Abnormal brain activation to visual stimulation in cocaine abusers

Chronic cocaine abuse has been associated with cerebrovascular pathology. This is likely to reflect its vasoactive effects; cocaine produces vasoconstriction and reduces cerebral blood flow. We propose that cerebrovascular pathology in chronic cocaine abusers would result in abnormal BOLD [blood oxygenation level dependent] responses to activation stimuli. Here, we used fMRI to compared the BOLD response to photic visual stimulation in neurologically intact active cocaine abusers to that in non-drug-using healthy controls. Cocaine abusers showed a significantly enhanced positive BOLD response to photic stimulation when compared to control subjects. The enhanced activation in the cocaine abusers could result from low resting cerebral blood flow secondary to increased vasoconstriction and/or from low oxidative metabolism during activation. Alternatively, the larger signal intensity in the cocaine abusers could result from inefficient neuronal processing as has been shown to occur in other conditions of cerebral pathology. These findings provide evidence of cerebral dysfunction with chronic cocaine abuse, which could reflect cerebral blood flow or neuronal changes. Further studies are required to determine if the cerebrovascular changes we observed in the cocaine abusers recover with detoxification and to assess their functional consequences.     

Neuroendocrine responses to cocaine do not exhibit sensitization following repeated cocaine exposure.

Cocaine-induced enhancement of motor activity and extracellular dopamine concentrations exhibits sensitization upon repeated exposure. In this study, the neuroendocrine responses to cocaine were examined following cocaine pretreatment regimens which have been shown to produce behavioral sensitization. Adult male rats were injected with cocaine (15 mg/kg, IP) once daily for 14 days, followed by a dose-response challenge with cocaine (1-15 mg/kg, IP) either 18 hours or 7 days after the final pretreatment injection. Blood was collected 15 minutes following injections for radioimmunoassay of ACTH, corticosterone, prolactin, and renin. Cocaine increased plasma ACTH and corticosterone, while it decreased prolactin and renin concentrations. Pretreatment with cocaine for 2 weeks did not alter any of these endocrine responses after either the 18 hour or 7 day interval between pretreatment and challenge injections. In contrast, sensitization to the locomotor stimulant effects of cocaine was observed on the final day of pretreatment injections, and 7 days later. These data suggest that these endocrine effects of cocaine do not exhibit sensitization following repeated cocaine exposure.     

Oxidative metabolism of cocaine: comparison of brain and liver

Norcocaine (NC) and N-hydroxynorcocaine (NHNC), products of the oxidative metabolism of cocaine, were examined in plasma, brain, and liver of mice injected intraperitoneally with cocaine. Plasma levels of NHNC were altered in vivo by inhibiting esterase activity with diazinon and chloral hydrate or activating esterase activity with phenobarbital, and activating the microsomal P-450 system with phenobarbital. Changes in plasma concentrations of NHNC resulted in similar changes in brain, which were often different from those in liver. After intracisternal administration of cocaine to mice, no appreciable amount of NC or NHNC could be detected in brain; the same results were obtained upon intracisternal and intraventricular administration to rats. Microsomal preparations from mouse brain were found to be considerably less active than those from liver in converting NC to NHNC. We conclude that the cerebral oxidative metabolism of cocaine is not appreciable and that most of the NC and NHNC found in the brain after systemic cocaine administration is derived from plasma rather than formed centrally by brain microsomal enzymes.     

Serotonin 5-HT2 receptor availability in chronic cocaine abusers

Serotonin 5-HT₂ receptor availability was evaluated in chronic cocaine abusers (n = 19) using positron emission tomography and F-18 N-methylspiperone and was compared to control subjects (n = 19). 5-HT₂ Receptor availability was measured in frontal, occipital, cingulate and orbitofrontal cortices using the ratio of the distribution volume in the region of interest to that in the cerebellum which is a function of B_max/K_d- 5-HT₂ Receptor availability was significantly higer in cingulate and orbitofrontal cortices than in other frontal regions or occipital cortex. The values were not different in normal subjects and cocaine abusers. These results did not show any changes in 5-HT₂ receptor availability in cocaine abusers as compared to the control subjects.     

