Everett H. Ellinwood

Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment

Research into methamphetamine-induced neurotoxicity has experienced a resurgence in recent years. This is due to (1) greater understanding of the mechanisms underlying methamphetamine neurotoxicity, (2) its usefulness as a model for Parkinsons disease and (3) an increased abuse of the substance, especially in the American Mid-West and Japan. It is suggested that the commonly used experimental one-day methamphetamine dosing regimen better models the acute overdose pathologies seen in humans, whereas chronic models are needed to accurately model human long-term abuse. Further, we suggest that these two dosing regimens will result in quite different neurochemical, neuropathological and behavioral outcomes. The relative importance of the dopamine transporter and vesicular monoamine transporter knockout is discussed and insights into oxidative mechanisms are described from observations of nNOS knockout and SOD overexpression. This review not only describes the neuropathologies associated with methamphetamine in rodents, non-human primates and human abusers, but also focuses on the more recent literature associated with reactive oxygen and nitrogen species and their contribution to neuronal death via necrosis and/or apoptosis. The effect of methamphetamine on the mitochondrial membrane potential and electron transport chain and subsequent apoptotic cascades are also emphasized. Finally, we describe potential treatments for methamphetamine abusers with reference to the time after withdrawal. We suggest that potential treatments can be divided into three categories; (1) the prevention of neurotoxicity if recidivism occurs, (2) amelioration of apoptotic cascades that may occur even in the withdrawal period and (3) treatment of the atypical depression associated with withdrawal.

Hypercortisolemia and hippocampal changes in depression

Hypercortisolemia is a frequently observed abnormality in patients with major depression. It has been hypothesized that the hippocampus, as a major feedback site for glucocorticoids, is involved in the pathophysiology of hypercortisolemia. Some have in fact posited that the hippocampus is marked by diminished size in depressed patients with hypercortisolemia. We tested this hypothesis by examining the relationship between hippocampal volume, assessed with magnetic resonance imaging, and hypercortisolemia using the dexamethasone suppression test (DST) in a group of 19 depressed patients. No differences in hippocampal volume were observed between patients and control subjects (n = 30). Within the patient group, DST suppressors did not differ from DST nonsuppressors in hippocampal volume. However, a relationship between hippocampal volume and 11 p.m. cortisol concentration was observed after covariance adjustment for age and sex. Furthermore, significant negative correlations were observed between hippocampal volume and both age of depressive onset and number of hospitalizations. The results of this study therefore provide limited support for the hypothesis regarding an essential role of the hippocampus in the neuroendocrine elevation of glucocorticoids in depression.

Leukoencephalopathy in patients diagnosed as major depressive

Bradley et al. (1984) reported that 30% of patients over the age of 60 demonstrate leukoencephalopathy or patchy, deep white matter lesions (PWML) of abnormal signal intensity on T2 weighted images on magnetic resonance imaging (MRI). These foci, which are not seen in normal individuals below the age of 45 (George et al. 1986b), are believed to be a function of the late stage of the aging process. With MRI, areas of deep white matter foci resemble those seen in known cerebral infarction (Erkinjuntti et al. 1984) and are reported to correspond to areas of moderate to severe arteriolar hyalinization and rarefaction on pathological examination (George et al. 1986a). The overall perspective on the clinical significance of PWML has yet to be determined. In patients with Alzheimer’s disease, the prevalence and severity of PWML is increased (Bent-~wad~i et al. 1985; George et al. 1986b). Prevalence of PWML of 36.67% was found in patients with Alzheimer’s disease at our medical center (mean age 64.3 years) (Heyman et al. 1986). Post (1962) and Roth (1986) suggested that the increased prevalence and severity of depressive illness and suicide in middle and late life is due to subtle cerebral (primarily vascular) changes correlated with aging. As PWML may reflect early and subtle alterations in cerebral function, we decided to assess the relationship, if any, between the occurrence of PWML (leuk~nceph~opa~y) and depression, especially depression in middle and late life. We also examined the relationship between PWML and early-onset affective disorder (i.e., onset of first episode before the age of 45) and affective disorder that first occurs after the age of 45. We used 45 years as the cutoff for the study because of the report that PWML are not seen in normal individuals below the age of 45 (George et al. 1986b). We also examined the hypothesis that the incidence of PWML would be higher in patients with the first episode of affective disorder above age 45 than in those patients above 45 with affective disorder that started before the age of 45. Such a finding would suggest that PWML may be causally related to depression in some of these individuals.

