Thorat V. M, Khanwelkar C. C, Matule S. M , Salve P. S, Surle-Patil S. A, Sadanandan S. Effect of Duloxetine Pretreatment on 5-HTP and Dexfenfluramine Induced Behaviours in Albino Rats. Biomed Pharmacol J 2019;12(3).

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Manuscript received on :10/06/2019
Manuscript accepted on :29/08/2019
Published online on: 12-09-2019

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Plagiarism Check: Yes
Reviewed by: Dr. Hiren B. Soni
Second Review by: M Mohan Varma
Final Approval by: Dr. Beatrice O. Ondondo

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Vandana Milind Thorat, Chitra C Khanwelkar, Somnath Mallikarjun Matule , Pratibha Satish Salve, Smita Ajit Surle-Patil and Seshla Sadanandan

Department of Pharmacology, Krishna Institute of Medical Sciences Karad.

Corresponding Author E-mail: vmthorat@yahoo.co.in

DOI : https://dx.doi.org/10.13005/bpj/1762

Abstract

Activation of central brain serotonergic receptors viz 5-HT_1A and 5-HT_2A by serotonin (5-HT) induces the 5-HT behavioural syndrome in rats. 5-HTP and dexfenfluramine produce 5-HT mediated behaviours. We have carried out the experiment with the aim to study the effect of duloxetine pretreatment on 5-hydroxytryptophan and dexfenfluramine induced behaviours in albino rats. Pre-treatment with 20 mg/kg duloxetine, a SNRI was found to potentiate 75 mg/kg 5-HTP mediated behavioural syndrome. However, 5, 10 and 20 mg/kg duloxetine had decreased the intensity of the behavioral syndrome produced by 10 mg/kg dexfenfluramine significantly. Duloxetine at 5, 10 and 20 mg/kg had produced inhibition of serotonin transporter (SERT) and inhibited dexfenfluramine uptake which had significantly antagonised its behavioural syndrome. Duloxetine at 5 and 10 mg/kg did not affect 5-HTP induced behavioral syndrome significantly where as 20 mg/kg duloxetine did significantly potentiate 5-HTP induced behavioral syndrome. This indicates 20 mg/kg dose of duloxetine blocks neuronal reuptake of 5-HT by blocking SERT and effectively increase its concentration to greater level in the synaptic gap which causes synergistic stimulation of the central postsynaptic 5-HT_1A and 5-HT_2A receptors and potentiation of 5-HTP behavioral syndrome.

Keywords

Behavioural Syndrome; Duloxetine; Dexfenfluramine; 5-Htp

Introduction

The stimulation of central brain serotonergic receptors viz 5-HT_1A and 5-HT_2A  , induces the serotonergic behaviours in rats characterized by lateral head weaving, forepaw treading, hind limb abduction, flat body posture, straub tail and wet-dog shakes^1,2,3. This serotonergic behaviours can be induced by drugs like 5-HT precursors viz tryptophan, 5-hydroxytryptophan ^4,5,6, 5-HT releasers like dexfenfluramine, p-chloroamphetamine (PCA) which selectively release neuronal 5-HT^7,8,9 and 5-HT receptor agonists^10,11,12  which stimulate 5-HT_1A and 5-HT_2A receptors. This behavioural syndrome induced by 5-HT has been scored by different methods on the basis of rating scales for its components^3,11,12,13.

This study has investigated the behavioural effects of 5-HTP and dexfenfluramine in rats pretreated with different doses of duloxetine and scored by scoring method of Sloviter et al³.

Materials and Methods

Animals

Male and female albino rats weighing 100-200 gm were used for experiments. Animals used for the experiments were bred in Central Animal House of the Institute. The animals were kept under standard conditions, maintained on a 12 hr light/dark cycle and they were given food and water ad libitum till the time of experimentation. The rats were brought to the experimental area at least 1 hr before the experimentation. Experimental design consisted of 8 groups of fresh rats ( n = 6 in each group). All observations were made blind with respect to the treatments used. The experimental protocol was reviewed and approved by the Institutional Animal Ethics Committee and carried according to the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) guidelines

Drugs

Duloxetine (Macleod), dexfenfluramine hydrochloride (Wockhardt), 5 – hydroxytryptophan (Sigma) were used in pure powder form. Fresh drug solutions were prepared by dissolving drug in distilled water (DW). Drugs were injected intraperitoneally and injection volume was 2 ml/kg body weight. Dose selection was done on the basis of literature and past studies carried out in our department.

Effect of Duloxetine Pretreatment on Behavioral Syndrome Induced by  5-HTP and Dexfenfluramine (DEX) In Rats.

Animals were placed separately in perspex cage. They were individually observed as per the method of Sloviter et al³ for 1 min, once after every 5 min, from 10 to 125 min timing after injection of 5-HTP and DEX for 20 scoring periods. Serotonergic behaviours observed were head and whole body shakes, reciprocal forepaw treading, lateral head weaving, flat body posture and hind limb abduction. Animals were scored separately (0 or 1) in each of the twenty intervals for 1 min observation period. Total score of each animal in the group for every scoring period was taken and the mean value of the group calculated. Control group (DW 2 ml/kg i.p.) and test group ( duloxetine 5,10,20 mg/kg) received the drug one hour before receiving 5-HTP/DEX.

Effect of Duloxetine pretreatment on 5-Hydroxytryptophan Induced Behaviour in Rats.

Effect of Duloxetine pretreatment on Dexfenfluramine Induced Behaviour in Rats.

Data Analysis

Data was analysed by using Graph pad instat software. Non-parametric ANOVA,

Kruskal Wallis test followed by post hoc Dunn’s multiple comparison test was used .

p < 0.05  was considered  statistically significant

Results                                                                                     

Effect of Duloxetine pretreatment on 5-HTP induced Behavioral Syndrome in Rats

As per table 1, 5-HTP treated control group rats showed the 5HT_1A and 5HT_2A receptor mediated behavioral syndrome. Pretreatment with 20 mg/kg duloxetine potentiated the behavioral syndrome intensity induced by 5-HTP (75 mg/kg) which is statistically significant.  Pretreatment with 5 & 10 mg/kg did not influence behavioural syndrome induced intensity by 5-HTP (75 mg/kg).

Table 1: Effect of Duloxetine pretreatment on 5-HTP Induced Behaviour in Rats.