RESUMO
Schizophrenia is a neuropsychiatric disorder characterized by multifactorial etiology involving complex interactions among genetic and environmental factors. "Multiple-hit" models of the disorder can explain its variable incidence and prevalence in related individuals. Hence, there is a dire need to understand these interactions in the emergence of schizophrenia. To test these factors in the emergence of schizophrenia-like behaviors, we employed a genetic mouse model of the disorder (harboring the DISC1 mutation) along with various environmental insults, such as early life stress (maternal separation of pups) and/or pharmacological interventions (ketamine injections). When assessed on a battery of behavioral tests, we found that environmental interventions affect the severity of behavioral phenotypes in terms of increased negative behavior, as shown by reduced mobility in the forced swim and tail suspension tests, and changes to positive and cognitive symptoms, such as increased locomotion and disrupted PPI along with reduced working memory, respectively. Among the various interventions, the genetic mutation had the most profound effect on behavioral aberrations, followed by an environmental intervention by ketamine injections and ketamine-injected animals that were maternally separated during early postnatal days. We conclude that although environmental factors increased the prevalence of aberrant behavioral phenotypes, genetic background is still the predominant influence on phenotypic alterations in these mouse models of schizophrenia.
RESUMO
Ketamine (KT) is used to induce and maintain general anaesthesia in combination with sedative drugs in human and animals. Because of its dissociative and hallucinogenic effects, KT has become a recreational drug in a variety of social settings and may be included in the panel of drugs of abuse that are controlled in driving under the influence (DUI) ascertainment. In a local driving license re-granting protocol, a case where a veterinary physician was found positive to KT and nor-ketamine (NK) in hair suggested the possibility of a professional exposure in a veterinary setting and prompted an experimental study. Male (7) and female (4) veterinary physicians were recruited on a voluntary base. Detailed information was collected on their habits, use of drugs, professional practice, frequency and mode of using KT injections. Hands and skin were examined. Head hair and pubic hair were collected. Two naïve subjects, starting their professional practice at a local veterinary clinic, were recruited and their hair (head, pubic, axillary, thoracic hair, and beard) and urine were collected before and after usual clinic activity. Hair were cut according to their length, washed, pulverized and 25mg were extracted and analyzed by liquid chromatography coupled to high accuracy, high resolution mass spectrometry. All the hair samples from the veterinary physicians turned to be positive for KT, at a concentration varying from 0.010 to 0.840ng/mg in head hair and from 0.040 to 2.04ng/mg in pubic hair; NK ranged from not detected to 0.080ng/mg in head hair, from not detected to 0.100 in pubic hair; when KT was ≥0.100, NK was always detected. For the two naïve subjects, hair from different body sites were negative before they started their activity, and positive one month later; some urine samples resulted positive and confirmed systemic exposure to KT. The possibility of unaware exposure to KT was demonstrated. The site of absorption is skin, independently from the presence of skin injuries due to hand contact with KT injection solutions and/or animal body fluids by veterinary physicians during clinical activities and animal handling. Possible adverse systemic effects by unaware KT exposure need to be studied and concerns have arisen as to healthy and safe workplace policies. Comparison with a population of subjects undergoing driving license re-granting evidenced a larger range of concentration in this latter setting (0.050-10.0ng/mg for KT, not detected to 0.100ng/mg for NK).