Does nicotine exposure during adolescence modify the course of schizophrenia-like symptoms? Behavioral analysis in a phencyclidine-induced mice model

Abstract

The first symptoms of schizophrenia (SCHZ) are usually observed during adolescence, a developmental period during which first exposure to psychoactive drugs also occurs. These epidemiological findings point to adolescence as critical for nicotine addiction and SCHZ comorbidity, however it is not clear whether exposure to nicotine during this period has a detrimental impact on the development of SCHZ symptoms since there is a lack of studies that investigate the interactions between these conditions during this period of development. To elucidate the impact of a short course of nicotine exposure across the spectrum of SCHZ-like symptoms, we used a phencyclidine-induced adolescent mice model of SCHZ (2.5mg/Kg, s.c., daily, postnatal day (PN) 38-PN52; 10mg/Kg on PN53), combined with an established model of nicotine minipump infusions (24mg/Kg/day, PN37-44). Behavioral assessment began 4 days after the end of nicotine exposure (PN48) using the following tests: open field to assess the hyperlocomotion phenotype; novel object recognition, a declarative memory task; three-chamber sociability, to verify social interaction and prepulse inhibition, a measure of sensorimotor gating. Phencyclidine exposure evoked deficits in all analyzed behaviors. Nicotine history reduced the magnitude of phencyclidine-evoked hyperlocomotion and impeded the development of locomotor sensitization. It also mitigated the deficient sociability elicited by phencyclidine. In contrast, memory and sensorimotor gating deficits evoked by phencyclidine were neither improved nor worsened by nicotine history. In conclusion, our results show for the first time that nicotine history, restricted to a short period during adolescence, does not worsen SCHZ-like symptoms evoked by a phencyclidine-induced mice model.

Nicotine Exposure in a Phencyclidine-Induced Mice Model of Schizophrenia: Sex-Selective Medial Prefrontal Cortex Protein Markers of the Combined Insults in Adolescent Mice

“…The higher number of potential protein markers of PCPNIC combined insults when compared to protein markers of SCHZ and NIC further corroborates this conclusion. Nevertheless, this study also identified a shared impact of phencyclidine and nicotine history, which supports evidence of interactive events between SCHZ and nicotine misuse in patients and comparable effects in animal models [55,61,62]. Consistent with this finding, despite the identification of proteins exclusively deregulated in the PCPNIC group, the top Reactome pathways were shared with other experimental groups.…”

“…These include hyperactivity in the mesolimbic dopaminergic system and hypoactivity in the mesocortical one, as well as hypofunction in the cortical glutamatergic and gamma aminobutyric acid (GABA) systems [50,52,54]. Most importantly, phencyclidine-induced SCHZ-like behavioral deficits were recently also demonstrated to occur when administration occurs during adolescence [55]. As for nicotine exposure, a subcutaneous osmotic minipump is an established model that has the advantage of being less stressful than other routes of administration, in addition to allowing for a constant dose and a controlled period of administration [56,57].…”

Advantages and Limitations of Animal Schizophrenia Models

“…Both acute and subchronic PCP injections at different doses cause various behavioral deficits in animals relevant to human schizophrenia symptoms, such as impairments in memory and learning [ 45 , 46 ], sociability [ 47 , 48 ], locomotor activity [ 49 ], and sensorimotor gating measured in PPI [ 50 ]. Notably, some studies have failed to confirm important features of schizophrenia-like behavior in rodents [ 47 ], indicating that the effects of PCP in behavioral studies may differ depending on the dose used and the administration paradigm.…”