ABSTRACT
The retinoic acid induced 1 (RAI1) gene when deleted or mutated results in Smith-Magenis syndrome (SMS), while duplication of 17p11.2, including RAI1, results in the dup(17)(p11.2) syndrome characterized by mental retardation, growth and developmental delays, and hyperactivity. Mouse models for these human syndromes may help define critical roles for RAI1 in mammalian development and homeostasis that otherwise cannot be deduced from patient studies. A mouse model for duplication, Dp(11)17+, involving Rai1 has been reported. However, this mutant was engineered on a mixed genetic background confounding phenotypic effects due to possible modifier genes. We have therefore created and evaluated mice with a graded series of four (hemizygous) and six (homozygous) copies of Rai1, and overexpressing Rai1>1.5-fold and >2-fold, respectively. Data show that Rai1-transgenic mice have growth retardation, increased locomotor activity, and abnormal anxiety-related behavior compared to wild-type littermates. Rai1-transgenic mice also have an altered gait with short strides and long sways, impaired ability on a cage-top hang test, decreased forelimb grip strength, and a dominant social behavior. Further, analyses of homozygous transgenic mice revealed a dosage-dependent exacerbation of the phenotype, including extreme growth retardation, severe neurological deficits, and increased hyperactivity. Our results show that Rai1 dosage has major consequences on molecular processes involved in growth, development, and neurological and behavioral functions, thus providing evidence for several dosage-thresholds for phenotypic manifestations causing dup(17)(p11.2) syndrome or SMS in humans.
Subject(s)
Abnormalities, Multiple/genetics , Disease Models, Animal , Gene Expression Regulation/physiology , Growth Disorders/genetics , Intellectual Disability/genetics , Learning Disabilities/genetics , Trans-Activators/genetics , Abnormalities, Multiple/pathology , Animals , Blotting, Southern , Craniofacial Abnormalities/genetics , Female , Gene Dosage , Growth Disorders/pathology , Learning Disabilities/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Phenotype , Psychomotor Performance/physiology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Volatile organic solvent (inhalant) abuse continues to be a major health concern throughout the world. Of particular concern is the abuse of inhalants by adolescents because of its toxicity and link to illicit drug use. Toluene, which is found in many products such as glues and household cleaners, is among the most commonly abused organic solvents. While studies have assessed outcomes of exposure to inhalants in adult male animals, there is little research on the neurobehavioral effects of inhalants in female or younger animals. In attempt to address these shortcomings, we exposed male and female Long-Evans rats to 20 min of 0, 2000, 4000, or 8000 parts per million (ppm) inhaled toluene for 10 days in rats aged postnatal (PN) day 28-39 (adolescent), PN44-PN55, or >PN70 (adult). Animals were observed individually in 29-l transparent glass cylindrical jars equipped with standard photocells that were used to measure locomotor activity. Toluene significantly increased activity as compared to air exposure in all groups of male and female rats with the magnitude of locomotor stimulation produced by 4000 ppm toluene being significantly greater for female adults than during any age of adolescence. The results demonstrate that exposure to abuse patterns of high concentrations of toluene through inhalation can alter spontaneous locomotor behavior in rats and that the expression of these effects appears to depend upon the postnatal age of testing and sex of the animal.
Subject(s)
Aging , Motor Activity/drug effects , Solvents/pharmacology , Toluene/pharmacology , Administration, Inhalation , Age Factors , Analysis of Variance , Animals , Animals, Newborn , Behavior, Animal , Dose-Response Relationship, Drug , Female , Male , Pregnancy , Rats , Rats, Long-Evans , Sex Factors , Time FactorsABSTRACT
Adolescents of many mammalian species exhibit rapid physiological change that is accompanied by behaviors such as increased risk taking and social interaction with peers. Marijuana abusers frequently report that their initial use occurred during adolescence. Our goal was to determine whether the in vivo effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) differed in adolescent and adult rats. Following initial testing with Delta(9)-THC in adolescent [postnatal day (PN)29] and adult (>PN60) rats of both sexes, we injected rats twice daily with 10 mg/kg Delta(9)-THC or vehicle for 9.5 days. Subsequently, rats were again injected with their initial dose of Delta(9)-THC and tested. In all rats, Delta(9)-THC produced dose-dependent locomotor suppression, antinociception, hypothermia and catalepsy. Some age-dependent differences in potency and efficacy were noted. Although Delta(9)-THC dose-effect functions were more similar across age after repeated exposure, subchronic dosing produced greater change in the hypothermic and locomotor effects of Delta(9)-THC in adolescents, but less change in its antinociceptive effects. These results suggest that the effects of initial exposure to Delta(9)-THC may not be entirely predictive of the effects of repeated exposure. Despite similarities in pharmacological effects of Delta(9)-THC after repeated use, adolescents and adults may exhibit differences in the pattern of transition from use to abuse.
