Behavior genetic investigation of the relationship between spontaneous locomotor activity and the acquisition of morphine self-administration behavior

There is a significant degree of individual variability in response to drugs of abuse. A goal of behavior genetic studies has been to determine the extent to which observed heterogeneity in drug use can be attributed to genetic and environmental factors and to identify the neurobiological factors involved in vulnerability. Recent hypotheses regarding the predictive value of spontaneous locomotor activity in the acquisition of drug-reinforced behavior are amenable to testing using a behavior genetics approach. Genetic differences in locomotor response to a novel environment were determined in naive and catheterized Lewis, F344, NBR and ACI rats. Operant drug-reinforced behavior was examined in a 23h access paradigm in which each lever press by a rat produced a 1mg/kg injection of morphine with a 30s timeout period (FR 1:TO 30"). Acquisition (7 days), extinction (6 days) and reacquisition (7 days) of morphine self-administration behavior was investigated in all four inbred strains. Large genetic differences in the rate of acquisition and extinction of morphine self-administration were found. Lewis rats responded at high rates beginning in the first two days, whereas F344 rats initially responded at low rates and responding increased gradually over seven days. NBR and ACI rats responded at intermediate levels. When vehicle was substituted for drug there was a significant effect of genotype on the rate of extinction; F344 and ACI increased responding to greater than 175% of drug-response levels, whereas the Lewis response rate decreased gradually and NBR response rate decreased immediately during the first several days. When drug was available again, rates of reacquisition did not differ from original acquisition rates. Drug maintained significantly greater amounts of behavior than vehicle in the Lewis, F344 and NBR rats and was thus shown to serve as a positive reinforcer in these three strains under these conditions. There was a significant genetic correlation among strains between drug intake during the first five days of acquisition and spontaneous locomotor response to a novel environment in catheterized rats. Only the ACI rats showed a significant within-strain correlation. The positive relationship between rate of acquisition of self-administration behavior and locomotor activity suggests that these two traits are influenced by common or closely linked genes. To this end, the neurobiological substrates that mediate spontaneous locomotor behavior under these environmental conditions may act, in part, as a template for determining the neurobiological substrates that mediate the relative rate of acquisition of morphine-taking behavior under these conditions.     

Assessment of thyroidal "C" cell secretion in osteoporotic girls with Turner''s syndrome. Basal and calcium-stimulated levels of total calcitonin, extractable calcitonin and katakalcin

Osteoporosis is a common finding in Turner's syndrome. To test the hypothesis that calcitonin deficiency may contribute to bone mineral loss in Turner's syndrome, we studied basal and calcium-stimulated (2 mg/kg body weight in 5 min) levels of total calcitonin, extractable calcitonin and katacalcin in 15 girls with Turner's syndrome and osteoporosis. Fifteen age-matched healthy girls were studied as controls. Both basal calcitonin (total and extractable) and katacalcin values were not significantly different in patients with Turner's syndrome in comparison with those of the controls. The calcium stimulation test showed a similar "C" cell secretory reserve in both groups. The calculation of delta CT/delta iCa of total and extractable calcitonin and delta KC/delta iCa, which accounts for individual variations in serum ionized calcium increases, did not show any significant difference between girls with Turner's syndrome and controls. We conclude that calcitonin deficiency is not a causative factor of osteoporosis in girls with Turner's syndrome and that in this syndrome long-life estrogen deficiency does not impair "C" cell secretory activity.     

Differential neuroendocrine responsiveness to morphine in Lewis, Fischer 344, and ACI inbred rats

Preclinical evidence suggests there is a link between the responsiveness to stress and the propensity to self-administer drugs of abuse. Our previous findings, for example, have shown a significant positive correlation between the locomotor response to novelty and the acquisition of morphine self-administration in Lewis (LEW), Fischer 344 (F344) and ACI inbred rat strains. As an extension of this work, we now report on the neuroendocrine responses (i.e., corticosterone and prolactin secretion) evoked by morphine administration in these same inbred strains. Male LEW, F344, and ACI rats were surgically prepared with indwelling jugular catheters 7 days prior to the study. Following a habituation period, rats were treated with i.p. saline or morphine (1, 5 or 10 mg/kg). Repeated blood samples were withdrawn via the catheters immediately before and at 20, 40, 60 and 120 min after injection. Plasma samples were assayed for hormone levels by radioimmunoassay. No differences in baseline corticosterone levels were found across strains. There was a significant effect of genotype on the corticosterone response to saline injection (i.e., mild stress), with F344 rats exhibiting sustained elevations in corticosterone compared to LEW and ACI rats. Morphine-induced stimulation of corticosterone release differed significantly across strains, and in this case LEW rats displayed a reduced sensitivity to morphine. Similar to the corticosterone results, LEW rats also had blunted prolactin responses to morphine when compared to F344 rats. Our data demonstrate that genotype is an important factor modulating the neuroendocrine sensitivity to morphine. It is noteworthy that LEW rats acquire self-administration more rapidly than F344 or ACI rats, yet LEW rats display reduced corticosterone responses to stress and morphine. Taking into account the particular conditions of this study (high i.p. doses used here vs. low i.v. doses in self-administration studies), our results do not suggest that corticosterone response to stress and morphine is related to vulnerability to intravenous opiate self-administration. The data, however, are consistent with the idea of that genetic factors might influence the sensitivity to the morphine-induced effects of glucocorticoids across these inbred strains.     

Applying horizontal gene transfer phenomena to enhance non-viral gene therapy

Horizontal gene transfer (HGT) is widespread amongst prokaryotes, but eukaryotes tend to be far less promiscuous with their genetic information. However, several examples of HGT from pathogens into eukaryotic cells have been discovered and mimicked to improve non-viral gene delivery techniques. For example, several viral proteins and DNA sequences have been used to significantly increase cytoplasmic and nuclear gene delivery. Plant genetic engineering is routinely performed with the pathogenic bacterium Agrobacterium tumefaciens and similar pathogens (e.g. Bartonella henselae) may also be able to transform human cells. Intracellular parasites like Trypanosoma cruzi may also provide new insights into overcoming cellular barriers to gene delivery. Finally, intercellular nucleic acid transfer between host cells will also be briefly discussed. This article will review the unique characteristics of several different viruses and microbes and discuss how their traits have been successfully applied to improve non-viral gene delivery techniques. Consequently, pathogenic traits that originally caused diseases may eventually be used to treat many genetic diseases.     

Neurofunctional and behavioral correlates of phonetic and temporal categorization in musically trained and untrained subjects

The perception of rapidly changing verbal and nonverbal auditory patterns is a fundamental prerequisite for speech and music processing. Previously, the left planum temporale (PT) has been consistently shown to support the discrimination of fast changing verbal and nonverbal sounds. Furthermore, it has been repeatedly shown that the functional and structural architecture of this supratemporal brain region differs as a function of musical training. In the present study, we used the functional magnetic resonance imaging technique, in a sample of professional musicians and nonmusicians, in order to examine the functional contribution of the left PT to the categorization of consonant-vowel syllables and their reduced-spectrum analogues. In line with our hypothesis, the musicians showed enhanced brain responses in the left PT and superior discrimination abilities in the reduced-spectrum condition. Moreover, we found a positive correlation between the responsiveness of the left PT and the performance in the reduced-spectrum condition across all subjects irrespective of musical expertise. These results have implications for our understanding of musical expertise in relation to segmental speech processing.