Short- and long-term effects of risperidone on catalepsy sensitisation and acquisition of conditioned avoidance response: Adolescent vs adult rats
Graphical abstract
Introduction
Adolescence is a period spanning between 10 years and 19 years, and is a critical transition period from childhood to adulthood. During this period, several important changes occur, for example, growth spurt, rise in gonadal hormones and changes in behaviour [1]. More importantly, major maturation changes occur in several neural systems of the adolescent brain. Both longitudinal and cross-sectional studies have identified changes in cortical and subcortical brain structures in adolescent human brain (for example, see [2], [3], [4], [5], [6], [7]). Concurrent with these maturation changes, onset of most psychiatric disorders, such as schizophrenia and mood disorders, which are often considered to be neurodevelopmental disorders, occurs during adolescence [8], [9], [10]. Correspondingly, prescription of antipsychotic drugs (APDs) to treat such disorders and off-label use for behavioural symptoms in adolescents and children has increased dramatically over the past twenty years [11], [12], [13], [14], [15], [16], [17], [18]. However, effects of APDs on the adolescent brain are still poorly understood.
A period equivalent to human adolescence exists in rodents [19], [20], [21]. Therefore, adolescent neuropharmacological exposure can be modelled and examined in laboratory rodents under stringent conditions. Major maturational changes have been identified during rodent adolescence in terms of brain structures [22] and neurotransmitter systems, including dopaminergic and serotonergic systems (for example, see [23], [24], [25], [26]), as well as gamma-aminobutyric acid (GABA)-ergic [27] and endocannabinoid systems [28], [29]. Given these important neurotransmitter systems are targeted by APDs, the use of such agents in adolescence may produce long-term adverse effects.
Recent preclinical studies in rodents have started to identify the neurobiological consequences of adolescent APD treatment, in particular, long-lasting changes in behaviour and neurochemistry after a drug-free interval. For example, adolescent APD treatment has been reported to produce long-term behavioural changes in adulthood such as deficits in fear conditioning and acquisition of a delayed non-match to sample task [30], increased amphetamine reward behaviour [31], altered locomotion and anxiety/depression-related phenotypes [32] and sensitised suppression of previously acquired conditioned avoidance response (CAR) [33], [34], [35]. Adolescent treatment with olanzapine has also been reported to induce long-lasting neurochemical changes such as altered dopaminergic neurotransmission in the nucleus accumbens (NAc) [31], reduction in GABA and glutamate in the NAc [36] and arrested maturation of D2 receptor-mediated corticostriatal electrophysiological responses in the NAc [37]. Moreover, long-term alterations in dopaminergic receptors and tyrosine hydroxylase expression could also occur in region- and sex-dependent manner following treatment with aripiprazole, olanzapine and risperidone during childhood and adolescent period [38]. Long-lasting alterations in protein levels of the prefrontal cortex which are involved in mitochondrial and cytoskeletal functions and cellular metabolism, have also been observed with adolescent risperidone treatment [39].
In our own previous study, we have shown adolescent APD exposure produces long-term alterations in behaviour compared with adult exposure [40]. We chose risperidone for detailed examination given that this is the most commonly prescribed APD to adolescents and children internationally [12], [13], [16]. We identified long-lasting neurobiological changes such as sensitised suppression of previously acquired CAR and downregulation of serotonergic 5HT2A receptor expression in the NAc of risperidone-exposed adolescents but not adults. In addition, after 17 days of chronic risperidone, adolescent rats had less escape failures i.e. a failure to respond to both conditioned and unconditioned stimuli (CS and US), in our CAR paradigm compared to adults [40]. Escape failures induced by APDs in the CAR paradigm are not well-understood, but may reflect an increased cataleptic response which has been suggested as analogous to the well-described extrapyramidal side effects of APDs [41], [42]. Therefore, we now wish to address cataleptic responses directly in animals chronically exposed to risperidone at either adolescence or adulthood.
Like certain psychomimetic agents, APDs have also been hypothesized to induce behavioural sensitisation, i.e. intensification of a behavioural effect during repeated treatment and/or following a drug-free interval [43], [44]. Indeed, a number of studies have demonstrated APD-induced sensitization of the suppression of CAR and catalepsy. While APD-induced sensitisation in CAR suppression has been demonstrated in both adolescents (for example, see [33]) and adults (for example, see [45]), studies of catalepsy sensitisation have mostly utilized adult animals (for example, see [46], [47]). To the best of our knowledge, only a single study has examined catalepsy sensitization response in adolescents and adults, reporting that adolescents developed lower level of catalepsy sensitisation than adults during repeated treatment with haloperidol, but not clozapine [48]. While the findings of this study support our hypothesis that risperidone could induce lower catalepsy sensitization in adolescents compared with adults, no study to date has examined chronic treatment with this APD in adolescents and adults with respect to catalepsy sensitisation. Therefore, our first aim was to assess whether chronic risperidone treatment could induce differential short- and long-term catalepsy sensitisation in adolescents and adults.
