Excessive habit formation in schedule‐induced polydipsia: Microstructural analysis of licking among rat strains and involvement of the orbitofrontal cortex

Compulsive behavior is observed in several neuropsychiatric disorders such as obsessive-compulsive disorder (OCD), anxiety, depression, phobia, and schizophrenia. Thus, compulsivity has been proposed as a transdiagnostic symptom with a highly variable pharmacological treatment. Recent evidence shows that glutamate pharmacotherapy may be of benefit in impaired inhibitory control. The purpose of the present study was: first, to test the comorbidity between compulsivity and other neuropsychiatric symptoms on different preclinical behavioral models; second, to assess the therapeutic potential of different glutamate modulators in a preclinical model of compulsivity. Long Evans rats were selected as either high (HD) or low (LD) drinkers corresponding with their water intake in schedule-induced polydipsia (SIP). We assessed compulsivity in LD and HD rats by marble burying test (MBT), depression by forced swimming test (FST), anxiety by elevated plus maze (EPM) and fear behavior by fear conditioning (FC) test. After that, we measured the effects of acute administration (i.p.) of glutamatergic drugs: N-Acetylcysteine (NAC; 25, 50, 100 and 200 mg/kg), memantine (3.1 and 6.2 mg/kg) and lamotrigine (15 and 30 mg/kg) on compulsive drinking on SIP. The results obtained showed a relation between high compulsive drinking on SIP and a higher number of marbles partially buried in MBT, as well as a higher percentage of freezing on the retrieval day of FC test. We did not detect any significant differences between LD and HD rats in FST, nor in EPM. The psychopharmacological study of glutamatergic drugs revealed that memantine and lamotrigine, at all doses tested, decreased compulsive water consumption in HD rats compared to LD rats on SIP. NAC did not produce any significant effect on SIP. These results indicate that the symptom clusters of different forms of compulsivity and phobia might be found in the compulsive phenotype of HD rats selected by SIP. The effects of memantine and lamotrigine in HD rats point towards a dysregulation in the glutamatergic signaling as a possible underlying mechanism in the vulnerability to compulsive behavior on SIP. Further studies on SIP, could help to elucidate the therapeutic role of glutamatergic drugs as a pharmacological strategy on compulsive spectrum disorders.

Section: Discussionmentioning

confidence: 99%

Increased Fear Memory and Glutamatergic Modulation in Compulsive Drinker Rats Selected by Schedule-Induced Polydipsia

Prados-Pardo

Martín-González

Mora

et al. 2019

“…Some of these preclinical models select groups of animals from a heterogeneous population on the basis of the different characteristics of a behavioral trait or behavioral response related with impulsivity. The Lister-Hooded rats selected for excessive premature (i.e., impulsive) responses in the 5C-SRT test (Robinson et al, 2009; Hayward et al, 2016; Dalley and Robbins, 2017) and the Wistar rats stratified for extreme values of schedule-induced polydipsia (Merchán et al, 2019, and references therein) are examples of these models of impulsive behavior. Other “behavior to biology” models use selective bidirectional breeding for a given phenotype and then systematically evaluate the underlying neurobiological mechanisms and associated traits.…”

Section: Tests and Models Of The Impulsivity Trait And Impulsive Actimentioning

confidence: 99%

“…In a delay discounting task, RHA rats also display enhanced impulsive choice and prefer the immediate and smaller reward as opposed to a delayed larger reinforcement (Moreno et al, 2010). In addition, in the procedure of schedule-induced polydipsia, the RHA strain shows stronger acquisition of the adjunctive responses, and a higher asymptotic response level of both water intake and licking responses than RLA rats (Moreno et al, 2010; see also Klein et al, 2014; Merchán et al, 2019).…”

