This study examined polydipsia in the context of animal models of schizophrenia-like symptoms. Animals exposed to an excessive drinking (SIP) paradigm following post-weaning social isolation, subchronic MK-801 or the two together (‘double-hit’) revealed that rearing animals in isolation significantly augmented drinking behavior. Isolating adult animals that have been group reared does not produce significant amounts of SIP behavior 
. Unlike our previous findings 
, blocking NMDA receptors with subchronic MK-801 treatment alone did not significantly increase drinking behavior nor add or synergize with the effects of isolation rearing on SIP. These findings suggest that post-weaning social isolation, a putative animal model of schizophrenia-like symptoms, may lead to polydipsia.
Exaggerated drinking patterns were apparent in experimental groups compared to control groups that were not exposed to the intermittent food delivery schedule, as observed by others previously 
. SIP, in which animals have been observed to drink more in a single 2-hr session than the amount they consume daily 
, is considered an adjunctive behavior 
that is non-regulatory in nature 
. In humans, primary polydipsia has been observed to be ‘excessive,’ ‘persistent’, ‘non-regulatory’, and ‘without physiologic cause’ 
and in this way is similar to SIP. This face-validity makes SIP potentially useful as a model of various neuropsychiatric disorders related to the impulsive-compulsive spectrum disorders 
. Accordingly, SIP has been proposed as a model for obsessive compulsive disorder (OCD; 
). Repetitive, obsessive-compulsive behaviors show significant co-morbidity in schizophrenia patients 
and there is growing evidence to suggest a complex interaction between OCD and schizophrenia-spectrum disorders 
. However, while OCD treatments (e.g., selective serotonin reputake inhibitors) have been shown to successful diminish SIP (for review see Monero and Flores 
), they have not been reported to improve polydipsia in schizophrenia. Regardless, the SIP paradigm studied in the context of a schizophrenia framework shows promise as a valid animal model of polydipsia observed in schizophrenia.
The mechanisms by which social isolation exacerbates SIP behavior is unclear. SIP is consistently reduced by acute treatments with dopamine (DA) receptor agonists or antagonists 
. Furthermore, D2-like receptor binding was increased in the nucleus accumbens (NAc), medial prefrontal cortex, amygdala and ventral tegmental areas in animals that were high drinkers in the SIP paradigm and D1-like receptors were decreased in the same areas 
. This suggests that an imbalance of DA receptor activation may facilitate abnormal drinking. Post-weaning social isolation also increased DA activity in the NAc in adults 
; for review see 
. Evidence of increased DA activity following amphetamine treatment has also been reported in other neurodevelopmental animal models of schizophrenia-like symptoms that specifically disrupt hippocampal GABAergic function (e.g., methylazoxymethanol acetate [MAM]-treated rats) resulting in hyperactivity of some cortical circuits 
Individually, social isolation and subchronic NMDA-receptor antagonism may alter GABAergic neurons to produce schizophrenia phenotypes. Rodents isolated throughout development show reduced dendritic arborization (and thus fewer synapses; 
) and deficits in adulthood of both parvalbumin- (PV+) and calbindin–positive immunoreactive GABA interneurons in the hippocampus 
thought to regulate glutamatergic pyramidal cell activity. Normal GABAergic function is critical for activity-dependent modeling of the glutamate system during neural development 
. Suppression of GABA-mediated inhibitory synaptic transmission 
in IR animals has been suggested by Hickey et al. 
who found increased GABA transporter 1 (GAT-1) activity in the frontal cortex and hippocampus and GABA(A) receptor expression only in the former. Like social isolation, pharmacologically reducing NMDA function before sexual maturation prevents normal development of GABA inhibitory circuits resulting in reduced parvalbumin levels and excessive cortical excitability 
. Hickey et al. 
demonstrated that MK-801 only increased GABA(A) receptor expression in the hippocampus. A loss of GABA interneurons specific to the hippocampus has also been reported following MK-801 treatment 
. While PV+ interneuron dysregulation has been implicated in the development of schizophrenia, the exact cause and time course of interneuron dysfunction and loss due to post-weaning isolation and MK-801 treatment is unknown.
The above findings might suggest that a ‘double-hit’ model could have more robust effects on behavior than either insult alone. Supporting this hypothesis, Lapiz et al. 
Simpson et al. 
and Hickey et al. 
found enhanced locomotor hyperactivity to a novel environment in IR animals following subchronic phencyclidine or and MK-801 treatment. However, our ‘double hit’ model did not yield more pronounced aberrant drinking behavior. Similarly, when challenged acutely with amphetamine, Simpson et al. 
, Ashby et al. 
and Hickey et al. 
failed to observe a ‘double hit’ effect on locomotor activity. Taken together, these results provide little support for the ‘double-hit’ as a more robust model of schizophrenia-like symptoms.
NMDA receptor-antagonist pretreatment in this study produced a small but non-significant increase in SIP (). Blunted SIP may have been due to the possible neuroprotective effects of group housing in the present study. Animals in the Hawken et al. 
study were individually housed upon arrival (P46–52) and throughout the study; in the present study animals arrived at P21 and remained group housed. Alternately, failure to demonstrate a significant effect of MK-801 in this study may have also been due to other inconsistencies either in or during injection procedures between the two studies, for example, age of animals or colonization of vivarium during the studies. Finally, failure to significantly replicate the MK-801 effect in this study may simply be due to a lack of power.
The development of SIP is highly variable across animals 
which may in part result from neurochemical differences between individuals 
. Jones et al. 
SIP in female rats following a social isolation protocol. Social isolation has been reported to induce sex-specific behavioral responses, increasing activity in female rats compared to males 
. Jones et al. 
reported that female rats showed significant hyperactivity during the SIP paradigm. Increased locomotor activity in the operant chamber could account for the observed decrease in SIP acquisition. As primary polydipsia is significantly associated with being male 
, employing male rats to model the illness may be preferable.
This study investigated the impact of two animal models of schizophrenia-like symptoms (isolation rearing and subchronic MK-801 pretreatment) on drinking behavior in a SIP paradigm. The findings that post-weaning social isolation rearing significantly increased SIP suggests that a putative schizophrenic-like neuropathology resulting from isolation rearing sets the stage for the development of disordered water drinking. The deficits, neuroanatomical correlates, and mechanisms that contribute to the development of SIP from both social isolation and schizophrenia, however, require further investigation.