Repeated Binge Exposures to Amphetamine and Methamphetamine: Behavioral and Neurochemical Characterization 1

ABSTRACT Stimulant psychosis and addiction are most commonly associated with repeated, high-dose binges or runs, typically preceded by a more intermittent pattern of stimulant abuse. We previously reported that rats exposed to an escalating dose-run pattern of amphetamine administration exhibited changes in their behavioral response profile that differed both qualitatively and quantitatively from the response to either acute or intermittent daily treatment. To determine the generality of these effects and characterize further the nature of the behavioral and neurochemical changes of this treatment, rats received single daily injections of amphetamine (2.5 or 4.0 mg/kg s.c.) or equimolar doses of methamphetamine, followed by multiple runs (four daily injections at 2-hr intervals) with the pretreatment dose. This treatment resulted in a unique behavioral profile, including a profound increase in the relative expression of locomotion vs. stereotypy. The markedly enhanced poststereotypy locomotor activation was characterized by repeated "burst"-like episodes of ambulation. The number of runs required for the emergence of this behavior was dose dependent and was similar for the two drugs except that with methamphetamine, there also was a marked prolongation of the poststereotypy locomotor response during run exposures. During runs, both drugs produced a decline in the caudate but not the nucleus accumbens microdialysate dopamine response, whereas only methamphetamine produced a decline in the serotonin response that was apparent in both regions. The possible relationship between these behavioral and neurochemical changes and their implications for high dose patterns of stimulant abuse are discussed

Evidence for genetic association of RORB with bipolar disorder

<p>Abstract</p> <p>Background</p> <p>Bipolar disorder, particularly in children, is characterized by rapid cycling and switching, making circadian clock genes plausible molecular underpinnings for bipolar disorder. We previously reported work establishing mice lacking the clock gene D-box binding protein (<it>DBP</it>) as a stress-reactive genetic animal model of bipolar disorder. Microarray studies revealed that expression of two closely related clock genes, <it>RAR</it>-related orphan receptors alpha (<it>RORA</it>) and beta (<it>RORB</it>), was altered in these mice. These retinoid-related receptors are involved in a number of pathways including neurogenesis, stress response, and modulation of circadian rhythms. Here we report association studies between bipolar disorder and single-nucleotide polymorphisms (SNPs) in <it>RORA </it>and <it>RORB</it>.</p> <p>Methods</p> <p>We genotyped 355 <it>RORA </it>and <it>RORB </it>SNPs in a pediatric cohort consisting of a family-based sample of 153 trios and an independent, non-overlapping case-control sample of 152 cases and 140 controls. Bipolar disorder in children and adolescents is characterized by increased stress reactivity and frequent episodes of shorter duration; thus our cohort provides a potentially enriched sample for identifying genes involved in cycling and switching.</p> <p>Results</p> <p>We report that four intronic <it>RORB </it>SNPs showed positive associations with the pediatric bipolar phenotype that survived Bonferroni correction for multiple comparisons in the case-control sample. Three <it>RORB </it>haplotype blocks implicating an additional 11 SNPs were also associated with the disease in the case-control sample. However, these significant associations were not replicated in the sample of trios. There was no evidence for association between pediatric bipolar disorder and any <it>RORA </it>SNPs or haplotype blocks after multiple-test correction. In addition, we found no strong evidence for association between the age-at-onset of bipolar disorder with any <it>RORA </it>or <it>RORB </it>SNPs.</p> <p>Conclusion</p> <p>Our findings suggest that clock genes in general and <it>RORB </it>in particular may be important candidates for further investigation in the search for the molecular basis of bipolar disorder.</p