Social behavior represents an integral part of behavioral repertoire of rats particularly sensitive to pharmacological and environmental influences. The aim of the present study was to investigate whether early postnatal clonazepam (CZP) exposure can induce age-dependent changes related to expression of social behavior. The drug was administered from postnatal day (P) 7 until P11 at daily doses of 0.1, 0.5 and 1.0 mg/kg i.p. We designed three experiments to assess whether exposure to CZP affects social behavior in respect to the age of rats and the test circumstances, specifically their familiarity with test conditions during adolescence (P32), social behavior in juveniles and adolescents (P18-P42) and social behavior in a resident-intruder paradigm. The frequency and duration of a various patterns of social behavior related to play and social investigation not related to play were evaluated. The results showed that CZP postnatal exposure decreased social play behavior regardless of age and familiarity or unfamiliarity of experimental environment but did not affect the social investigation per se. When rats were confronted with an intruder in their home cages intense wrestling and inhibition of genital investigation were found. In conclusion, these findings show that short-term CZP postnatal exposure inhibits social play behavior and alters specific patterns of social behavior in an age and environment related manner.

Institute of Physiology Academy of Sciences of the Czech Republic Prague Czech Republic

Zobrazit více v PubMed

American Psychiatric Association. (1994). Diagnostic and Statistical Manual of Mental Disorders. Washington, DC: American Psychiatric Press

André M., Boutroy M. J., Dubruc C., Thenot J. P., Bianchetti G., Sola L., et al. (1986). Clonazepam pharmacokinetics and therapeutic efficacy in neonatal seizures. Eur. J. Clin. Pharmacol. 30, 585–589 10.1007/bf00542419 PubMed DOI

Auger A. P., Olesen K. M. (2009). Brain sex differences and the organisation of juvenile social play behaviour. J. Neuroendocrinol. 21, 519–525 10.1111/j.1365-2826.2009.01871.x PubMed DOI PMC

Avishai-Eliner S., Brunson K. L., Sandman C. A., Baram T. Z. (2002). Stressed-out, or in (utero)? Trends Neurosci. 25, 518–524 10.1016/s0166-2236(02)02241-5 PubMed DOI PMC

Bittigau P., Sifringer M., Genz K., Reith E., Pospischil D., Govindarajalu S., et al. (2002). Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc. Natl. Acad. Sci. U S A 99, 15089–15094 10.1073/pnas.222550499 PubMed DOI PMC

Blanchard R. J., Yudko E., Dulloog L., Blanchard D. C. (2001). Defense changes in stress nonresponsive subordinate males in a visible burrow system. Physiol. Behav. 72, 635–642 10.1016/s0031-9384(00)00449-2 PubMed DOI

Burgdorf J., Panksepp J. (2006). The neurobiology of positive emotions. Neurosci. Biobehav. Rev. 30, 173–187 10.1016/j.neubiorev.2005.06.001 PubMed DOI

Clancy B., Finlay B. L., Darlington R. B., Anand K. J. (2007). Extrapolating brain development from experimental species to humans. Neurotoxicology 28, 931–937 10.1016/j.neuro.2007.01.014 PubMed DOI PMC

Darbra S., Pallarès M. (2009). Neonatal allopregnanolone increases novelty-directed locomotion and disrupts behavioural responses to GABA(A) receptor modulators in adulthood. Int. J. Dev. Neurosci. 27, 617–625 10.1016/j.ijdevneu.2009.05.008 PubMed DOI

Dobbing J., Sands J. (1979). Comparative aspects of the brain growth spurt. Early. Hum. Dev. 3, 79–83 10.1016/0378-3782(79)90022-7 PubMed DOI

Engelmann M., Hadicke J., Noack J. (2011). Testing declarative memory in laboratory rats and mice using the nonconditioned social discrimination procedure. Nat. Protoc. 6, 1152–1162 10.1038/nprot.2011.353 PubMed DOI

Engelmann M., Wotjak C. T., Landgraf R. (1995). Social discrimination procedure: an alternative method to investigate juvenile recognition abilities in rats. Physiol. Behav. 58, 315–321 10.1016/0031-9384(95)00053-l PubMed DOI

File S. E. (1986a). Behavioral changes persisting into adulthood after neonatal benzodiazepine administration in the rat. Neurobehav. Toxicol. Teratol. 8, 453–461 PubMed

File S. E. (1986b). Effects of neonatal administration of diazepam and lorazepam on performance of adolescent rats in tests of anxiety, aggression, learning and convulsions. Neurobehav. Toxicol. Teratol. 8, 301–306 PubMed

File S. E. (1986c). The effects of neonatal administration of clonazepam on passive avoidance and on social, aggressive and exploratory behavior of adolescent male rats. Neurobehav. Toxicol. Teratol. 8, 447–452 PubMed

