Increased amygdala and decreased hippocampus volume after schedule-induced polydipsia in high drinker compulsive rats
Introduction
Compulsivity is a core feature in obsessive-compulsive disorder (OCD), being a comorbid symptom across several neuropsychiatric conditions, such as schizophrenia, autism and addiction [[1], [2], [3]]. This behavior can be defined as a perseveration of a response, irresistible and inappropriate to the individual and unavoidable despite its negative consequences [4]. Concerning the brain bases of compulsivity, a strong role of serotoninergic and dopaminergic activity within the cortical fronto-striatal-limbic circuits has been reported by studies with both human patients and animal models [[5], [6], [7], [8],9].
Recent evidence points towards the implication of neuroplastic brain changes underlying the vulnerability to inhibitory control deficit. A recent meta-analysis by Boedhoe et al. [10] concluded that OCD patients have a significantly bigger amygdala volume than healthy controls. These structural and neurochemical alterations seem to be not only responsible, to some degree, of the behavioral manifestations, but also a consequence of genetic and/or environmental conditions. In fact, the brain neuroplastic features might account for both the increased risk of suffering OCD and related disorders and the therapeutic outcomes of treatment. Thus, neuroimaging studies concerning cognitive-behavioral therapy (CBT) in OCD patients have shown: 1) an increased white matter in orbitofrontal cortex (OFC) and capsula externa in children and adolescents [11], 2) a decreased activity in prefrontal cortex and thalamus [[12], [13], [14]], 3) and a correlation between symptom reduction and medial prefrontal cortex volume [15].
Moreover, the pharmacological treatment in OCD patients with Selective serotonin reuptake inhibitors (SSRIs), also modulates brain plasticity: a systemic single dose administration of SSRIs modulates amygdalo-hippocampal formation and prefrontal cortex activity during presentation of faces and pictures [16], and normalize the decreased small-world neural efficiency (the ability of a network to connect and efficiently exchange information) resulting from 16 weeks of treatment [17]. Subchronic and chronic escitalopram treatment is associated with a reduction in amygdala activation during an emotional face paradigm [18], and subchronic citalopram treatment has shown to reduce functional connectivity between amygdala and prefrontal cortex ([19]; for review, see [9]).
Clinical and preclinical evidences have shown that the 5-HT2A receptor seems to play a prominent role in OCD and compulsive behaviors. Pharmacologically, 5-HT2A activation enhances the anti-compulsive action of SSRIs [20]. SRI treatment outcome in OCD patients is influenced by serotonin genes polymorphism [21], and a meta-analysis of genetic polymorphism [22] suggest a role of serotonin transporter (SERT) and 2A receptor subtype in OCD vulnerability. Reduced 5-HT2A binding is reported in cortical areas in high compulsive rats [23], companion dogs with a compulsive behavior [24] and drug-naïve OCD patients [25]. Post-mortem studies in schizophrenia patients, show a 5-HT2A reduction within prefrontal cortex [26,[105], [106], [107], [108], [109]) and hippocampus [110] when compared to healthy controls (for review, see: [27]). This extensive evidence adds to the hypothesis of its implication in cortical and amygdaloid regulation of emotion-based behaviors [5]. However, the relevance of brain plasticity changes and the role of 5-HT2A receptor in vulnerable compulsive populations remains unknown.
Schedule-induced polydipsia (SIP) is an animal model commonly employed for studying the brain substrates of compulsive behavior underlying in disorders such as OCD and schizophrenia [[28], [29], [30], [31], [32]]. In this procedure, where food-deprived rats are exposed to an intermittent reinforcement schedule in operant chambers with water available ad libitum, some animals develop an excessive drinking behavior, not driven by physiological demands [33]. Animals that develop SIP have shown different corticosterone levels [34], and increased dendritic spine density in striatal neurons [35]. Moreover, the study of individual differences by the selection of high drinkers (HD) and low drinkers (LD) rats according to their drinking rates on SIP [30], have also revealed divergent neuroplastic features: HD rats selected by SIP show reduced levels of myelin basic protein (MBP) in corpus callosum, striatum and amygdala compared to LD rats [31]. Regarding 5-HT2A receptor, the systemic administration of citalopram and DOI –a 5-HT2A/C receptors agonist– reduced compulsive drinking only in HD rats without affecting LD rats behavior, effect that only ketanserin and M100907 –5-HT2A antagonists– but not SB242084 –5-HT2C antagonist– blocked [36]. This effect was replicated when drugs were directly infused into the medial prefrontal cortex: HD rats also decreased compulsive drinking on SIP when administered with DOI, and the effect was blocked by M100907 but not by SB242084 co-administration [37]. However, to our knowledge no research has been done to investigate which neuroplastic features underlie populations with different predispositions towards compulsive behavior (HD and LD), whether they might differentially arise as a result of SIP exposure, and if any re-exposure effect is influenced by the existing vulnerabilities.
The aims of the present study were, first, to investigate whether animals selected into high and low drinkers according to SIP acquisition differ in volume and 5-HT2A receptor binding of fronto-limbic structures implicated in compulsivity (prelimbic and infralimbic cortices, amygdala and hippocampus) and, second, if re-exposure to SIP after one month off can induce significant differences between re-exposed and non-re-exposed animals within same groups related to neuroplastic changes, and between high and low drinkers within same re-exposure conditions.
Section snippets
Animals
Twenty-eight male Wistar rats (Janvier, France), weighing approximately 250−300 g at arrival were used in the present study. The animals were housed in groups of four rats per cage (50 × 35 × 20 cm) at a temperature of 22 °C, with a 12:12-h dark–light cycle with lights off at 07:00 h am, environmental enrichment, and food and water provided ad libitum. Animals were proximately two months old by the beginning of the experiment, and four months old when the procedures were finished. After 10 days
HD and LD selected by SIP
Fig. 2 shows SIP acquisition and maintenance during 20 sessions. The mean of water intake over the last 5 days of SIP was 24.561 ± 0.913 mL for HD and 6.174 ± 0.66 mL for LD (shown in Fig. 2A and C). The total number of licks over the last 5 sessions were 5,356.214 ± 291.502 licks for HD and 1,474.485 ± 190.154 licks for LD (shown in Fig. 2B).
One-way repeated measures ANOVA revealed differences in SIP acquisition concerning water intake as shown by the interaction between sessions and group
Discussion
The present study explored the differences in brain volumetry and neurobiology of serotonin 5-HT2A receptor binding in animals with a compulsive phenotype selected by SIP in comparison to their non-compulsive counterparts, and the differential effect of SIP re-exposure in these two populations. In high drinker (HD) rats, SIP re-exposure increased basolateral amygdala volume and decreased dorsal hippocampus volume compared to non-re-exposed HD group, while it did not affect brain volumetry in LD
Funding sources
This work was supported by the Ministerio de Ciencia, Innovación y Universidades (Spanish Government) and FEDER funds (Grant numbers: PSI2015-70037-R, PGC2018-099117-B-C21; BES-2013-064824 and EEBB-I-16-11260).
Declaration of Competing Interest
The authors declare no conflict of interest.
Acknowledgements
The authors wish to thank Luis Ruedas for his invaluable help. Further, the authors thank Hans-Jørgen Jensen for his skilled assistance.
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