Permanent alterations in 5-hydroxytryptamine metabolism in discrete areas of rat brain following exposure to drugs during the period of development

Methylamphetamine, chlorpromazine, phencyclidine and imipramine were administered in the drinking water of rats during pregnancy and the suckling period. Male offspring were given no drugs after weaning until nine months later; groups were then injected with p-chlorophenylalanine or saline, killed nine hours later and the brains dissected into eight areas. Exposure to methylamphetamine, chlorpromazine or phencyclidine during the period of brain development was found to have had permanent effects both on 5-hydroxytryptamine concentrations and on the rate of depletion after synthesis blockade.     

Influence of lead exposure on catecholamine metabolism in discrete rat brain nuclei

1. Using the rat exposed both acutely and chronically to lead as a model of lead neurotoxicity, various parameters of catecholamine metabolism were investigated. 2. The steady-state concentrations of noradrenaline, adrenaline and dopamine together with the activities of tyrosine hydroxylase and phenylethanolamine N-methyl transferase were measured in discrete brain nuclei--periventricular, paraventricular, median eminence, posterior and anterior hypothalamus, caudate putamen and globus pallidus. 3. Lead exposure resulted in significant fall in the activity of the rate-limiting enzyme of catecholamine synthesis, tyrosine hydroxylase which was associated with alterations in concentrations of catecholamines in the median eminence, periventricular nucleus and anterior hypothalamus. 4. No other brain nuclei investigated exhibited any effect of lead on the catecholaminergic nervous system and, therefore, the effect of lead on rat brain can be considered to be regionally specific.     

Alterations in some membrane properties in rat brain following exposure to lead

The effect of lead exposure on intracellular calcium levels, membrane fluidity, lipid peroxidation, acetylcholinesterase and monoamine oxidase activity and its accumulation in different regions of the brain were studied to understand the molecular mechanism of lead induced neurotoxicity. Lead treatment (20 mg/kg lead nitrate, intraperitoneally, once daily for 15 days) resulted in a significant accumulation of lead in all brain regions with the maximum being in the hippocampus. Levels of glutathione, lipid peroxidation, intracellular calcium and membrane fluidity, as well as the activity of the membrane bound enzymes, acetylcholinesterase and monoamine oxidase, increased to a significant level in certain areas of the rat brain. The results suggest that lead exerts neurotoxic effects by altering certain membrane bound enzymes and may cause oxidative stress.     

Effect of subchronic exposure to tetradifon on bone remodelling and metabolism in female rat

This study investigates the effect of subchronic exposure to tetradifon, an organochlorine pesticide with an oestrogen-like structure, in female rat. A single cumulative dose of 2430 mg/kg BW was administrated orally for 12 female rats of 190 g BW. Twelve non-treated additional rats have served as controls. Animals were sacrificed after 6 and 12 weeks of treatment. We studied bone remodelling through histomorphometry and scanning electron microscopy (SEM) analyses. The serum and the right femora were used to determine phosphatase alkaline (AlkP) and/or calcium and phosphorus content. No sign of toxicity was observed until the end of the experiment. The SEM results revealed no structural alteration of the treated animal bone tissue. However, in both treated groups, we have noted an increase in the trabecular distance and a heterogeneous aspect of the endosteum that could be explained by bone-remodelling disturbance, with relative delay of ossification. Following histomorphomotric analysis, these results were coupled with significant increases in Tb.Th and OS/BS. Elsewhere, tetradifon intoxication increased significant serum AlkP level in the group treated for 12 weeks, which could be explained by an osteoblastic hyperactivity. Tetradifon intoxication decreased significantly bone calcium end phosphorus contents. Tetradifon seems not to exert major effects on bone remodelling. However, the osteoblastic hyperactivity could be explained by the oestrogen-like activity of tetradifon and its fatty metabolism. In fact, oestrogen inhibits bone remodelling, and enhances bone formation, which could result in an increase of the osteoid surface and explain the relative delay of ossification.     

Tyrosine hydroxylase activity in rat brain following "REM" sleep deprivation

I n R ecent years biogenic amines have been implicated in the control mechanism for induction and maintenance of sleep processes (J ouvet , 1969). Investigators have looked for changes in the rate of synthesis of cerebral norepinephrine from [³H]tyrosine after REM sleep deprivation and reported increased rates of synthesis during REM sleep deprivation (M ark , H einer , M andel and G odin , 1969) and REM sleep rebound following 91 h of deprivation (P ujol , M ouret and G lowinski , 1968). Because tyrosine is thought to be the rate-limiting enzyme (U denfriend , 1966) in the synthetic pathways for norepinephrine and since the above-mentioned studies are suggestive of changes in the activity of the enzyme, we decided to measure tyrosine hydroxylase activity following REM sleep deprivation.     

