O extrato etanólico da planta tóxica brasileira, Psedocalymma elegans apresenta efeitos estimulantes sobre o sistema nervoso central / The central nervous system stimulant effects of the ethanolic extract from the toxic Brazilian plant Pseudocalymma elegans

Os efeitos do extrato etanólico da planta tóxica Pseudocalymma elegans (Vell.) Kuhlm. sobre o comportamento de camundongos foi estudado. Camundongos que receberam injeçöes intraperitoneais (i.p.), nas doses de 1.6 a 3g/kg de peso corporal, apresentaram convulsöes e morreram com uma latência média de 8 min. A LD50 foi estimada em 1.8g/kg. Os camundongos que receberam 1g/kg (i.p.) do extrato apresentaram um maior número de "rearings" e um maior tempo de "freezing" do que o grupo controle, quando observados em um campo aberto 30 min após a injeçäo. Durante o tempo em que esses animais foram observados no campo aberto näo ocorreram alteraçöes significativas no número de cruzamentos, tempo de "grooming" e número de bolos fecais. Quando esses animais foram colocados em um labirinto em cruz elevado exploraram menos os braços abertos do labirinto que os animais controle: apresentaram uma menor porcentagem de entradas e uma menor porcentagem de tempo de permanência nos braços abertos do labirinto. Esses animais apresentaram também uma menor atividade locomotora medida de forma automatizada e nenhuma alteraçäo no tônus muscular, avaliado pelo tempo de permanência em um arame esticado. Os três primeiros testes sugerem que a administraçäo de doses moderadas do extrato desencadeia um efeito "ansiogênico" contrário ao observado com a administraçäo de ansiolíticos depressores do sistema nervoso central (SNC). Doses maiores do extrato provocam uma super-estimulaçäo do SNC com convulsöes que, eventualmente, podem contribuir para a letalidade do extrato

Modulation of the brain aversive system by GABAergic and serotonergic mechanisms.

Experiments performed in our laboratory, using electrical stimulation combined with microinjection of drugs in the dorsal midbrain central grey (CG) of the rat, evidenced that direct stimulation of GABA receptors with locally administered gamma-aminobutyric acid (GABA) or the GABAA receptor agonists 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol, isoguvacine and muscimol raised the aversive threshold, defined as the lowest electrical current intensity inducing flight or escape behaviour when applied to the dorsal CG. The GABAB receptor agonist baclofen was ineffective. Also, enhancement of endogenous GABA action through local injection of the benzodiazepines chlordiazepoxide and midazolam or of pentobarbital resulted in anti-aversive effects. Ro 15-1788 antagonized both chlordiazepoxide and midazolam, suggesting benzodiazepine receptor mediation. In contrast to pro-GABAergic drugs, microinjection of the GABA antagonists bicuculline and picrotoxin into the CG elicited flight behaviour, like the electrical stimulation. Similar experiments with drugs influencing serotonergic neurotransmission evidenced that intra-CG microinjection of serotonin (5-HT) or of the direct 5-HT receptor agonist 5-methoxy-N,N-dimethyltryptamine increased the aversive threshold. The anti-aversive effect of 5-HT was potentiated by the selective inhibitor of 5-HT neuronal uptake, zimelidine. Also, the latter drug increased the aversive threshold when given alone. The anti-aversive effect of 5-HT was antagonized by local pretreatment with either metergoline or ketanserin, the latter being a selective blocker of 5-HT2 receptors. In contrast to the GABA antagonists mentioned above, the 5-HT receptor blockers did not evoke aversive behaviour per se. Therefore, both GABAergic and serotonergic mechanisms are likely to play an inhibitory role in the dorsal CG integrating aversive behaviour. The former seem to act tonically, whereas 5-HT would act in a phasic way. The implications of these results for the pathophysiology and drug treatment of chronic anxiety, panic states and pain disorders are briefly discussed.

Modulation of the brain aversive system by GABAergic and serotonergic mechanisms.

