Excessive drinking and checking in the rat model of Schedule-Induced Polydipsia reveal impaired bi-directional plasticity at BNST GABA synapses

Abstract

23Compulsions, defined by debilitating repetitive actions, permeate many mental illnesses and are 24 challenging to treat partly because of a limited understanding of their neurobiological 25 underpinnings. Accumulating evidence suggests the rodent model of Schedule-Induced Polydipsia 26 (SIP) as a promising pre-clinical assay to elucidate the neurobiological and behavioural 27 manifestations of compulsivity. In the rodent SIP paradigm, susceptible rats develop adjunctive 28 excessive drinking when they are chronically food restricted and presented with food pellets 29 according to a fixed-time schedule. We found that normally, bi-directional plasticity of GABA 30 synapses in the oval bed nucleus of the stria terminalis (ovBNST) tightly followed the rats' satiety 31 state where low-frequency stimulation-induced potentiation (LTPGABA) prevailed in sated rats 32 whilst food restriction uncovered long-term depression (LTDGABA). In rats that developed 33 excessive drinking during SIP, removing the caloric restriction failed at reverting LTDGABA to 34 LTPGABA whereas bi-directional plasticity at ovBNST GABA synapses was unaltered in low-35 drinking SIP-trained rats. Excessive drinking ceased in polydipsic rats removed from their caloric 36 restriction; however, these rats retained a form of compulsive schedule-induced checking (SIC) 37 and impaired plasticity at ovBNST GABA synapses for several days following termination of the 38 caloric restriction. We conclude that altered bi-directional plasticity at ovBNST GABA synapses 39 is a neurophysiological trace of compulsivity in susceptible rats in the SIP model. 40 41 42Compulsions are time-consuming, repetitive actions that cause significant distress and 43 impairments in both the function and quality of daily life (American Psychiatric Association, 44 2013). Compulsive behaviours are symptomatic of many psychiatric disorders including 45 obsessive-compulsive disorder (OCD), addictions, and schizophrenia (Berman et al., 1995; 46 Drubach, 2015; Everitt and Robbins, 2005; Hariprasad et al., 1980). Despite common etiological 47 characteristics across psychiatric diagnoses, the underlying neurophysiology of compulsivity 48 remains largely unknown. Existing preclinical rodent models may help elucidate where and how 49 in the brain is pathological compulsivity represented (Everitt and Robbins, 2016; Szechtman et al., 50 2017). 51In the schedule-induced polydipsia (SIP) paradigm, food-restricted rats develop adjunctive 52 excessive drinking when presented with food pellets according to a fixed-time schedule (Falk, 53 1966; Platt et al., 2008). Interestingly, only a subset of rats within any given cohort develops 54 excessive drinking suggesting a powerful pre-clinical tool to understand how environment and 55 genetics interact to trigger the maladaptive behaviour (Moreno and Flores, 2012; Rosenzweig-56 Lipson et al., 2007; Toscano et al., 2008). Although the drinking behaviour in SIP is clearly 57 excessive, non-physiological, and maladaptive due to the r...

Neurochemical substrates linked to impulsive and compulsive phenotypes in addiction: A preclinical perspective

“…In general, whereas low doses of diazepam increase compulsive adjunctive drinking (López-Grancha et al, 2008), higher doses reduce the temporal regulation of licking responses during intervals between food delivery (Pellon & Blackman, 1992). Although an emerging area of interest, one recent report indicates a potential role of GABA in the bed nucleus of the stria terminalis in modulating SIP (Angelis et al, 2019).…”