Section: The Roman Rats: a Genetic Model Of Differential Anxiety Novmentioning

confidence: 99%

“…More than four decades of research have characterized RHA rats as less fearful, anxious and stress-sensitive than their RLA counterparts (Steimer and Driscoll, 2003; Driscoll et al, 2009; Río-Álamos et al, 2017a,b). Remarkably, compared with RLAs, RHA rats display an impulsive phenotype, as shown by their response profiles in the delayed response latency 20 (DRL-20), schedule-induced polydipsia, and 5-choice serial reaction time (5CSRT) tasks (Zeier et al, 1978; Moreno et al, 2010; Merchán et al, 2019; see “The Roman Rats: A Genetic Model of Differential Anxiety, Novelty Seeking, Impulsivity, Attention Deficits and Associated Traits” section). Moreover, relative to RLAs, RHA rats display several impairments in schizophrenia-relevant phenotypes, such as prepulse inhibition (PPI; Oliveras et al, 2015; Río-Álamos et al, 2019), latent inhibition (LI; Fernández-Teruel et al, 2006), spatial working memory (Oliveras et al, 2015) and reversal learning (Río-Álamos et al, 2019) as well as a trend towards a reduction of some types of social behavior (Coppens et al, 2012; Del Rio et al, 2014; see “RHA Rats as a Model of Deficits in Attentional Processes, Cognitive Impairments and Other Features Relevant for Schizophrenia Research” section).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A Genetic Model of Impulsivity, Vulnerability to Drug Abuse and Schizophrenia-Relevant Symptoms With Translational Potential: The Roman High- vs. Low-Avoidance Rats

Giorgi

Corda

Fernandez-Teruel

2019

The bidirectional selective breeding of Roman high- (RHA) and low-avoidance (RLA) rats for respectively rapid vs. poor acquisition of active avoidant behavior has generated two lines/strains that differ markedly in terms of emotional reactivity, with RHA rats being less fearful than their RLA counterparts. Many other behavioral traits have been segregated along the selection procedure; thus, compared with their RLA counterparts, RHA rats behave as proactive copers in the face of aversive conditions, display a robust sensation/novelty seeking (SNS) profile, and show high impulsivity and an innate preference for natural and drug rewards. Impulsivity is a multifaceted behavioral trait and is generally defined as a tendency to express actions that are poorly conceived, premature, highly risky or inappropriate to the situation, that frequently lead to unpleasant consequences. High levels of impulsivity are associated with several neuropsychiatric conditions including attention-deficit hyperactivity disorder, obsessive-compulsive disorder, schizophrenia, and drug addiction. Herein, we review the behavioral and neurochemical differences between RHA and RLA rats and survey evidence that RHA rats represent a valid genetic model, with face, construct, and predictive validity, to investigate the neural underpinnings of behavioral disinhibition, novelty seeking, impulsivity, vulnerability to drug addiction as well as deficits in attentional processes, cognitive impairments and other schizophrenia-relevant traits.

“…Repeated activation of OFC-ventral striatal pathway in mice produced grooming sensitization over days further supporting cortical-striatal involvement in compulsive behaving (Ahmari et al, 2013). Additionally, SIP-prone rats exhibited more c-Fos activity in the OFC and basolateral amygdala compared to non-compulsive drinking animals (Merchán et al, 2018). This is in line with human studies that show increased metabolic activity of the striatum and OFC in OCD patients and during symptom provocation (Breiter and Rauch, 1996; Saxena et al, 1999).…”

Section: Schedule-induced Polydipsia As a Model Of Obsessive Compulsimentioning

confidence: 99%

The Bed Nucleus of the Stria Terminalis, Homeostatic Satiety, and Compulsions: What Can We Learn From Polydipsia?

Banasikowski

Hawken

2019

A compulsive phenotype characterizes several neuropsychiatric illnesses – including but not limited to – schizophrenia and obsessive compulsive disorder. Because of its perceived etiological heterogeneity, it is challenging to disentangle the specific neurophysiology that precipitates compulsive behaving. Using polydipsia (or non-regulatory water drinking), we describe candidate neural substrates of compulsivity. We further postulate that aberrant neuroplasticity within cortically projecting structures [i.e., the bed nucleus of the stria terminalis (BNST)] and circuits that encode homeostatic emotions (thirst, hunger, satiety, etc.) underlie compulsive drinking. By transducing an inaccurate signal that fails to represent true homeostatic state, cortical structures cannot select appropriate and adaptive actions. Additionally, augmented dopamine (DA) reactivity in striatal projections to and from the frontal cortex contribute to aberrant homeostatic signal propagation that ultimately biases cortex-dependent behavioral selection. Responding becomes rigid and corresponds with both erroneous, inflexible encoding in both bottom-up structures and in top-down pathways. How aberrant neuroplasticity in circuits that encode homeostatic emotion result in the genesis and maintenance of compulsive behaviors needs further investigation.