Lack of evidence for opioid tolerance or dependence in rhesus monkeys following high-dose anabolic-androgenic steroid administration.

Prolonged use of high-dose anabolic-androgenic steroids (AAS) may induce a dependence syndrome, and emerging evidence suggests that AAS effects on endogenous opioid systems may contribute to AAS abuse. The present study tested the hypothesis that high dose AAS treatment enhances endogenous opioid activity in rhesus monkeys as revealed by 1) tolerance to the antinociceptive effects of the mu opioid agonist morphine and 2) physical dependence as indicated by evidence of opioid withdrawal following administration of the opioid antagonist naloxone. Three rhesus monkeys were treated for 14 days with 3.2 mg/kg/day testosterone propionate, and the effects of morphine (0.32-10 mg/kg) and naloxone (0.01-0.32 mg/kg) were examined both before and during treatment. Morphine antinociception was evaluated using a warm-water tail-withdrawal procedure, and naloxone-precipitated withdrawal was evaluated using checked behavioral signs and measures of ventilatory rate. Chronic testosterone administration for 14 days produced a 100-fold increase in mean plasma testosterone levels. However, testosterone treatment did not significantly alter the antinociceptive effects of morphine, and naloxone did not precipitate signs of opioid withdrawal either before or during testosterone treatment. These data do not support the hypothesis that high-dose AAS treatment enhances endogenous opioid activity in rhesus monkeys in a way that produces opioid tolerance or dependence.

Over-the-counter drug use in gymnasiums: an underrecognized substance abuse problem?

OBJECTIVE: Many individuals, attempting to gain muscle or lose fat, use 'dietary supplements'. Though widely available over the counter or by mail order in America and Europe, some of these 'supplements' are actually potent drugs such as androstenedione and ephedrine. We sought to estimate the prevalence of these forms of drug use in American gymnasiums. METHODS: We distributed anonymous questionnaires to 511 clients entering five gymnasiums, asking about use of both supplements and anabolic steroids. RESULTS: Among men, 18% reported use of androstenedione and/or other adrenal hormones, 25% reported ephedrine use, and 5% reported anabolic steroid use within the last 3 years; among women these rates were 3, 13 and 0%. Extrapolating from these figures to the United States as a whole, we estimated that possibly 1.5 million American gymnasium clients have used adrenal hormones and 2.8 million have used ephedrine within the last 3 years. CONCLUSIONS: Millions of men and women are currently using potent drugs, widely sold over the counter as 'supplements', despite their known adverse effects, unknown long-term risks, and possible potential for causing abuse or dependence.

fMRI during affect discrimination in bipolar affective disorder.

OBJECTIVE: It has been hypothesized that disturbances in affect may represent distinct etiologic factors for bipolar affective disorder. The neural mechanisms mediating affective processes and their relationship to brain development and the pathophysiology of bipolar affective disorder remain to be clarified. Recent advances in neuroimaging techniques have made possible the non-invasive examination of specific brain regions during cortical challenge paradigms. This study reports findings based on fMRI data acquired during fearful and happy affect recognition paradigms in patients with bipolar affective disorder and in healthy adult subjects. METHODS: Prior to the scan, subjects were instructed to view the stimuli and to identify the type of facial expression presented. Echo planar scanning was performed on a 1.5 Tesla scanner which had been retrofitted with a whole body echo planar coil, using a head coil. RESULTS: The data indicate that in adult subjects with bipolar affective disorder, there is a reduction in dorsolateral prefrontal cortex activation and an increase in amygdalar activation in response to fearful facial affect. In a healthy comparison group, signal intensity changes were not found in these regions. In addition, although the patients with bipolar affective disorder completed the task demands, they demonstrated an impaired ability to correctly identify fearful facial affect but not the happy facial affect displayed. CONCLUSION: These findings are consistent with the hypothesis that in some patients with bipolar affective disorder, there may be a reduction of frontal cortical function which may be associated with affective as well as attentional processing deficits.

Temporal and regional profiles of cytoskeletal protein accumulation in the rat brain following traumatic brain injury.

