain DOPAC and HVA without affecting brain DA. These effects are obtained with doses 25 times lower than those which produce hypermotility. The decrease of brain DOPAC is correlated to the hypomotility both on a dose- and on a time-basis.Potent neuroleptics as pimozide, benzperidol and droperidol, which are considered to be fairly specific DA-receptor blockers, antagonize the hypomotility and the decrease of brain DOPAC produced by bromocriptine. These effects are obtained with very low doses (0.05–0.3 mg/kg) of neuroleptics which per se do not affect motility or brain DOPAC. The maximal decrease of brain DOPAC and HVA produced by bromocriptine is similar to that produced by apomorphine and the combination of these drugs does not result in a further decrease of brain DOPAC or HVA. On the basis of these results it is postulated that bromocriptine decreases brain DA-turnover and produces hypomotility by acting on “regulatory” DA-receptors different from the post-synaptic ones of the “terminal” dopaminergic areas.

Effect of 1,4-butanediol and other butyric acid congeners on brain catecholamines.

Abstract 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.

Possible role of brain serotonin in the central effects of ketamine

Abstract Ketamine increased serotonin turnover in the rat brain. This effect persisted for several hours after the anaesthetic effect of ketamine had terminated. Pretreatment with para -chlorophenyl-alanine, an inhibitor of serotonin synthesis, or with methergoline, a serotonin receptor blocker, potentiated the anaesthetic and analgesic effect of ketamine.