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.
Highlights
Compulsivity has been defined as ‘‘the performance of repetitive, unwanted and functionally impairing overt or covert behavior without adaptive function according to either rigid rules or as a means of avoiding perceived negative consequences’’ (Fineberg et al, 2014)
We found significant differences in the number of magazine entries according to the interaction between Schedule-induced polydipsia (SIP) acquisition sessions and low drinker rats (LD) vs. high compulsive drinking rats (HD) (session × group effect: F(19,266) = 2.124; p < 0.01; session effect: F(19,266) = 4.515, p < 0.001; group effect: F(1,14) = 5.577, p < 0.05)
The findings showed that HD rats, characterized by excessive and persistent compulsive drinking on SIP, exhibited a compulsive behavior on marble burying test (MBT) by a higher number of marbles partially buried (2/3) compared to LD rats
Summary
Compulsivity has been defined as ‘‘the performance of repetitive, unwanted and functionally impairing overt or covert behavior without adaptive function according to either rigid rules or as a means of avoiding perceived negative consequences’’ (Fineberg et al, 2014) It is one of the principal symptoms in obsessive-compulsive disorder (OCD), that affects 2%–3% of the population and is considered as one of the ten leading neuropsychiatric disorders of disability (WHO, 2018). Torres et al (2014, 2016) found that OCD patients, evaluated using the Dimensional Yale-Brown Obsessive–Compulsive Scale and Structured Clinical Interview for DSM-IV-TR Axis I Disorders, presented a lifetime prevalence of: 15.3% panic disorder (Torres et al, 2014), 56.4% major depression, 34.6% social phobia, 34.3% generalized anxiety disorder, and 31.4% specific phobia (Torres et al, 2016) Despite these studies, there are few experimental approaches in animals that have characterized the comorbidity with other altered pathological behaviors in preclinical models of compulsivity
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