Neuropharmacology Poster Session
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Introduction
The better known neuroleptic drugs as major tranquillizers are chemically related to the phenothiazines (chlorpromazine) or to the butyrophenones (haloperidol). They tend to reduce aggressive, assaultive, combative ,destructive behavior ,inhibit panic, fear, and hostility, realive emotional tension,excitement and agitation.(Janssen,1965)
The neuroleptic therapy have been associated with undesirable effects including:excessive sedation, autonomic blockade, extrapyramidal effects, metabolic or endocrine effects,etc.The desiderable reason are to find some compounds without this effects, potential calcium channel blockers(CCB).
Also,in some psychoses the classic treatement is without desirable effects,and we try to study: How influence CCB this psychiatric disorders?
CCB,also know as calcium channel inhibitors or antagonists, inhibit calcium entry trough the calcium voltage- sensitive channels. This heterogenous class of compounds are very well study in cardiovascular therapy because they have been found to modulate heart and vascular activity(Ferrari,1994)
In panic, fear and emotional tension from anxiety the autonomic effects can be influence by CCB. From all this reason the present study investigates two distinct CCB(verapamil and nifedipine) as potential tranquillizer drugs.(Kostowski,1990).
Materials and Methods
Animals:
The experiments were performed on male Wistar rats (100-150) kept 6-8 per cage with free access to food, water ad libitum and natural day/night cycle. The experiments were performed in august always between 8-12 a.m.
Drugs:
The following drugs were used: Verapamil (leb)5-10 mg/kg weight ,(DL50=60mg/kg,i.p.),nifedipine (Terapia S.A.), 5-10 mg/kg i.p.(DL50=40,66mg/kg i.p.), propilenglicol solvent( Farmec S.A.),and the following agents specifically from each test: diazepam 0,25 mg/kg(DL50=0,25-1 mg/kg,i.p.), haloperidol 0,25-0,5 mg/kg (DL50=)
Tests:
-Open-field for motility and rearing behavior(lupu,Janssen)
-Disapear righting reflex in rats for muscle tonicity(Boissier)
- Shuttle- box - from learning
- Heckt aggressive test(heckt)-for aggressive behavior
The ability of the compounds to modify various pharmacological effects is further investigated. The doses of the compounds used were approximately 1/10-1/5 of the DL50 as determined in the previous test in administrated intraperitoneally(i.p.)
Statistics:
Microsoft Excel 1997 analysis
Results
In open field - motility was decreased by Verapamil 5 compared with control group (p = 0,05) and Diazepam-group that means an anxiolitic activity, higher than Diazepam. Also, Nifedipin 10 are the same effect. But Verapamil 10 (Ver10 mg) (p=0,1) and Nif-5 (p=0,22) have an anxiogen effect compared with control group.
At righting reflex our results show an decrease of the muscle tonus for haloperidol, Ver-5 and Nif-5, 10 (p=0,001 - 0,04). The average of time for the first 5 seconds show us an increase of the time for all the drugs used.
For Nifedipin we observe the same aggressive effect compared with solvent propylenglycol and control group. Verapamil have more aggressive effect compared to control group. That means Verapamil have an anxiogen effect wich increase aggressive state. The effect is unsignificant between both doses and uncomparable with Haloperidol.
In shuttle-box we saw the learning by a conditional negative reg\flex. The results are pozitive at Verapamil in both doses, in first day and after 5 days compared with control goup.
Discussion and Conclusion
In open field an reduce exploratory movements indicated low motility and increase of dejection indicated higher emotivity. These indicate axiolitic effect .
If we compared the results of diazepam and Propranolol raported to the control group we see p=0,3 and respectively p=0,1. That means nonsignificant values but the average gave us from Propranolol anxiogen action and from Diasepam tranquillizant action that corespond with references (keave).
From the emotions Ver-5 (p=0,06), Ver-10 (p=0,07) Prop. P=0,03 and Diazepam p=0,05. Probably Verapamil influence emotions but not enough compared with Diazepam and Propranolol. In the effects or another benzodiazepines we can say than exist an seduction and than tranquillizer effect. That is the reason why we used high doses of Verapamil and Nifedipin. Keane say that Diazepam was more active like anxiolitic but only at high doses. Also doses of CCB used was at cardiovascular doses and higher doses (Kostovski). Than cardiovascular effect because CNS effects depend on hematocerebral flow (bariera). Also it was a differences between the bilding sites if verapamil and nifedipin. Verpamil has inside binding site like diltiazem also, but Nifedipin has an outside binding site. Fulga obtein with Nifedipin anxiogen effect at high doses (1,6 mg/kg) at mouse and anxiolitic effect at low doses (0,1-0,4 mg/kg). We also obtein different effects depend on doses from the movements effect and we can say anxiogen effect at Nifedipin doses used by us (5-10 mg/kg).
That confirm our results on the relation dose-effect for Nifedipin (Fulga). The results was singnificant at 5 mg Nifedipin trough solvent Propylenglycol.
Openfield couldn't make the differences between the miorelaxant and tranquillizant effect. From this reason we used another test for miorelaxant effect - righting reflex.
