Long-term behavioral effects of neonatal blockade of gastrin-releasing peptide receptors in rats: similarities to autism spectrum disorders.
Gastrin releasing peptide, the mammalian counterpart of the amphibian peptide, bombesin, has been increasingly implicated in regulating normal brain function as well as in the pathogenesis of psychiatric and/or neurodevelopmental disorders. We have previously shown that the neonatal blockade of the gastrin-releasing peptide receptor (GRPr) in rats produces long-lasting consequences during central nervous system development that are commonly observed in neurodevelopmental disorders such as autism spectrum disorders. The present investigation assessed in further detail, long-term behavioral effects of neonatal GRPr blockade. During postnatal days 1-10, male Wistar rat pups (n=5-10/litter) were injected (subcutaneously) with the GRPr antagonist, RC-3095 (1 mg/kg), or a vehicle (control), twice daily. Following the drug treatment regimen, several behaviors were assessed (starting on postnatal day 14) including specific social behaviors (namely, group huddling characteristics, social interaction, and social approach), restrictive/repetitive and stereotyped behaviors (y-maze, repetitive novel object contact task, observation for stereotypies) and anxiety/fear-related responses (open field, elevated plus maze and contextual fear conditioning). Rats treated neonatally with RC-3095 showed reduced sociability, restrictive interests, motor stereotypies and enhanced learned fear response compared to the controls (vehicle-treated rats). These behavioral abnormalities are consistent with those observed in autism spectrum disorders and provide further evidence that neonatal blockade of GRPr could potentially serve as a useful model to gain a better understanding of the underlying neurodevelopmental disruptions contributing to the expression of autism-relevant phenotypes.
School of Psychology, University of Ottawa, Ottawa, ON K1N 6N5, Canada; Department of Psychiatry, University of Ottawa, Ottawa, ON K1N 6N5, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada; University of Ottawa, Institute of Mental Health Research, Ottawa, ON, K1Z 7K4, Canada. Electronic address: merali@uottawa.ca.
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Merali
University of Ottawa, Institute of Mental Health Research, Ottawa, ON, K1Z 7K4, Canada; Neurobiology and Developmental Biology Laboratory, Pontifical Catholic University, Porto Alegre, 90619-900, Brazil.
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Presti-Torres
School of Psychology, University of Ottawa, Ottawa, ON K1N 6N5, Canada; University of Ottawa, Institute of Mental Health Research, Ottawa, ON, K1Z 7K4, Canada.
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Mackay
School of Psychology, University of Ottawa, Ottawa, ON K1N 6N5, Canada; University of Ottawa, Institute of Mental Health Research, Ottawa, ON, K1Z 7K4, Canada.
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Johnstone
University of Ottawa, Institute of Mental Health Research, Ottawa, ON, K1Z 7K4, Canada.
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Du
School of Psychology, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
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St-Jean
School of Psychology, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
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Levesque
School of Psychology, University of Ottawa, Ottawa, ON K1N 6N5, Canada; University of Ottawa, Institute of Mental Health Research, Ottawa, ON, K1Z 7K4, Canada.
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Kent
Department of Internal Medicine, School of Medicine, Federal University of Rio Grande do Sul, 90035-003, Porto Alegre, RS, Brazil; Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003, Porto Alegre, RS, Brazil; National Institute for Translational Medicine (INCT-TM), 90035-003, Porto Alegre, RS, Brazil.
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Schwartsmann
Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003, Porto Alegre, RS, Brazil; National Institute for Translational Medicine (INCT-TM), 90035-003, Porto Alegre, RS, Brazil; Laboratory of Neuropharmacology and Neural Tumor Biology, Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, 90050-170, Porto Alegre, RS, Brazil.
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Roesler
Neurobiology and Developmental Biology Laboratory, Pontifical Catholic University, Porto Alegre, 90619-900, Brazil; National Institute for Translational Medicine (INCT-TM), 90035-003, Porto Alegre, RS, Brazil.
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Schroder
Institute of Neuroscience, Carleton University, Ottawa, ON, K1S 5B6, Canada; University of Ottawa, Institute of Mental Health Research, Ottawa, ON, K1Z 7K4, Canada.
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Anisman
D000375:Aging / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D001007:Anxiety / Q000139:chemically induced / Q000503:physiopathology; D001835:Body Weight / Q000187:drug effects; D001839:Bombesin / Q000031:analogs & derivatives / Q000494:pharmacology; D002491:Central Nervous System Agents / Q000494:pharmacology; D002659:Child Development Disorders, Pervasive / Q000503:physiopathology; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005239:Fear / Q000187:drug effects* / Q000502:physiology; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012919:Social Behavior; D013239:Stereotyped Behavior / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
D002491:Central Nervous System Agents; D010446:Peptide Fragments; D018004:Receptors, Bombesin; C071363:bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-; D001839:Bombesin
Autism spectrum disorder; Gastrin-releasing peptide receptor; Learned fear; RC-3095; Restrictive behavior; Social interaction