& Comparison of Trazodone, Diazepame and Dibenzepine Influences on Rat Brain Beta Endorphins Content Radivoj Jadrić Et Al.: Comparison of Trazodone, Diazepame and Dibenzepine Influences on Rat Brain Beta-endorphins Content

Th e aim of our study was to establish the extent of infl uence of diff erent psychotropic drugs to brain β-endorphins in experimental animals. Th e study was performed on al-bino Wistar rats (weight  g), treated with diff erent psychoactive drugs. RIA technique was employed for quantifi cation of brain β-endorphins. Brain β-endorphins were higher in experiment group treated with trazodone ( pg/g ± ,; X±SD), and dibenzepine (, pg/g ± ,), yet with lower brain content in rats treated with diazepame (, pg/g ± ,), compared to brain β-endorphins content of control group treated with saline solution (, NaCl) (, pg/g ± ,). Significant diff erences were obtained comparing brain β-endorphins of trazodone vs. diaze-pame treated animals, with diazepame group having lower values (p<,). Th is study showed diff erences in changes of rat brain β-endorphins contents when diff erent psy-choactive drugs are used. Th erefore, we consider that β-endorphins could be used for evaluation of eff ects of psychoactive drugs, as a useful parameter in therapy with these psycho pharmaceuticals.


Introduction
Investigations in the field of psycho pharmaceutical drugs gave us a lot of knowledge about their positive and side eff ects.Tricycle antidepressants were fi rst in use, expressing their effects as a supplement for primary role -inhibition of norepinephrin and serotonin uptake by the nervous ends.Th e research of relation between endorphins and psychiatric disorders began with fi ndings of enkephalin and opioid receptors located in mood-response areas of the brain (, ).Antipsychotics, also known as neuroleptics (dibenzepine, Figure .), are a heterogenous group of medications used to treat psychotic disorders such as schizophrenia, depression, dementia, and non-specific agitation.Antidepressants (trazodone, Figure .), given systemically, are widely used for the treatment of various chronic and neuropathic pain conditions in humans.Th ere are numerous antidepressant medications, which are specifi cally designed to mimic the eff ects of endorphins in the brain to make a depressed person feel better or cope with stressful situations.In animal studies, antidepressants exhibit analgesic properties in nociceptive, infl ammatory and neuropathic test systems, with outcomes depending on the specifi c agent, the particular test, the route of administration and the treatment method used.Anxiolytics are a group of medications used for treatment of anxiety disorders.Th e medications included in this group are benzodiazepines and buspirone.All benzodiazepines share the same three ring structure, but differ mainly in substitution on the heptagonal ring.Th ere are three established subgroups: ) -ketobenzodiazepines (diazepame, Figure .), ) -hidroxybenzodiazepines and ) triazolobenzodiazepines (, ).β-endorphins are cleaved from the prohormone proopiomelanocortin (POMC), which is a protein found in the pituitary gland and the brain.POMC undergoes cleavage to give way to a number of hormones, including melanocortins and the opiate peptides.β-endorphins, a class of opiate peptide, share a common N-terminal sequence, function as neuromodulators and are cleaved from C-terminus of the POMC protein.
When β-endorphins bind to their receptors in neural membranes, cyclic adenosine monophosphate (cAMP) levels in the neurons are reduced, and the conductance of voltage-gated Ca+ channels is decreased.Although β-endorphin is not known to cross the blood-brain barrier, levels of plasma β-endorphin-like immunoactivity may indirectly refl ect central opioid activity.Importantly, β-endorphins can infl uence neurogenesis and other hippocampal functions ().A vide range of techniques have been described, investigating various characteristics of human and rat specifi c antibodies.β-endorphins radioimmunoassays are widely performed following physical, emotional and environmental challenges in rat ().Endorphins serve as an analgesic (pain killing), anesthetic and cause dissociation, immobilization and loss of self.Th ey are released in shock, freeze, "fi ght or fl ight", trauma, physical pain and in all stress including psychological stress ().Th e aim of our study was to establish the extent of infl uence of diff erent psychotropic drugs to brain β-endorphins in experimental animals.

Results and Discussion
O Previous investigations showed that acute amitriptyline and clomipramine produce naloxone-reversible antinociception.Th is apparent opioid-like involvement was further investigated by measuring β-endorphin levels in the hypothalamus following acute and chronic treatment with these antidepressants.They demonstrated signifi cantly raised levels of β-endorphin.Th e support was provided for the suggestion that antidepressants activate opioid systems, through both a direct opioid receptor interaction and an indirect action through enhanced release of opioid peptides ().Desipramine and paroxetin, used in animal depression models, did not signifi cantly aff ect the extra cellular levels of β-endorphin in nucleus accumbens, but chronic antidepressant treatment did normalize serotonin-induced release of β-endorphin, as well as behavioral manifestation of depressive behavior ().Our data, presented by graphic (X±SD), show brain β-endorphins values after -day period of different drugs administration.Obtained values for each drug were compared to the other, and to those of control group treated with saline solution.Results after chronic treatment show increase of brain β-endorphins, as was described in other studies ().
Antidepressant trazodone produced strongest response in brain β-endorphins content ( pg/g ± ,).Those results were higher then those of control group (, pg/g ± ,).Also, content of brain β-endorphins was higher in trazodone treated rats, compared to changes obtained in rat brains after other drugs were used, yet significantly higher only compared to diazepame treated group (, pg/g ± ,; p<,).Dibenzepine produced higher β-endorphins concentration in rat brains (, pg/g ± ,) compared to values of diazepame treated rats and control rats, but without significance (Figure ).
We consider that all of these changes can be caused by differences in mechanism of triazolopyridine (trazodone), dibenzepine and benzodiazepine (diazepame) action on brain β-endorphins content.That points at possible differences in synthesis intensity of β-endorphins, degradation of brain β-endorphins and possible releasing into blood stream, caused by constant psychotropic drugs administration.
Limitations of this investigation are in fact that starting values (serum, cerebrospinal fluid) were not obtained for animals used for quantification of brain β-endorphins content.However, we consider our results of brain β-endorphins in treated animals as eligible, compared with values obtained for control group, and previous studies () showing that chronic treatment with diff erent drugs produced β-endorphins content changes in CNS, as was presented in our study.
RADIVOJ JADRIĆ ET AL.: COMPARISON OF TRAZODONE, DIAZEPAME AND DIBENZEPINE INFLUENCES ON RAT BRAIN BETA-ENDORPHINS CONTENTMaterial and MethodsAlbino Wistar rats, weight  g were used, divided in groups of .Ethical Committee of Faculty of Medicine, University of Sarajevo approved the experiment.
tion (SD) and standard error of the mean (SEM).Th e level of signifi cance was determined by use of Student's T test, with values p≤, considered as significant.
RADIVOJ JADRIĆ ET AL.: COMPARISON OF TRAZODONE, DIAZEPAME AND DIBENZEPINE INFLUENCES ON RAT BRAIN BETA-ENDORPHINS CONTENT