Monoterpenoids (thymol, carvacrol and S-(+)-linalool) with anesthetic activity in silver catfish (Rhamdia quelen): evaluation of acetylcholinesterase and GABAergic activity

This study evaluated the anesthetic potential of thymol and carvacrol, and their influence on acetylcholinesterase (AChE) activity in the muscle and brain of silver catfish (Rhamdia quelen). The AChE activity of S-(+)-linalool was also evaluated. We subsequently assessed the effects of thymol and S-(+)-linalool on the GABAergic system. Fish were exposed to thymol and carvacrol (25, 50, 75, and 100 mg/L) to evaluate time for anesthesia and recovery. Both compounds induced sedation at 25 mg/L and anesthesia with 50-100 mg/L. However, fish exposed to carvacrol presented strong muscle contractions and mortality. AChE activity was increased in the brain of fish at 50 mg/L carvacrol and 100 mg/L thymol, and decreased in the muscle at 100 mg/L carvacrol. S-(+)-linalool did not alter AChE activity. Anesthesia with thymol was reversed by exposure to picrotoxin (GABAA antagonist), similar to the positive control propofol, but was not reversed by flumazenil (antagonist of benzodiazepine binding site), as observed for the positive control diazepam. Picrotoxin did not reverse the effect of S-(+)-linalool. Thymol exposure at 50 mg/L is more suitable than carvacrol for anesthesia in silver catfish, because this concentration did not cause any mortality or interference with AChE activity. Thymol interacted with GABAA receptors, but not with the GABAA/benzodiazepine site. In contrast, S-(+)-linalool did not act in GABAA receptors in silver catfish.

The bradycardic and hypotensive responses to serotonin are reduced by activation of GABA A receptors in the nucleus tractus solitarius of awake rats

We investigated the effects of bilateral injections of the GABA receptor agonists muscimol (GABA A) and baclofen (GABA B) into the nucleus tractus solitarius (NTS) on the bradycardia and hypotension induced by iv serotonin injections (5-HT, 2 æg/rat) in awake male Holtzman rats. 5-HT was injected in rats with stainless steel cannulas implanted bilaterally in the NTS, before and 5, 15, and 60 min after bilateral injections of muscimol or baclofen into the NTS. The responses to 5-HT were tested before and after the injection of atropine methyl bromide. Muscimol (50 pmol/50 nl, N = 8) into the NTS increased basal mean arterial pressure (MAP) from 115 ± 4 to 144 ± 6 mmHg, did not change basal heart rate (HR) and reduced the bradycardia (-40 ± 14 and -73 ± 26 bpm at 5 and 15 min, respectively, vs -180 ± 20 bpm for the control) and hypotension (-11 ± 4 and -14 ± 4 mmHg, vs -40 ± 9 mmHg for the control) elicited by 5-HT. Baclofen (12.5 pmol/50 nl, N = 7) into the NTS also increased basal MAP, but did not change basal HR, bradycardia or hypotension in response to 5-HT injections. Atropine methyl bromide (1 mg/kg body weight) injected iv reduced the bradycardic and hypotensive responses to 5-HT injections. The stimulation of GABA A receptors in the NTS of awake rats elicits a significant increase in basal MAP and decreases the cardiac Bezold-Jarisch reflex responses to iv 5-HT injections.

Ethanol, GABA end epilepsy

Ethanol exerts its behavioral effects largely by interacting with receptors to brain neurotransmitters. The molecular mechanisms involving these interactions are still not well known since an ideal model for their study is currently unavailable. In addition, responses to alcohol may vary due to factors such as genetic predisposition, ethanol concentration consumed, and stimuli such as stress, socialization, etc. The chronc consumption of alcohol, similar to that of other drugs such as benzodiazepines and barbiturates, is linked to GABAerigc neurotransmission. GABA is the predominant inhibitory neurotransmitter in the brain. In context of substance abuse, these three drugs first cause a gratifying effect, later tolerance and finally, physical and psychological dependence. If cosumption is interrupted abruptly, a withdrawal syndrome occurs. The Alcohol Withdrawal Syndrome (AWS) is state of hyperexcitability characterized by anxiety, fear, muscular rigidity and tonic-clonic seizures with epileptiform-type charactermental epilepsy models such as "Kindling" or GABA Withdrawal Syndrome (GWS) models. A possible correlation between these models and AWS will allow for a better understanding of the cellular and molecular effects that alcohol exerts on the brain

