Effects of amitriptyline, risperidone, and nooclerin on the behavior of male and female rats in the valproate model of autism

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Abstract

BACKGROUND: Autism spectrum disorder is characterized by anxiety and stereotypical behaviors and is more commonly diagnosed in boys. Therefore, developing behavioral correction strategies for autism spectrum disorder with consideration of sex differences is especially relevant.

AIM: To assess the effects of amitriptyline, risperidone, and nooclerin on anxiety-like and stereotypical behaviors in male and female rats in the valproate model of autism.

MATERIAL AND METHODS: Anxiety-like and stereotypical behaviors were studied in 32 male and 32 female rats prenatally exposed to valproic acid and treated subcutaneously for 30 days with amitriptyline (4 mg/kg), risperidone (1 mg/kg), or nooclerin (20 mg/kg). Control groups included 8 males and 8 females. Behavioral testing included the elevated plus maze, extrapolative escape test, and marble burying test. Statistical analysis was performed using one-way ANOVA in GraphPad Prism 8.0.1.

RESULTS: In the elevated plus maze, rats in the autism model showed increased anxiety: time spent in the open arms decreased by 3.0-fold in females (p = 0.00001) and 1.9-fold in males (p = 0.00001); the number of open-arm entries decreased by 1.9-fold in females (p = 0.002) and 4.2-fold in males (p = 0.0001), compared with controls. In male rats, administration of amitriptyline and nooclerin reduced anxiety: time spent in the open arms increased by 3.7-fold (p = 0.001) and 3.9-fold (p = 0.0001), respectively, and the number of open-arm entries increased by 5.3-fold (p = 0.0001). In female rats, only nooclerin demonstrated an anxiolytic effect, with a 2.5-fold increase in the number of open-arm entries (p = 0.003). In the extrapolative escape test, female rats with autism exhibited increased anxiety, as evidenced by a 3.3-fold increase in jump duration (p = 0.0004) and a 2.3-fold increase in jump count (p = 0.004), compared with controls. All treatments normalized these parameters. Stereotypical behavior was observed in both sexes in the autism model, indicated by a 4.8-fold reduction in the number of untouched marbles in males (p = 0.00002) and a 4.2-fold reduction in females (p = 0.003), compared with controls. All treatments normalized this parameter.

CONCLUSION: Nooclerin showed anxiolytic effects in both male and female rats in the model of autism, whereas amitriptyline was effective only in males. Under high-stress conditions, anxiety developed only in females, and all tested drugs demonstrated anxiolytic effects.

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About the authors

Dmitry O. Nikitin

Kazan State Medical University

Email: richard4777@yandex.ru
ORCID iD: 0000-0001-5773-867X
SPIN-code: 3132-2628

Cand. Sci. (Med.), Assis., Depart. of Pharmacology

Russian Federation, 49 Butlerova st, Kazan, 420012

Elena V. Valeeva

Kazan State Medical University

Author for correspondence.
Email: vevaleeva@ya.ru
ORCID iD: 0000-0001-7080-3878
SPIN-code: 4670-8980

Cand. Sci. (Biol.), Res., Depart. of Mol. Gen., Central Research Lab.

Russian Federation, 49 Butlerova st, Kazan, 420012

Lubov S. Nikiforova

Kazan State Medical University

Email: nikiforova.liuba.99@mail.ru
ORCID iD: 0009-0005-1613-9749
SPIN-code: 3251-5206

doc. of clin. lab. diagnostics

Russian Federation, 49 Butlerova st, Kazan, 420012

Irina I. Semina

Kazan State Medical University

Email: seminai@mail.ru
ORCID iD: 0000-0003-3515-0845
SPIN-code: 4385-3650

MD, Dr. Sci. (Med.), prof., Depart. of Pharmacology, head of Central Research Lab.

Russian Federation, 49 Butlerova st, Kazan, 420012

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2. Fig. 1. Effects of amitriptyline (A), risperidone (P), and nooсlerine (H) on anxiety behaviour under stress (Duration of jumping period — a; Number of jumps — b) of male and female rats in the “Extrapolatory Escape” test. ВМА — valproate model of autism. *p <0.05 — differences with respect to the performance of the control group, **p <0.05 — differences with respect to the performance of the group in the VMA. +p <0.05 — differences between males and females.

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3. Fig. 2. Effect of amitriptyline (A), risperidone (R), and nooclerin (N) on the time in the “open arms” (a) and the number of entries into the “open arms” (b) in male and female rats in the elevated plus maze test. VMA, valproate-induced model of autism; OA, “open arm.” *р <0.05, differences compared to the control group; **р <0.05, differences compared to the VMA group; +р <0.05, differences between males and females.

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4. Fig. 3. Effect of amitriptyline (A), risperidone (R), nooclerin (N) on the severity of stereotyped behavior in male and female rats in the marble burying model. VMA, valproate-induced model of autism. *р < 0.05, differences compared to the control group; **р < 0.05, differences compared to the VMA group.

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