Schedule-induced polydipsia as a model of compulsive behavior: neuropharmacological and neuroendocrine bases

Moreno, Margarita; Flores, Pilar

doi:10.1007/s00213-011-2570-3

Cited by 75 publications

(96 citation statements)

References 116 publications

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“…Taken together, these results suggest that CFL induced by dopaminergic drugs models some key hallmarks of the obsessive-compulsive disorder (OCD) in that the contingent response is excessive, time consuming, and disconnected to the outcome it is performed for. Our findings are in line with the notion that dopaminergic stimulation enhances compulsive drinking during schedule-induced polydipsia (SIP), a reliable model of OCD whereby rats drink in excess of need following intermittent food presentation (Platt et al 2008;Moreno and Flores 2012;Hawken and Beninger 2014).…”

Section: Introductionsupporting

confidence: 89%

Inhibition of hippocampal plasticity in rats performing contrafreeloading for water under repeated administrations of pramipexole

et al. 2015

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Rationale Compulsive symptoms develop in patients exposed to pramipexole (PPX), a dopaminergic agonist with high selectivity for the D3 receptor. Consistently, we demonstrated that PPX produces an exaggerated increase in contrafreeloading (CFL) for water, a repetitive and highly inflexible behavior that models core aspects of compulsive disorders. Objectives Given the role of the hippocampus in behavioral flexibility, motivational control, and visuospatial working memory, we investigated the role of hippocampus in the expression of PPX-induced CFL. To this aim, rats were subjected to CFL under chronic PPX, and then examined for the electrophysiological, structural, and molecular properties of their hippocampus. Methods We measured long-term potentiation (LTP) at CA1 Schaffer collaterals, dendritic spine density in CA1 pyramidal neurons, and then glutamate release and expression of pre and postsynaptic proteins in hippocampal synaptosomes. The effects of PPX on hippocampal-dependent working memory were assessed through the novel object recognition (NOR) test.Results We found that PPX-treated rats showing CFL exhibited a significant decrease in hippocampal LTP and failed to exhibit the expected increase in hippocampal spine density. Glutamate release and PSD-95 expression were decreased, while pSYN expression was increased in hippocampal synaptosomes of PPX-treated rats showing CFL. Despite a general impairment of hippocampal synaptic function, working memory was unaffected by PPX treatment. Conclusions Our findings demonstrate that chronic PPX affects synaptic function in the hippocampus, an area that is critically involved in the expression of flexible, goalcentered behaviors. We suggest that the hippocampus is a promising target in the pharmacotherapy of compulsive disorders.

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Section: Introductionsupporting

confidence: 89%

Inhibition of hippocampal plasticity in rats performing contrafreeloading for water under repeated administrations of pramipexole

et al. 2015

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“…SIP therefore has several features of the compulsions observed in OCD and related illnesses. As suggested by Moreno and Flores (2012), consideration of the variables affecting SIP and the neurocircuitry underlying this maladaptive behavior may provide novel insights into OCD.…”

Section: Insights Into Ocd From Animal Models Of Enhanced Schedulementioning

confidence: 99%

“…It is not necessary to require an operant response of the animal in order to observe SIP; Falk (1969) showed that presenting response-independent food pellets at the same inter-pellet intervals that were used in the VI 1-min schedule described above led to the same level of SIP as that observed when a response was required. Fixed-time (FT) schedules of response-independent food presentations produce optimal SIP when the inter-pellet interval is 60 s (see Moreno and Flores, 2012). …”

Section: Insights Into Ocd From Animal Models Of Enhanced Schedulementioning

confidence: 99%

“…In general they do. Thus, SIP is reduced by DA receptor antagonist drugs including typical (e.g., haloperidol) and atypical antipsychotics (e.g., clozapine) and by serotonergic drugs including chronic SSRIs (e.g., fluoxetine, clomipramine), a 5-HT 1A antagonist and 5-HT 2C agonists (reviewed by Moreno and Flores, 2012). As discussed in Section 2, CBGTC circuits have been implicated in OCD (Chamberlain et al, 2008; Menzies et al, 2008).…”

