Pharmacological characterization of social isolation-induced hyperactivity

Fabricius, Katrine; Helboe, Lone; Fink-Jensen, Anders; Wörtwein, Gitta; Steiniger‐Brach, Björn

doi:10.1007/s00213-010-2128-9

Cited by 35 publications

(21 citation statements)

References 45 publications

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“…Despite there being no overall significant effect of lamotrigine on locomotor activity [F (2,31) = 2.985, p = 0.065], there was a significant housing x drug interaction [F (1,31) = 5.501, p = 0.025] over the 60min session, reflecting a reduction in activity due to lamotrigine treatment in the isolation-reared animals only (Figure 1A). Furthermore, two-way ANOVA of total activity during the first 30min (where activity differences were most marked, as often found in isolation studies; Bianchi et al, 2006; Fabricius et al, 2010; McIntosh et al, 2013) revealed a significant rearing x drug interaction [F (1,32) = 6.719, p = 0.014], but no main effect of either rearing condition or drug treatment alone (Figure 1B). Of note, post hoc analysis confirmed there was a significant increase ( p < 0.05) in locomotion in PCP-SI-V compared to control V-GH-V rats, which was significantly reduced ( p < 0.05) by the highest dose of lamotrigine (PCP-SI-L15) compared to that in PCP-SI-V rats.…”

Section: Resultsmentioning

confidence: 53%

“…In this study, lamotrigine significantly reduced hyperactivity in PCP-SI rats placed in a novel arena, a potential index of positive symptoms of schizophrenia (Fone and Porkess, 2008; Fabricius et al, 2010), but had no effect in V-GH littermates. In previous studies, the novelty-induced hyperactivity seen in GluA1 AMPA subunit knockout mice was suppressed following a 28 day dietary administration of lamotrigine (Maksimovic et al, 2014).…”

Section: Discussionmentioning

confidence: 57%

“…In order to assess the exploratory response to a novel arena, which is recognized as a valid marker for positive symptoms sensitive to antipsychotic treatment (Fabricius et al, 2010; Jones et al, 2011; McIntosh et al, 2013), open field locomotor exploratory activity (LMA) was recorded in infrared activity chambers (clear Perspex boxes 39 x 23.5 x 24.5cm). Rats were assigned individual chambers crossed by infrared beams (Photobeam Activity System, San Diego Instruments) to measure horizontal ambulatory movements as number of beams broken in 10min bins for 1h (Bianchi et al, 2006; Jones et al, 2011).…”

Section: Methodsmentioning

confidence: 99%

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Down-Regulation of Hippocampal Genes Regulating Dopaminergic, GABAergic, and Glutamatergic Function Following Combined Neonatal Phencyclidine and Post-Weaning Social Isolation of Rats as a Neurodevelopmental Model for Schizophrenia

Gaskin

Toledo-Rodriguez

Alexander

et al. 2016

IJNPPY

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Background:Dysfunction of dopaminergic, GABAergic, and glutamatergic function underlies many core symptoms of schizophrenia. Combined neonatal injection of the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP), and post-weaning social isolation of rats produces a behavioral syndrome with translational relevance to several core symptoms of schizophrenia. This study uses DNA microarray to characterize alterations in hippocampal neurotransmitter-related gene expression and examines the ability of the sodium channel blocker, lamotrigine, to reverse behavioral changes in this model.Methods:Fifty-four male Lister-hooded rat pups either received phencyclidine (PCP, 10mg/kg, s.c.) on post-natal days (PND) 7, 9, and 11 before being weaned on PND 23 into separate cages (isolation; PCP-SI; n = 31) or received vehicle injection and group-housing (2–4 per cage; V-GH; n = 23) from weaning. The effect of lamotrigine on locomotor activity, novel object recognition, and prepulse inhibition of acoustic startle was examined (PND 60–75) and drug-free hippocampal gene expression on PND 70.Results:Acute lamotrigine (10–15mg/kg i.p.) reversed the hyperactivity and novel object recognition impairment induced by PCP-SI but had no effect on the prepulse inhibition deficit. Microarray revealed small but significant down-regulation of hippocampal genes involved in glutamate metabolism, dopamine neurotransmission, and GABA receptor signaling and in specific schizophrenia-linked genes, including parvalbumin (PVALB) and GAD67, in PCP-SI rats, which resemble changes reported in schizophrenia.Conclusions:Findings indicate that alterations in dopamine neurotransmission, glutamate metabolism, and GABA signaling may contribute to some of the behavioral deficits observed following PCP-SI, and that lamotrigine may have some utility as an adjunctive therapy to improve certain cognitive deficits symptoms in schizophrenia.