Rapid estrogen regulation of DHEA metabolism in the male and female songbird brain

In the songbird brain, dehydroepiandrosterone (DHEA) is metabolized to the active and aromatizable androgen androstenedione (AE) by 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase (3β-HSD). Thus, brain 3β-HSD plays a key role in regulating the steroidal milieu of the nervous system. Previous studies have shown that stress rapidly regulates brain 3β-HSD activity in a sex-specific manner. To elucidate endocrine regulation of brain 3β-HSD, we asked whether 17β-estradiol (E₂) regulates DHEA metabolism in adult zebra finch ( Taeniopygia guttata ) and whether there are sex-specific effects. Brain tissue was homogenized and centrifuged to obtain supernatant lacking whole cells and cell nuclei. Supernatant was incubated with [³H]DHEA and radioinert E₂ in vitro . Within only 10 min, E₂ significantly reduced 3β-HSD activity in both male and female brain. Interestingly, the rapid effects of E₂ were more pronounced in females than males. These are the first data to show a rapid effect of estrogens on the songbird brain and suggest that rapid estrogen effects differ between male and female brains.     

Testosterone metabolism in Neomysis integer following exposure to benzo(a)pyrene

Cytochromes P450 (CYPs) are important enzymes involved in the regulation of hormone synthesis and in the detoxification and/or activation of xenobiotics. CYPs are found in virtually all organisms, from archae, and eubacteria to eukaryota. A number of endocrine disruptors are suspected of exerting their effects through disruption of normal CYP function. Consequently, alterations in steroid hormone metabolism through changes in CYP could provide an important tool to evaluate potential effects of endocrine disruptors. The aim of this study was to investigate the potential effects of the known CYP modulator, benzo(a)pyrene (B(a)P), on the testosterone metabolism in the invertebrate Neomysis integer (Crustacea; Mysidacea). N. integer were exposed for 96 h to 0.43, 2.39, 28.83, 339.00 and 1682.86 μg B(a)P L^− 1 and a solvent control, and subsequently their ability to metabolize testosterone was assessed. Identification and quantification of the produced phase I and phase II testosterone metabolites was performed using liquid chromatography coupled with multiple mass spectrometry (LC–MS²). Significant changes were observed in the overall ability of N. integer to metabolize testosterone when exposed to 2.39, 28.83, 339.00 and 1682.86 μg B(a)P L^− 1 as compared to the control animals.     

Cancer mortality following in utero exposure among offspring of female mayak worker cohort members

Little is known about long-term cancer risks following in utero radiation exposure. We evaluated the association between in utero radiation exposure and risk of solid cancer and leukemia mortality among 8,000 offspring, born from 1948-1988, of female workers at the Mayak Nuclear Facility in Ozyorsk, Russia. Mother's cumulative gamma radiation uterine dose during pregnancy served as a surrogate for fetal dose. We used Poisson regression methods to estimate relative risks (RRs) and 95% confidence intervals (CIs) of solid cancer and leukemia mortality associated with in utero radiation exposure and to quantify excess relative risks (ERRs) as a function of dose. Using currently available dosimetry information, 3,226 (40%) offspring were exposed in utero (mean dose = 54.5 mGy). Based on 75 deaths from solid cancers (28 exposed) and 12 (6 exposed) deaths from leukemia, in utero exposure status was not significantly associated with solid cancer: RR = 0.94, 95% CI 0.58 to 1.49; ERR/Gy = -0.1 (95% CI < -0.1 to 4.1), or leukemia mortality; RR = 1.65, 95% CI 0.52 to 5.27; ERR/Gy = -0.8 (95% CI < -0.8 to 46.9). These initial results provide no evidence that low-dose gamma in utero radiation exposure increases solid cancer or leukemia mortality risk, but the data are not inconsistent with such an increase. As the offspring cohort is relatively young, subsequent analyses based on larger case numbers are expected to provide more precise estimates of adult cancer mortality risk following in utero exposure to ionizing radiation.