Section: Insights Into Ocd From Animal Models Of Enhanced Schedulementioning

confidence: 99%

“…Hypothalamic-pituitary axis changes are also implicated in OCD and SIP. Reduced levels of plasma corticosterone and increased levels of prolactin are observed in animals showing SIP and blockade of corticosterone synthesis reduces SIP (reviewed by Moreno and Flores, 2012). Results may reveal some overlap of the neural mechanisms of OCD and SIP.…”

Section: Insights Into Ocd From Animal Models Of Enhanced Schedulementioning

confidence: 99%

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Obsessive-compulsive disorder: Insights from animal models

Szechtman

Ahmari

Beninger

et al. 2017

Neuroscience & Biobehavioral Reviews

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Research with animal models of obsessive-compulsive disorder (OCD) shows the following: (1) Optogenetic studies in mice provide evidence for a plausible cause-effect relation between increased activity in cortico-basal ganglia-thalamo-cortical (CBGTC) circuits and OCD by demonstrating the induction of compulsive behavior with the experimental manipulation of the CBGTC circuit. (2) Parallel use of several animal models is a fruitful paradigm to examine the mechanisms of treatment effects of deep brain stimulation in distinct OCD endophenotypes. (3) Features of spontaneous behavior in deer mice constitute a rich platform to investigate the neurobiology of OCD, social ramifications of a compulsive phenotype, and test novel drugs. (4) Studies in animal models for psychiatric disorders comorbid with OCD suggest comorbidity may involve shared neural circuits controlling expression of compulsive behavior. (5) Analysis of compulsive behavior into its constitutive components provides evidence from an animal model for a motivational perspective on OCD. (6) Methods of behavioral analysis in an animal model translate to dissection of compulsive rituals in OCD patients, leading to diagnostic tests.

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Impact of putamen inhibition byDREADDson schedule‐induced drinking in rhesus monkeys

Grant

Newman

Gonzales

et al. 2022

J Exper Analysis Behavior

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The putamen is a nucleus within the sensory-motor striatal network that is involved in automatic, habitual actions. Schedule-induced polydipsia (SIP) is highly automated behavior, reliably occurring under intermediate interval schedules of reinforcement. The effect of putamen inhibition in mediating SIP of water and ethanol (4% w/v) under a Fixed Time 5-min (FT-5 min) schedule for food delivery was tested in 12 rhesus monkeys (6 male, 6 female). Water and ethanol SIP sessions ended after set volumes were consumed. Baseline patterns of SIP intake differed between water and ethanol SIP in volume but not in pattern of drinking. Activation of the designer receptor exclusively activated by designer drug (DREADD: hM4Di) with deschloroclozapine (DCZ; 300 μg/kg, i.m.) administered 30 min prior to the onset of the SIP session, for four consecutive sessions. DCZ administration increased the postpellet drink volume and reduced the time to drink both water and ethanol. Although the effect of DCZ treatment was similar for increasing SIP with either water or ethanol, post-DCZ return to baseline SIP rates of differed, perhaps highlighting the effect of a state dependency with ethanol SIP. Overall, the study shows that targeting the putamen with the inhibitory DREADD produces a reversible, reproducible and reliable increase in adjunctive drinking.

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Schedule-induced polydipsia as a model of compulsive behavior: neuropharmacological and neuroendocrine bases

Abstract: SIP represents an animal model of non-regulatory and excessive drinking that may be valid for studying the psychopharmacology of the compulsive phenotype and modeling different psychopathologies from compulsivity spectrum disorders.

Cited by 75 publications

References 116 publications

Inhibition of hippocampal plasticity in rats performing contrafreeloading for water under repeated administrations of pramipexole

Inhibition of hippocampal plasticity in rats performing contrafreeloading for water under repeated administrations of pramipexole

Obsessive-compulsive disorder: Insights from animal models

Impact of putamen inhibition byDREADDson schedule‐induced drinking in rhesus monkeys

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