Experiments performed in our laboratory, using electrical stimulation combined with microinjection of drugs in the dorsal midbrain central grey (CG) of the rat, evidenced that direct stimulation of GABA receptors with locally administered gamma-aminobutyric acid (GABA) or the GABAA receptor agonists 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol, isoguvacine and muscimol raised the aversive threshold, defined as the lowest electrical current intensity inducing flight or escape behaviour when applied to the dorsal CG. The GABAB receptor agonist baclofen was ineffective. Also, enhancement of endogenous GABA action through local injection of the benzodiazepines chlordiazepoxide and midazolam or of pentobarbital resulted in anti-aversive effects. Ro 15-1788 antagonized both chlordiazepoxide and midazolam, suggesting benzodiazepine receptor mediation. In contrast to pro-GABAergic drugs, microinjection of the GABA antagonists bicuculline and picrotoxin into the CG elicited flight behaviour, like the electrical stimulation. Similar experiments with drugs influencing serotonergic neurotransmission evidenced that intra-CG microinjection of serotonin (5-HT) or of the direct 5-HT receptor agonist 5-methoxy-N,N-dimethyltryptamine increased the aversive threshold. The anti-aversive effect of 5-HT was potentiated by the selective inhibitor of 5-HT neuronal uptake, zimelidine. Also, the latter drug increased the aversive threshold when given alone. The anti-aversive effect of 5-HT was antagonized by local pretreatment with either metergoline or ketanserin, the latter being a selective blocker of 5-HT2 receptors. In contrast to the GABA antagonists mentioned above, the 5-HT receptor blockers did not evoke aversive behaviour per se. Therefore, both GABAergic and serotonergic mechanisms are likely to play an inhibitory role in the dorsal CG integrating aversive behaviour.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-aversive role of serotonin in the dorsal periaqueductal grey matter.

Microinjection of 5, 10, and 20 nmol serotonin (5-HT) and of 0.5, 1, and 2 nmol 5-methoxy-N, N-dimethyltryptamine (5-MeODMT) into the dorsal midbrain of rats bearing chronically implanted chemitrodes raised the electrical threshold for inducing escape behaviour following stimulation of the dorsal periaqueductal grey matter (DPAG). Linear regressions of log dose against drug-induced increase in aversive threshold were obtained for 5-HT and 5-MeODMT. The 5-MeODMT dose-effect curve was steeper and lay to the left of the 5-HT dose-effect curve. Local pre-treatment with 10 nmol metergoline or ketanserin blocked the anti-aversive effect of 10 nmol 5-HT, whereas pre-treatment with 100 nmol zimelidine potentiated this effect of 5-HT. The same dose of zimelidine raised the aversive threshold when given alone. These results suggest that 5-HT plays an inhibitory role in the DPAG controlling aversion, probably mediated by 5-HT2 receptors.

Gender differences in open-field behavior as a function of age.

Male and female rats were observed in an open field at 30, 45, 60, 90, and 120 days of age. Thirty- and 45-day-old rats of both genders presented similar defecation, ambulation, and rearing scores. From 60 days on the male rats showed higher defecation scores and less ambulation and rearing than did the females. The gender difference observed in the adult rats reflected a decrease of defecation by females and a decrease of ambulation and rearing by males when compared to the earlier ages.

Brain dopamine and noradrenaline levels in rats submitted to four different aversive behavioral tests.

Rats were trained to perform shuttle responses to a buzzer in four different situations: Pseudoconditioning (buzzers and footshocks presented at random), classical conditioning (buzzers and footshocks paired on every trial), avoidance without stimulus pairing (buzzer--shock intervals varied at random, shocks contingent upon the nonemission of a shuttle response to the preceding buzzer), and standard two-way avoidance (buzzers paired to shocks, but the latter omitted every time there was a shuttle to the buzzer). Animals were killed immediately after the last trials and the noradrenaline and dopamine content of their hypothalamus, amygdala, caudate nucleus, and nucleus accumbens was determined. There were falls of dopamine content in the caudate and accumbens and falls of noradrenaline levels in all structures except the caudate after the pseudoconditioning test. Noradrenaline levels were normal, and dopamine levels were partially recovered, in the animals submitted to the other training situations. Thus learning factors (stimulus pairing and/or the avoidance contingency) offset the depleting influence of footshocks per se on both catecholamines in at least the structures studied.

Genetically selected winner and loser rats: what was selected?

Throughout the 6--12th generation, genetically selected winner and loser rats in the straight runway test, were studied, in relation to weight, open field behavior, behavioral responses to footshock and adrenocortical response following stimulation. The results showed that the Loser Runway Strain (LRS) when compared to the Winner Runway Strain (WRS), were (1) lighter in weight, (2) defecated less, ambulated more and showed higher frequency of rearing-up when submitted to an open field (3) defecated less and jumped more in reaction to footshock and (14) had a higher rise of corticosterone levels following handling or footshock. These differences between WRS--LRS are the same found between male-female rats. This conclusion does not favor the validity of the runway test as a social measure, and suggests that WSR--LRS were selected according to male-female characteristics instead of a winning or losing trait.