These findings highlight the contribution of serotoninergic 5-HT2A/C receptors compared with noradrenergic mechanisms on SIP and reveal the "therapeutic" activation of serotonin 5-HT2A in the inhibition of the compulsive drinking behaviour in HD rats. Thus, it may represent a potentially new marker of vulnerability and provides additional insight for potential treatments on compulsive behaviours in neuropsychiatric populations.

Psychogenic polydipsia, which is compulsive, non-regulatory fluid consumption, is present in 6%–20% of chronic psychiatric patients and frequently associated with the schizophrenia diagnosis. In the present study, we investigated the relation between schizophrenia-like symptoms and biomarkers with a compulsive drinking behavior phenotype in rats. Rats that were selected for low drinking vs high drinking behavior following schedule-induced polydipsia (SIP) were assessed in a latent inhibition (LI) paradigm using tone and electrical foot shock and in a spatial reversal learning task to evaluate behavioral inflexibility. We also analyzed the myelin basic protein in different brain areas of high drinker (HD) and low drinker (LD) rats. The HD rats, which were characterized by a compulsive drinking behavior on SIP, had a reduced level of LI effect and increased behavioral inflexibility in the spatial reversal learning task in comparison to the LD group. Moreover, HD rats showed less myelination in the center of the corpus callosum, striatum, and amygdala in comparison to LD rats. These findings strengthen the validity of HD rats that were selected by SIP as a possible phenotype of compulsive neuropsychiatric disorders, as evidenced by the existence of behaviors and biological markers that are related to schizophrenia and obsessive-compulsive disorder, including a reduced LI effect, behavioral inflexibility and reduced brain myelination. Future studies could contribute to the elucidation of the mechanisms underlying the compulsive phenotype of HD rats and its relation to vulnerability to schizophrenia.

RationaleCompulsive behaviour, present in different psychiatric disorders, such as obsessive-compulsive disorder, schizophrenia and drug abuse, is associated with altered levels of monoamines, particularly serotonin (5-hydroxytryptamine) and its receptor system.ObjectivesThe present study investigated whether 5-HT manipulation, through a tryptophan (TRP) depletion by diet in Wistar and Lister Hooded rats, modulates compulsive drinking in schedule-induced polydipsia (SIP) and locomotor activity in the open-field test. The levels of dopamine, noradrenaline, serotonin and its metabolite were evaluated, as well as the 5-HT2A and 5-HT1A receptor binding, in different brain regions.MethodsWistar rats were selected as high (HD) or low (LD) drinkers according to their SIP behaviour, while Lister hooded rats did not show SIP acquisition. Both strains were fed for 14 days with either a TRP-free diet (T−) or a TRP-supplemented diet (T+)ResultsThe TRP depletion diet effectively reduced 5-HT levels in the frontal cortex, amygdala and hippocampus in both strains of rats. The TRP-depleted HD Wistar rats were more sensitive to 5-HT manipulation, exhibiting more licks on SIP than did the non-depleted HD Wistar rats, while the LD Wistar and the Lister Hooded rats did not exhibit differences in SIP. In contrast, the TRP-depleted Lister Hooded rats increased locomotor activity compared to the non-depleted rats, while no differences were found in the Wistar rats. Serotonin 2A receptor binding in the striatum was significantly reduced in the TRP-depleted HD Wistar rats.ConclusionsThese results suggest that alterations of the serotonergic system could be involved in compulsive behaviour in vulnerable populations.

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responsible for GABA synthesis, glutamate decarboxylase (GAD 65/67, P < 0.01), as well as the dendritic marker microtubule associated protein (MAP2, P < 0.05), and the dendritic spine marker spinophilin (P < 0.05) in the left NAcb core of HI rats compared with LI rats. There were no significant differences in any of these markers in the other brain regions investigated. We also identified a strong inverse relationship between impulsivity and the lower levels of GAD 65/67 (P < 0.01; r = -0.71) and MAP2 (P < 0.05; r = -0.66) in the left NAcb core. Finally, we investigated the effects of bilateral microinfusions of GAD 65/67 antisense into the NAcb core on the level of impulsivity in LI rats. Infusions of GAD65/67antisense in this region resulted in a robust and selective increase in impulsive responding compared to a second group of LI rats infused with a scramble sequence. These findings indicate that while the number of neurons in the NAcb core may be unaltered by variation in impulsivity, the structural integrity and density of dendritic spines, together with GABA neurotransmission, may be deficient in HI rats. Collectively, these data suggest that decreased dopamine D2/3 receptor availability in the ventral striatum of HI rats may be secondary to a reduction in the density of spines on medium spiny GABA-ergic neurons in the NAcb core.