Benzodiazepine receptor ligand influences on learning: an endogenous modulatory mechanism mediated by benzodiazepines possibly of alimentary origin

In rats pre-but not post-training ip administration of either flumazenil, a central benzodiazepine (BSD) receptor antagonist, or of n-butyl-B-carboline-carboxylate (BCCB), an inverse agonist, enhanced retention of inhibitory avoidance learning. Flumazenil vlocked the enhancing effect of BCCB, and the inhibitory effect of the BZD agonists clonazepam and diazepam also given pre-training. Post-training administration of these drugs had no effects. The peripheral BZD receptor agonist/chloride channel blocker Ro5-4864 had no effect on the inhibitory avoidance task when given ip prior to training, buth it caused enhancement when given immediately post-training either ip or icv. This effect was blocked by PK11195, a competitive antagonist of Ro5-4864. These results suggest that ther is an endogenous mechanism mediated by BZD agonists, which is sensitive to inverse agonists and that normally down-regulates the formation of memories through a mechanism involving GABA-A receptors and the corresponding chloride channels. The most likely agonists for the endogenous mechanism suggested are the diazepam-like BZDs found in brain whose origin is possibly alimentary. Levels of these BZDs in the cortex were found to sharply decrease after inhibitory acoidance training or mere exposure to the training apparatus.

Struture activity relationship in GABA receptors / Relación estructura actividad en receptores de GABA

Isoguvacine, isonipecotic acid, THIP and muscimol, agonist on GABA-receptors, were studied, looking for a structure-activity relationship. In this way, a conformational analysis was performed with an empirical atom-atom potential calculation method that was proved with success in previous works on biologically active substances. It has been assumed that hydration should eliminate electrostatic interactions and consequently, calculations are performed on molecules without charges. Muscimol, THIP, isoguvacine and isonipecotic acid are rigid structural analogues of GABA. The conformational analysis yield following result. Muscimol show a free rotation but, for different positions of the rotational group. a distance of 4,4 A- between CO and N was obtained. For the other compounds studied, twisted conformation was obtained, with an important population in each case. For these conformations a common pattem to all of them was found: adistance of about 4,4 A- betweeb the CO and N groups. This distance is found in partially folded (gauche-trans) conformations of GABA, with a 50% of the whole population. Then, we assumed that partially folded conformations, with a distance between potentially active sites of 4,4 A- may be important for the recognition at the BABA-receptors

Fisiopatologia da síndrome do pânico / Physiopathology of panic syndrome

Qualquer pessoa pode ter um ataque de pânico, dependendo das condiçöes e circunstâncias do momento. Entretanto, a repetiçäo de ataques de pânico resulta em um conjunto de sintomas, emoçöes e alteraçöes de comportamento, denominado síndrome do pânico. Sintomas semelhantes aos dos ataques de pânico ocorrem em diversas doenças e síndromes médicas. Essas porém näo têm papel etiopatogênico nestes quadros. A fisiopatologia do pânico é concebida como uma ativaçäo intermitente, ictal, dos sistemas de reaçäo e defesa do sistema nervoso central, resultando em alerta central e autonômico generalizado. As principais hipóteses sobre a patogenia destes quadros (catecolaminas circulantes, sistema GABA/benzodiazepínicos, hiperatividade noradrenérgica central, lacto/"reddox" intraneuronal e supersensibilidade 5-HT) säo analisadas criticamente. A síndrome do pânico parece decorrer de uma baixa de limiar para esses ataques. Fatores emocionais, ambientais e "situacionais", provavelmente interagindo com uma disfunçäo biológica básica, determinam o momento da eclosäo das crises e sua progressäo para a síndrome do pânico