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

Abstract

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.

The development of compulsive coping behaviour is associated with a downregulation of Arc in a Locus Coeruleus neuronal ensemble

“…Thus, Arc is well positioned to influence glutamate-dependent plasticity and its function in learning and memory [ 130 ]. In agreement with other clinical and preclinical studies having established the involvement of altered glutamatergic function in compulsive disorders, the tendency compulsively to express a polydipsic adjunctive behaviour under a SIP procedure has been shown to be associated with a lower level of glutamate in the medial prefrontal cortex [ 45 ], and reduced by glutamatergic drugs such as memantine [ 131 ]. Together with the previous evidence that compulsive symptoms are decreased by glutamatergic drugs in patients with ICSDs [ 132 , 133 ], this observation suggests that the downregulation of Arc mRNA levels in the LC observed in vulnerable individuals when they express a compulsive adjunctive behaviour may be reflective of altered glutamatergic integration by LC neurons.…”

The individual vulnerability to develop compulsive adjunctive behavior is associated with the recruitment of activity-regulated cytoskeleton-associated protein (Arc) within the Locus Coeruleus

“…Thus, Arc is well positioned to influence glutamate-dependent plasticity and its function in learning, and memory [117]. In agreement with other clinical and preclinical studies having established the involvement of altered glutamatergic function in compulsive disorders , the tendency compulsively to express a polydipsic adjunctive behaviour under a SIP procedure has been shown to be associated with a lower level of glutamate in the medial prefrontal cortex [47], and reduced by glutamatergic drugs such as memantine [118]. Together with the previous evidence that compulsive symptoms are decreased by glutamatergic drugs in patients [119,120], this observation suggests that the downregulation of Arc mRNA levels in the LC observed in vulnerable individuals when they express a compulsive adjunctive behavior may be reflective of altered glutamatergic integration by LC neurons.…”

NMR-based Metabolomics and Fatty Acid Profiles to Unravel Biomarkers in Preclinical Animal Models of Compulsive Behavior

“…The dramatic effect found in the present work adds evidence not only to the stressful properties of intermittent reinforcement in SIP inducing compulsive behavior but also to severe physiological effects, such as increased corticosterone levels, increased amygdaloid and decreased hippocampal volume, and increased dendritic spinal density in the dorsal striatum . In this sense, the aforementioned finding of increased glutamine levels in HD in the present study is not surprising given its major role in the brain as the precursor of glutamate, which is a key factor regarding neuroplasticity , and one of the altered mechanisms and putative therapeutic targets in compulsive drinking in SIP.…”