Another important question is whether adolescent APD treatment can induce long-term deficits in cognitive performance. A recent preclinical study suggested that adolescent olanzapine treatment could impair the rate of learning in a delayed non-matched to sample task in adulthood [30]. While these data are suggestive of an adolescent APD exposure impairing later learning, it is still unclear whether this deficit was selective to adolescent treatment given a lack of comparison age group. Here we aimed to assess long-term effects of risperidone on cognition by examining an animal’s ability to acquire CAR after a lengthy drug-free interval following either adolescent or adult risperidone treatment. CAR is the gold-standard behavioural test used in the screening of novel compounds with APD potential [42], [49]. In addition, the ability to acquire a CAR is frequently investigated in studies of fear and anxiety (for example, see [50], [51]). Existing preclinical studies in rodents have investigated acquisition of the CAR in adults only during chronic treatment with risperidone [52], [53]. No study to date has examined long-term effect of adolescent risperidone treatment on first-time CAR learning after a drug-free interval. Therefore, our second aim was to assess whether chronic risperidone treatment could induce differential abilities in adolescents and adults to acquire a CAR. In addition, in all experiments we examined monoamine levels and gene expression of dopaminergic receptors and dopamine-metabolizing enzymes in the striatum and the NAc that might contribute to observed behavioural changes. We chose to examine the levels of dopamine receptors in the striatum given their dynamic remodelling during adolescence [54], [55] and given the reported roles of these receptors in catalepsy sensitisation [46].
Section snippets
Subjects
Male Sprague Dawley (SD) rats were used. Rats arrived at the animal facility either on postnatal day (PND) 28 (for adolescent cohort) or PND 70 (for adult cohort). Rats from the same drug and age groups were pair-housed in Macrolon cages (39 cm x 23.5 cm x 16 cm) with Sani chip bedding (Able Scientific) and wire lids in a temperature (21 ± 1 °C) and lighting (lights on at 6 am and off at 6 pm) controlled room. All rats were given ad libitum access to food and water throughout the whole experiment.
Short-term cataleptic responses
Cataleptic responses progressively increased in both adults and adolescents treated with risperidone across 17 days of treatment, indicating development of catalepsy sensitisation. This effect was not observed in saline-treated controls (Fig. 3a). In risperidone-treated animals, cataleptic response was apparently lower in adolescents compared with adults. Two-way repeated measures ANOVA revealed significant main effects of Day (F5,200 = 23.63), Drug (F1,40 = 96.64), Day x Drug interaction (F5,200 =
Discussion
There were three major experimental findings from this study. First, repeated exposure to risperidone induced catalepsy sensitisation independent of the age of exposure. However, in the adolescent exposed animals it would appear that the degree of sensitisation was inversely related to dopamine turnover. Second, catalepsy sensitisation was long-lasting because re-exposure to a challenge dose of risperidone showed dramatic sensitisation even after 36-day washout. This is again independent of age
Conclusions
To conclude, the current study examined and compared short- and long-term neurobiological outcomes of chronic risperidone treatment in adolescent and adult rats. We show that the same regimen of chronic risperidone treatment could induce catalepsy sensitisation in both adolescents and adults not only during chronic treatment but also after a lengthy drug-free interval. We also show that this risperidone treatment could induce long-term impairment in CAR acquisition selectively in rats treated
Conflict of interest
None.
Acknowledgements
Financial support was provided by National Health and Medical Research Council (NHMRC) Australia grant APP1042259 to DE and TB and The University of Queensland International PhD scholarship to AAKM. The funding organizations did not have any roles in the design and conduct of the study, interpretation of data or writing of the manuscript. The authors would like to thank Mrs. Suzy Alexander for her support with experimental logistics.
References (109)
- et al.
Structural MRI of pediatric brain Development: what have we learned and where are we going?
Neuron
(2010) The influence of puberty on subcortical brain development
Neuroimage
(2014)Changes in the adolescent brain and the pathophysiology of psychotic disorders
Lancet Psychiatry
(2014)- et al.
Adolescence as a sensitive period of brain development
Trends Cogn. Sci.
(2015) Ensuring the safety of children treated with second-generation antipsychotics
The Science and Ethics of Antipsychotic Use in Children
(2015)Trends in prescribing of psychotropic medications for inpatient adolescents in Israel: a 10 years retrospective analysis
Eur. Psychiatry
(2011)The adolescent brain and age-related behavioral manifestations
Neurosci. Biobehav. Rev.
(2000)Assessment of adolescent neurotoxicity: rationale and methodological considerations
Neurotoxicol. Teratol.
(2007)Brain maturation of the adolescent rat cortex and striatum: changes in volume and myelination
Neuroimage
(2014)- et al.
Long-term impacts of adolescent risperidone treatment on behavioral responsiveness to olanzapine and clozapine in adulthood
Prog. Neuro-Psychopharmacol. Biol. Psychiatry
(2014)
Differential effects of intermittent versus continuous haloperidol treatment throughout adolescence on haloperidol sensitization and social behavior in adulthood
Prog. Neuro-Psychopharmacol. Biol. Psychiatry
Olanzapine antipsychotic treatment of adolescent rats causes long term changes in glutamate and GABA levels in the nucleus accumbens
Schizophr. Res.