File S. E. (1987). Diazepam and caffeine administration during the first week of life: changes in neonatal and adolescent behavior. Neurotoxicol. Teratol. 9, 9–16 10.1016/0892-0362(87)90063-8 PubMed DOI

File S. E., Seth P. (2003). A review of 25 years of the social interaction test. Eur. J. Pharmacol. 463, 35–53 10.1016/s0014-2999(03)01273-1 PubMed DOI

Forcelli P. A., Kozlowski R., Snyder C., Kondratyev A., Gale K. (2012). Effects of neonatal antiepileptic drug exposure on cognitive, emotional and motor function in adult rats. J. Pharmacol. Exp. Ther. 340, 558–566 10.1124/jpet.111.188862 PubMed DOI PMC

Fraňková S., Mikulecká A. (1990). Ontogeny of social behavior of pups of laboratory rats genetically selected for activity level. Act. Nerv. Super. (Praha) 32, 167–173 PubMed

Gai N., Grimm V. E. (1982). The effect of prenatal exposure to diazepam on aspects of postnatal development and behavior in rats. Psychopharmacology (Berl) 78, 225–229 10.1007/bf00428155 PubMed DOI

Garrett K. M., Saito N., Duman R. S., Abel M. S., Ashton R. A., Fujimori S., et al. (1990). Differential expression of gamma-aminobutyric acidA receptor subunits. Mol. Pharmacol. 37, 652–657 PubMed

Hol T., Van den Berg C. L., Van Ree J. M., Spruijt B. M. (1999). Isolation during the play period in infancy decreases adult social interactions in rats. Behav. Brain Res. 100, 91–97 10.1016/s0166-4328(98)00116-8 PubMed DOI

Homberg J. R., Schiepers O. J., Schoffelmeer A. N., Cuppen E., Vanderschuren L. J. (2007). Acute and constitutive increases in central serotonin levels reduce social play behaviour in peri-adolescent rats. Psychopharmacology (Berl) 195, 175–182 10.1007/s00213-007-0895-8 PubMed DOI PMC

Hoogerkamp A., Arends R. H., Bomers A. M., Mandema J. W., Voskuyl R. A., Danhof M. (1996). Pharmacokinetic/pharmacodynamic relationship of benzodiazepines in the direct cortical stimulation model of anticonvulsant effect. J. Pharmacol. Exp. Ther. 279, 803–812 PubMed

Hulin M. W., Amato R. J., Winsauer P. J. (2012). GABA(A) receptor modulation during adolescence alters adult ethanol intake and preference in rats. Alcohol. Clin. Exp. Res. 36, 223–233 10.1111/j.1530-0277.2011.01622.x PubMed DOI PMC

Kellogg C. K. (1988). Benzodiazepines: influence on the developing brain. Prog. Brain Res. 73, 207–228 10.1016/s0079-6123(08)60506-3 PubMed DOI

Koros E., Rosenbrock H., Birk G., Weiss C., Sams-Dodd F. (2007). The selective mGlu5 receptor antagonist MTEP, similar to NMDA receptor antagonists, induces social isolation in rats. Neuropsychopharmacology 32, 562–576 10.1038/sj.npp.1301133 PubMed DOI

Kubová H., Mareš P. (1989). Time course of the anticonvulsant action of clonazepam during ontogenesis in the rat. Arch. Int. Pharmacodyn. Ther. 298, 15–24 PubMed

Lader M. (1994). Biological processes in benzodiazepine dependence. Addiction 89, 1413–1418 10.1111/j.1360-0443.1994.tb03737.x PubMed DOI

Lalive A. L., Rudolph U., Luscher C., Tan K. R. (2011). Is there a way to curb benzodiazepine addiction? Swiss Med. Wkly. 141:w13277 10.4414/smw.2011.13277 PubMed DOI

Laviolette S. R., van der Kooy D. (2001). GABA(A) receptors in the ventral tegmental area control bidirectional reward signalling between dopaminergic and non-dopaminergic neural motivational systems. Eur. J. Neurosci. 13, 1009–1015 10.1046/j.1460-9568.2001.01458.x PubMed DOI

Leussis M. P., Bolivar V. J. (2006). Habituation in rodents: a review of behavior, neurobiology, and genetics. Neurosci. Biobehav. Rev. 30, 1045–1064 10.1016/j.neubiorev.2006.03.006 PubMed DOI

Lippa A. S., Beer B., Sano M. C., Vogel R. A., Meyerson L. R. (1981). Differential ontogeny of type 1 and type 2 benzodiazepine receptors. Life Sci. 28, 2343–2347 10.1016/0024-3205(81)90498-7 PubMed DOI

Meaney M., Stewart J. (1981). A descriptive study of social development in the rat (Rattus norvegicus). Anim. Behav. 29, 34–45 10.1016/s0003-3472(81)80149-2 DOI