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Section: Resultsmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 57%

Section: Methodsmentioning

confidence: 99%

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Down-Regulation of Hippocampal Genes Regulating Dopaminergic, GABAergic, and Glutamatergic Function Following Combined Neonatal Phencyclidine and Post-Weaning Social Isolation of Rats as a Neurodevelopmental Model for Schizophrenia

Gaskin

Toledo-Rodriguez

Alexander

et al. 2016

IJNPPY

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“…Fabricius and colleagues (2011) compared locomotor activity in 45 cohort replications using aGH and aSI Lister hooded rats and showed that aSI subjects were hyperactive in 44 of these cohorts (Fabricius et al, 2011). This phenotype has also been reported in aSI Long–Evans (Butler et al, 2014a; Chappell et al, 2013) and Sprague Dawley (Ishikawa et al, 2014) strains.…”

Section: Hyperlocomotion and Response To Noveltymentioning

confidence: 99%

Adolescent Social Isolation as a Model of Heightened Vulnerability to Comorbid Alcoholism and Anxiety Disorders

Butler

Karkhanis

Jones

et al. 2016

Alcoholism Clin & Exp Res

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Individuals diagnosed with anxiety-related illnesses are at increased risk of developing alcoholism, exhibit a telescoped progression of this disease and fare worse in recovery, relative to alcoholics that do not suffer from a comorbid anxiety disorder. Similarly, preclinical evidence supports the notion that stress and anxiety represent major risk factors for the development of alcohol use disorder (AUD). Despite the importance of understanding the link between anxiety and alcoholism, much remains unknown about the neurobiological substrates underlying this relationship. One stumbling block has been the lack of animal models that reliably reproduce the spectrum of behaviors associated with increased vulnerability to these diseases. Here, we review the literature that has examined the behavioral and neurobiological outcomes of a simple rodent adolescent social isolation procedure and discuss its validity as a model of vulnerability to comorbid anxiety disorders and alcoholism. Recent studies have provided strong evidence that adolescent social isolation of male rats leads to the expression of a variety of behaviors linked with increased vulnerability to anxiety and/or AUD, including deficits in sensory gating and fear extinction, and increases in anxiety measures and ethanol drinking. Neurobiological studies are beginning to identify mesolimbic adaptations that may contribute to the behavioral phenotype engendered by this model. Some of these changes include increased excitability of ventral tegmental area dopamine neurons and pyramidal cells in the basolateral amygdala and significant alterations in baseline and stimulated catecholamine signaling. A growing body of evidence suggests that adolescent social isolation may represent a reliable rodent model of heightened vulnerability to anxiety disorders and alcoholism in male rats. These studies provide initial support for the face, construct, and predictive validity of this model and highlight its utility in identifying neurobiological adaptations associated with increased risk of developing these disorders.

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“…As other psychostimulants, such as cocaine, have been shown to have effects on the concentrations of DA D1-like and D2-like receptors in rats (Kleven et al, 1990; Unterwald et al, 1996), and monkeys (Beveridge et al, 2009; Nader et al, 2002), these two targets were chosen for examination. Additionally, because early rearing conditions profoundly alter the expression of locomotor (Bardo et al, 1995; Bowling et al, 1993; Fabricius et al, 2011; Hoffmann et al, 2009; Shao et al, 2009; Smith et al, 1997; Varty et al, 2000) and anxiety-like behaviors (Bickerdike et al, 1993; Chappell et al, 2013; Lodge and Lawrence, 2003; Lukkes et al, 2009; McCool and Chappell, 2009; Wright et al, 1991; Yorgason et al, 2013), we hypothesized that chronic MPH treatment would produce differential effects on the expression of these behaviors.…”

Section: Introductionmentioning

confidence: 99%

The effects of rearing environment and chronic methylphenidate administration on behavior and dopamine receptors in adolescent rats

et al. 2013

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Rearing young rodents in socially isolated or environmentally enriched conditions has been shown to affect numerous components of the dopamine system as well as behavior. Methylphenidate (MPH), a commonly used dopaminergic agent, may affect animals differently based on rearing environment. Here we examined the interaction between environment and chronic MPH treatment at clinically relevant doses, administered via osmotic minipump. Young Sprague Dawley rats (PND 21) were assigned to environmentally enriched, pair-housed, or socially isolated rearing conditions, and treated with either 0, 2, 4, or 8 mg/kg/day MPH for three weeks. At the end of the treatment period, animals were tested for locomotor activity and anxiety-like behavior. The densities of D1-like and D2-like receptors were measured in the striatum using in vitro receptor autoradiography. Locomotor activity and anxiety-like behavior were increased in isolated animals compared to pair-housed and enriched animals. The density of D1-like receptors was greater in isolated animals, but there were no differences between groups in D2-like receptor density. Finally, there were no effects of MPH administration on any reported measure. This study provides evidence for an effect of early rearing environment on the dopamine system and behavior, and also suggests that MPH administration may not have long-term consequences.

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Pharmacological characterization of social isolation-induced hyperactivity

Cited by 35 publications

References 45 publications

Down-Regulation of Hippocampal Genes Regulating Dopaminergic, GABAergic, and Glutamatergic Function Following Combined Neonatal Phencyclidine and Post-Weaning Social Isolation of Rats as a Neurodevelopmental Model for Schizophrenia

Down-Regulation of Hippocampal Genes Regulating Dopaminergic, GABAergic, and Glutamatergic Function Following Combined Neonatal Phencyclidine and Post-Weaning Social Isolation of Rats as a Neurodevelopmental Model for Schizophrenia

Adolescent Social Isolation as a Model of Heightened Vulnerability to Comorbid Alcoholism and Anxiety Disorders

The effects of rearing environment and chronic methylphenidate administration on behavior and dopamine receptors in adolescent rats

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