Risperidone induces long-lasting changes in the conditioned avoidance response and accumbal gene expression selectively in animals treated as adolescents
Neuropharmacology
Time-dependence of risperidone and asenapine sensitization and associated D2 receptor mechanism
Behav. Brain Res.
The role of NMDA and AMPA/Kainate receptors in the consolidation of catalepsy sensitization
Behav. Brain Res.
Evaluation of age and sex differences in locomotion and catalepsy during repeated administration of haloperidol and clozapine in adolescent and adult rats
Pharmacol. Res.
The conditioned avoidance response test re-evaluated: is it a sensitive test for the detection of potentially atypical antipsychotics?
Neurosci. Biobehav. Rev.
Sidman instrumental avoidance initially depends on lateral and basal amygdala and is constrained by central amygdala-mediated pavlovian processes
Biol. Psychiatry
Effects of acute or chronic administration of risperidone on motor and sexual behavior of male rats
Pharmacol. Res.
Chronic administration of risperidone to healthy rats: a behavioural and morphological study
Behav. Brain Res.
Evidence for dopamine receptor pruning between adolescence and adulthood in striatum but not nucleus accumbens
Dev. Brain Res.
Dopamine D2 receptor occupancy is a common mechanism underlying animal models of antipsychotics and their clinical effects
Neuropsychopharmacology
Serotonergic mechanisms in neuroleptic-induced catalepsy in the rat
Neurosci. Biobehav. Rev.
Conditioning to injection procedures and repeated testing increase SCH 23390-induced catalepsy in mice
Neuropsychopharmacology
Is experimental catalepsy properly measured?
Pharmacol. Biochem. Behav.
Inter-individual vs line/strain differences in psychogenetically selected Roman High-(RHA) and Low-(RLA) Avoidance rats: neuroendocrine and behavioural aspects
Neuroscie. Biobehav. Rev.
Endocrine and behavioral traits in low-avoidance performing Sprague-Dawley rats
Regul. Pept.
Reduced expression of haloperidol conditioned catalepsy in rats by the dopamine D3 receptor antagonists nafadotride and NGB 2904
Eur. Neuropsychopharmacol.
Increase of spiny I activity in striatum after development of context-dependent sensitization of catalepsy in rats
Neurosci. Lett.
Brain regions associated with inverse incentive learning: c-Fos immunohistochemistry after haloperidol sensitization on the bar test in rats
Behav. Brain Res.
Distinct sites of dopaminergic and glutamatergic regulation of haloperidol-induced catalepsy within the rat caudate-putamen
Brain Res.
Striatal and nucleus accumbens D1/D2 dopamine receptors in neuroleptic catalepsy
Eur. J. Pharmacol.
Comparative postnatal development of dopamine D1, D2 and D4 receptors in rat forebrain
Int. J. Dev. Neurosci.
Behavioural effects of serotonin agonists and antagonists in the rat and marmoset
Neuropharmacology
The effect of serotonergic agents on haloperidol-induced catalepsy
Life Sci.
Stimulation of median, but not dorsal, raphe 5-HT1A autoreceptors by the local application of 8-OH-DPAT reverses raclopride-induced catalepsy in the rat
Neuropharmacology
Effects of local application of 5-hydroxytryptamine into the dorsal or median raphe nuclei on haloperidol-induced catalepsy in the rat
Neuropharmacology
The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants
Prog. Neurobiol.
Adolescent olanzapine sensitization is correlated with hippocampal stem cell proliferation in a maternal immune activation rat model of schizophrenia
Brain Res.
Asenapine sensitization from adolescence to adulthood and its potential molecular basis
Behav. Brain Res.
Amisulpride the ‘atypical' atypical antipsychotic − Comparison to haloperidol, risperidone and clozapine
Schizophr. Res.
Less is more: antipsychotic drug effects are greater with transient rather than continuous delivery
Biol. Psychiatry
How antipsychotics work—From receptors to reality
NeuroRx
Adolescent brain development: a period of vulnerabilities and opportunities—Keynote Address
Ann. N. Y. Acad. Sci.
Brain development during childhood and adolescence: a longitudinal MRI study [2]
Nat. Neurosci.
Dynamic mapping of human cortical development during childhood through early adulthood
Proc. Natl. Acad. Sci. U. S. A.
Longitudinal four-dimensional mapping of subcortical anatomy in human development
Proc. Natl. Acad. Sci. U. S. A.
Adolescent mental health-opportunity and obligation: emerging neuroscience offers hope for treatments
Science
The adolescent brain: implications for the understanding, pathophysiology, and treatment of schizophrenia
Schizophr. Bull.
A population-based study of antipsychotic prescription trends in children and adolescents in British Columbia: from 1996 to 2011
Can. J. Psychiatry
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