To characterize the cytoskeletal aberration due to traumatic injury, temporal and regional profiles of changes in immunoreactivity of microtubule-associated protein 2 (MAP2), neurofilament heavy subunit protein (NFH) and heat shock protein 72 (HSP72) were investigated after different magnitudes of traumatic brain injury by fluid percussion. The experimental rat brain was perfusion-fixed at 1, 6 and 24 hours after traumatic brain injury. Conventional histological staining has demonstrated that the mildest traumatic brain injury (1.0 atm) induced no neuronal loss at the impact site and that neuron loss was apparent when traumatic brain injury was increased to 4.3 atm. The mildest traumatic brain injury, however, caused a significant increase in HSP72 immunoreactivity in the superficial cortical layers at the impact site as early as 1 hour after the injury. In the case of severe traumatic brain injury (4.3 atm), neuron loss was apparent in the area at the impact site, but the increase in HSP72 immunoreactivity was moderate, and it was observed only after 6 hours in the deep cortical layers under the necrotic area. The increased immunostaining of MAP2 was demonstrated in damaged axons and neuronal perikarya in the wider area surrounding the impact site at 6 and 24 hours after the injury. Six and 24 hours after the injury, perikaryal accumulation of neurofilament was observed, and the accumulated neurofilament was mostly phosphorylated. These results indicate that the severe traumatic brain injury of 4.3 atm triggers the abnormal accumulation of cytoskeletal proteins in neuronal perikarya, most probably due to an impairment of axonal transport. It is implied that the increased expression of HSP72 may be involved in the protective process of neurons after traumatic brain injury.

The effects of repetitive mild brain injury on cytoskeletal protein and behavior.

The purpose of this study was to examine the hypothesis if repetition of mild mechanical brain injury induces the pathological process related to Alzheimer's disease. After defining the magnitude of the subthreshold brain injury which does not induce brain tissue damage by a single hit, the subthreshold mild impact (1.0 atm) was repeated 7 times every 24 h. One week after the last impact, abnormal accumulation of microtubule-associated protein 2 (MAP2) and phosphorylated neurofilament 200 kD (p-NFH) was observed in neuronal perikarya and dendrites. One month after percussion, the number of MAP2-and p-NFH-positive neuronal perikarya was increased and observed in remote areas including the contralateral cortex and the hippocampus. Tau-1 immunoreactivity was increased in deep cortical neurons of the ipsilateral side after dephosphorylation, indicating the accumulation of phosphorylated tau in neuronal perikarya. The abnormal accumulation of cytoskeletal proteins in neuronal perikarya may be due to impaired axonal transport caused by mechanical brain injury. The behavioral study revealed that after repetitive mild percussion, rats show less efficient habituation to a new environment. It is suggested that the repetition of subthreshold mechanical brain injury may trigger cytoskeletal alteration related to neuronal degeneration.

Cell-cycle-dependent abnormal calcium response in fibroblasts from patients with familial Alzheimer's disease.

Change in calcium response was studied to clarify the pathological process of Alzheimer's disease (AD). Cultured fibroblasts from patients with familial Alzheimer's disease (FAD; n = 6), sporadic Alzheimer's disease (SAD; n = 4), and age-matched healthy control subjects (n = 4) were studied with an ACAS Interactive Laser Cytometer (ACAS-470). Fibroblasts from two independent families with FAD (OS-1, and OS-2 families) showed a suppressed calcium response after stimulation by 100 nM bradykinin (BK) 100 nM vasopressin (VP) or 10% FCS in Ca(2+)-free condition compared with control fibroblasts at 48 h after plating. However, on the 7th day after plating, the abnormal calcium response was no longer observed. The height of the calcium peak showed periodic variation, indicating a relationship of calcium response with the cell cycle. When fibroblasts from OS-1 and OS-2 families were arrested in S phase, they showed a significantly suppressed calcium peak after BK stimulation. However, when those fibroblasts were arrested in other phases, they showed the same calcium peak as the other cells. The suppression of calcium response in S phase was indistinguishable from the calcium suppression induced by A23187 administration. Since Hardy type mutation on amyloid precursor protein gene is found in the OS-1 family, the observed abnormalities in calcium response might be related with pathological processing of amyloid precursor protein in AD. The reported abnormal calcium response, which is observed most obviously in fibroblasts in S phase, may indicate participation of the cell-cycle-dependent process in the pathology of AD.