The anxiolitic drugs give a disapear of righting reflex at rats. But the miorelaxant effect depend on heart frecquence and muscle tonus. At all the rats we have miorelaxant effect. The dose wich give an anxiolitic effect can be different from those with miorelaxant effect. CCB decrease heart frequence. In thisd case we could have miorelaxant effect with or without anxiolitic effect. If we want to separate this effect we make Heckt effect for anxiolitic effect.
By reviewing the effect induced by different classes of CNS - active drugs it was found that several componds coul be easily characterized through behavioral and neurological signs. However, other clinicaly useful compounds caused only few or uncharacteristic effects. It apparead necessary to integrate to initial screening in mice and rat with the study of drug interactions. The standard pharmacological methods use a variety of conditions, employing either in vitro or in vivo tests diferent animals species and wide ranges of dosages. We haven't a significant combative fight with Verapamil or Nifedipin compared with control group. But Haloperidol give us the significant combative aggressive reaction like major tranquillizer (Jansen). If we compared the aggressivity with anxiety state by the agitation, hostility, combative, excitement, Verapamil have an anxiogen effect, amplificated at higher doses. Nifedipin have no effect.
This aggressive state is induced by conditional reflex of footshock. At Verapamil the animals have a passive reaction (Heckt) without fight reaction (they cry).
CCB have been found in CNS, especially the limbic areas and the cortex (Kostovski). Hipocamp and the limbic areas have a significant role in afectivity - emotivity (Lupu). Both drugs can not atenuated stress in Heckt-test. In this test Verapamil was given in single doses or chronically. In both situation the results was the same.
The mechanism of action it is not clearly known. probably it is an interaction between calcium blockade entrance throght slow calcium channel, excitatory aminoacids channel, or K-channel calcium dependent (Lupu, Safta).
Ver-5 and Ver-10 inhance the learning process. The results are established only for Veerapamil becouse for Nifedipi (Fulga) and Flunarisine (Lupu) and nomodipine (Scriabine) we have the same results in the same condition. The mechanism of action is probably through slow voltage calcium channel.
CONCLUSIONS
1. The results obteined on the different tests can not be easily confronted for drawing the profiles of the compounds.
2. It is necessary more tests for the differences between anxiolitic/antidepressant/ miorelaxant effects.
3. It is very well know CCB inhance learning.
References
1.Boissier,J.R.,Simon,P-La reaction d'exploration chez la souris,Therapie,1962,17,1225-1232.
2.Boer, J.A.,colab-Panic disorders induced with CCK and pentagastrine.1998(internet)
3.Carminaty, C.M.-Archs.Int.Pharmacodyn.Ther. 1969,181,68
4.Danila Gh.,Cotrau M., Nechifor M.-Lexicon of toxicological dates, Ed.Med.,Bucharest,1984 .
5.Fulga, I.G.-Calcium channel antagonists influence trough some central nervous processes,1994 , abstract of doctorate theses.
6.Graeff.-Inhibitory avoidance task in rat,1998(internet)
7.Hect.K, Huller H.,Scheller W.-Zur Pharmakologie einer neuer Benzilsaurederivate,Acta biol.med.germ.,1963,Band 11,Seite 539-551
8.Imaizumi,M,Miyazaki,S,and colab-Pharmacological profile of the novel putative anxiolytic agent 1-NH2-5-Br-uracil,Arzneim.Forsch./Drug.Res.,1994,44,1,3,285-288
9.Keane,P.E.,Simiand,J,Moore,M,Biziere,K.-Tetrazepam:a benzodiazepine wich dissociates sedation from other benzodiazepine activities.Psychopharmacological profile in rodents.,J.Pharmacol.Experim.Therap.1998,245,2,692-698.
10.Kostowski,W,Wanda Dyr,Pucilowski,O.-Activity of diltiazem and nifedipine in some animal models of depression.,Pol.J.Pharmacol.Pharm,1990,42,121-127
11.Lupu,V,Dorofteiu,M.-The effect of flunarizine on emotivity, motility and learning ability in perinatally hipoxic rats,1996,Clujul-Medical veterinary,nr.5,40-44.
12.Safta L.,Cuparencu,B,and colab.Some behavioral changes induced by amantadine,Acta biol.med.germ.,1976,Band 35,229-233.
13.Safta L.,Cuparencu B.,-Some central nervous actions of centrophenoxine in anials.,Acta biol.med.germ.,1978,Band 37,1255-1259.
14.Scriabine A.,Schurman,T., Traber,T.-Pharmacological basis for the use of nimodipine in CNS disorders, The faseb J.,vol.3,1799-1806,1989.
15.Clara Morpurgo-A new design for the Sreening of CNS active drugs in mice,Drug Res.21,1971,1727-1734
16.Janssen,P.J.,Carlos,J.E.Niemegeers,K.H.L.Schellekens-Is it possible to predict the clinical effects of neuroleptic drugs(Major tranquillisers) from animal data?,Drug Res.,Arzneim.Forsch.15,104-117,1965.
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