Mikulecká A., Mareš P., Kubová H. (2011). Rebound increase in seizure susceptibility but not isolation-induced calls after single administration of clonazepam and Ro 19–8022 in infant rats. Epilepsy Behav. 20, 12–19 10.1016/j.yebeh.2010.10.021 PubMed DOI

Mikulecká A., Šubrt M., Stuchlík A., Kubová H. (2014). Consequences of early postnatal benzodiazepines exposure in rats. I. Cognitive-like behavior. Front. Behav. Neurosci. 8:101 10.3389/fnbeh.2014.00101 PubMed DOI PMC

Mitchell P. J., Redfern P. H. (2005). Animal models of depressive illness: the importance of chronic drug treatment. Curr. Pharm. Des. 11, 171–203 10.2174/1381612053382250 PubMed DOI

Mòdol L., Darbra S., Vallèe M., Pallarès M. (2013). Alteration of neonatal Allopregnanolone levels affects exploration, anxiety, aversive learning and adult behavioural response to intrahippocampal neurosteroids. Behav. Brain Res. 241, 96–104 10.1016/j.bbr.2012.11.043 PubMed DOI

Mooney S. M., Varlinskaya E. I. (2011). Acute prenatal exposure to ethanol and social behavior: effects of age, sex and timing of exposure. Behav. Brain Res. 216, 358–364 10.1016/j.bbr.2010.08.014 PubMed DOI PMC

Morishita S. (2009). Clonazepam as a therapeutic adjunct to improve the management of depression: a brief review. Hum. Psychopharmacol. 24, 191–198 10.1002/hup.1015 PubMed DOI

Panksepp J. (1981). The ontogeny of play in rats. Dev. Psychobiol. 14, 327–332 10.1002/dev.420140405 PubMed DOI

Pellis S. M., Mckenna M. (1995). What do rats find rewarding in play fighting—an analysis using drug-induced non-playful partners. Behav. Brain Res. 68, 65–73 10.1016/0166-4328(94)00161-8 PubMed DOI

Pellis S. M., Pellis V. C. (1987). Play fighting differs from serious fighting in both target of attack and tactics of fighting in the laboratory rat (Rattus norvegicus). Aggress. Behav. 13, 227–242 10.1002/1098-2337(1987)13:4<227::aid-ab2480130406>3.0.co;2-c DOI

Pellis S. M., Pellis V. C. (1990). Differential rates of attack, defense and counterattack during the developmental decrease in play fighting by male and female rats. Dev. Psychobiol. 23, 215–231 10.1002/dev.420230303 PubMed DOI

Pellis S. M., Pellis V. C. (1997). The prejuvenile onset of play fighting in laboratory rats (Rattus norvegicus). Dev. Psychobiol. 31, 193–205 10.1002/(sici)1098-2302(199711)31:3<193::aid-dev4>3.3.co;2-# PubMed DOI

Pellis S. M., Pellis V. C. (1998). Play fighting of rats in comparative perspective: a schema for neurobehavioral analyses. Neurosci. Biobehav. Rev. 23, 87–101 10.1016/s0149-7634(97)00071-7 PubMed DOI

Pellis S. M., Pellis V. C. (2006). “Play and the development of social engagement: a comparative perspective,” in The Development of Social Engagement: Neurobiological Perspectives, eds Marshall P. J., Fox N. A. (New York: Oxford University Press; ), 247–274

Primus R. J., Kellogg C. K. (1989). Pubertal-related changes influence the development of environment-related social interaction in the male rat. Dev. Psychobiol. 22, 633–643 10.1002/dev.420220608 PubMed DOI

Primus R. J., Kellogg C. K. (1990). Developmental influence of gonadal function on the anxiolytic effect of diazepam on environment-related social interaction in the male rat. Behav. Pharmacol. 1, 437–446 10.1097/00008877-199000150-00005 PubMed DOI

Raol Y. H., Zhang G., Budreck E. C., Brooks-Kayal A. R. (2005). Long-term effects of diazepam and phenobarbital treatment during development on GABA receptors, transporters and glutamic acid decarboxylase. Neuroscience 132, 399–407 10.1016/j.neuroscience.2005.01.005 PubMed DOI

Robinson D. L., Zitzman D. L., Smith K. J., Spear L. P. (2011). Fast dopamine release events in the nucleus accumbens of early adolescent rats. Neuroscience 176, 296–307 10.1016/j.neuroscience.2010.12.016 PubMed DOI PMC

Schneider M., Koch M. (2005). Deficient social and play behavior in juvenile and adult rats after neonatal cortical lesion: effects of chronic pubertal cannabinoid treatment. Neuropsychopharmacology 30, 944–957 10.1038/sj.npp.1300634 PubMed DOI

Schroeder H., Humbert A. C., Desor D., Nehlig A. (1997). Long-term consequences of neonatal exposure to diazepam on cerebral glucose utilization, learning, memory and anxiety. Brain Res. 766, 142–152 10.1016/s0006-8993(97)00538-6 PubMed DOI

Siviy S. M., Crawford C. A., Akopian G., Walsh J. P. (2011). Dysfunctional play and dopamine physiology in the Fischer 344 rat. Behav. Brain Res. 220, 294–304 10.1016/j.bbr.2011.02.009 PubMed DOI PMC

Siviy S. M., Panksepp J. (2011). In search of the neurobiological substrates for social playfulness in mammalian brains. Neurosci. Biobehav. Rev. 35, 1821–1830 10.1016/j.neubiorev.2011.03.006 PubMed DOI

Smart J. L., Dobbing J., Adlard B. P., Lynch A., Sands J. (1973). Vulnerability of developing brain: relative effects of growth restriction during the fetal and suckling periods on behavior and brain composition of adult rats. J. Nutr. 9, 1327–1338 PubMed

Terranova M. L., Cirulli F., Laviola G. (1999). Behavioral and hormonal effects of partner familiarity in periadolescent rat pairs upon novelty exposure. Psychoneuroendocrinology 24, 639–656 10.1016/s0306-4530(99)00019-0 PubMed DOI

Trezza V., Baarendse P. J., Vanderschuren L. J. (2009). Prosocial effects of nicotine and ethanol in adolescent rats through partially dissociable neurobehavioral mechanisms. Neuropsychopharmacology 34, 2560–2573 10.1038/npp.2009.85 PubMed DOI PMC

Trezza V., Baarendse P. J., Vanderschuren L. J. (2010). The pleasures of play: pharmacological insights into social reward mechanisms. Trends Pharmacol. Sci. 31, 463–469 10.1016/j.tips.2010.06.008 PubMed DOI PMC

Trezza V., Campolongo P., Vanderschuren L. J. (2011). Evaluating the rewarding nature of social interactions in laboratory animals. Dev. Cogn. Neurosci. 1, 444–458 10.1016/j.dcn.2011.05.007 PubMed DOI PMC

Tsoory M., Cohen H., Richter-Levin G. (2007). Juvenile stress induces a predisposition to either anxiety or depressive-like symptoms following stress in adulthood. Eur. Neuropsychopharmacol. 17, 245–256 10.1016/j.euroneuro.2006.06.007 PubMed DOI

Tucker J. C. (1985). Benzodiazepines and the developing rat: a critical review. Neurosci. Biobehav. Rev. 9, 101–111 10.1016/0149-7634(85)90036-3 PubMed DOI

Vanderschuren L. J., Niesink R. J., Spruijt B. M., van Ree J. M. (1995a). Effects of morphine on different aspects of social play in juvenile rats. Psychopharmacology (Berl) 117, 225–231 10.1007/bf02245191 PubMed DOI

Vanderschuren L. J., Niesink R. J., Spruijt B. M., van Ree J. M. (1995b). Influence of environmental factors on social play behavior of juvenile rats. Physiol. Behav. 58, 119–123 10.1016/0031-9384(94)00385-i PubMed DOI

Vanderschuren L. J., Niesink R. J., van Ree J. M. (1997). The neurobiology of social play behavior in rats. Neurosci. Biobehav. Rev. 21, 309–326 10.1016/s0149-7634(96)00020-6 PubMed DOI

Varlinskaya E. I., Spear L. P. (2002). Acute effects of ethanol on social behavior of adolescent and adult rats: role of familiarity of the test situation. Alcohol. Clin. Exp. Res. 26, 1502–1511 10.1111/j.1530-0277.2002.tb02449.x PubMed DOI

Varlinskaya E. I., Spear L. P. (2008). Social interactions in adolescent and adult Sprague-Dawley rats: impact of social deprivation and test context familiarity. Behav. Brain Res. 188, 398–405 10.1016/j.bbr.2007.11.024 PubMed DOI PMC

Varlinskaya E. I., Spear L. P., Spear N. E. (1999). Social behaviour and social motivation in adolescent rats: role of housing conditions and partner’s activity. Physiol. Behav. 67, 475–482 10.1016/s0031-9384(98)00285-6 PubMed DOI

Epilepsy Research in the Institute of Physiology of the Czech Academy of Sciences in Prague

The outcome of early life status epilepticus-lessons from laboratory animals

The GluN2B-Selective Antagonist Ro 25-6981 Is Effective against PTZ-Induced Seizures and Safe for Further Development in Infantile Rats

Neonatal Clonazepam Administration Induced Long-Lasting Changes in GABAA and GABAB Receptors

Neonatal Clonazepam Administration Induces Long-Lasting Changes in Glutamate Receptors

Cognitive deficits in schizophrenia and other neuropsychiatric disorders: convergence of preclinical and clinical evidence