Neuroanatomical substrates of depression in the elderly

SummaryThe etiology of depression in the elderly is poorly understood. In this study, magnetic resonance imaging was used to evaluate the role of subcortical structures in the pathophysiology of depression in the elderly. Elderly depressed patients were found to have smaller caudate nuclei, smaller putaminal complexes and in increased frequency of subcortical hyperintensities compared with normal, healthy controls. These findings were more pronounced in patients with lateonset depression. Based on these findings, the authors discuss the role of the basal ganglia in the pathophysiology of depression in the elderly.

In vivo assessment of pituitary volume with magnetic resonance imaging and systematic stereology: Relationship to dexamethasone suppression test results in patients

The relationship between dexamethasone suppression test (DST) results and in vivo pituitary volume was studied in 24 psychiatric inpatients. The principles of systematic stereology were used to measure pituitary volume from 3-mm contiguous sagittal spin-echo magnetic resonance (MR) images of the brain. There was no correlation between pituitary volume and 3 p.m. or 10 p.m. postdexamethasone (post-DEX) plasma cortisol concentrations. However, when multiple regression analysis was performed to relate pituitary volume to gender, age, and post-DEX plasma cortisol concentrations, there was a significant relationship between pituitary volume and age, gender, and 10 p.m. post-DEX cortisol plasma concentration. This is the first study to demonstrate a method that directly measures, rather than estimates, in vivo pituitary volume. Furthermore, it suggests that activation of the hypothalamic-pituitary-adrenal axis in psychiatric patients, as manifested by elevated post-DEX cortisol concentrations, may influence pituitary volume.

Intermittent and Continuous cocaine Administration: Residual Behavioral states during withdrawal

Rats were pretreated with 40 mg/kg/day cocaine for 14 days by either subcutaneous injections or osmotic minipumps. Rats were then withdrawn from the pretreatment regime for 1 or 7 days and given a 20-mg/kg IP cocaine challenge (day 1) or a 0-, 10-, 20-, or 40-mg/kg IP cocaine challenge (day 7). The results indicate that rats receiving intermittent, daily injections exhibited sensitization to the behavioral effects of a cocaine challenge on days 1 and 7 of withdrawal. In contrast, rats receiving continuous cocaine exhibited tolerance to the behavioral effects of a cocaine challenge on days 1 and 7 of withdrawal. The present results support and extend previous research that indicates that the route and temporal pattern of administration influences the effects of chronic cocaine. Furthermore, the present results indicate that the continuous infusion paradigm may represent an alternative animal model of some aspects of high-dose cocaine abuse, as compared to the typical procedure of single, or multiple, daily cocaine injections.

Posterior fossa abnormalities in major depression: a controlled magnetic resonance imaging study

High‐field magnetic resonance (MR) images were used to study posterior fossa morphology in 27 patients with major depression and 36 normal control subjects. Depressed patients demonstrated smaller brain stem and cerebellar vermis than controls. These differences were highly significant for the anterior cerebellar vermis and medulla. There was also a striking age‐related decline in midbrain size in depressed patients as well as in controls. Our results are consistent with several lines of evidence implicating a role for the cerebellar vermis in affective disorders and, in addition, provide the first MR documentation of the differential effects of aging on posterior fossa morphology in normal subjects compared with patients with major depression.

Comparative pharmacokinetics and pharmacodynamics of lorazepam, alprazolam and diazepam

The contribution of differential absorption-distribution pharmacokinetics to drug activity can be partially determined by comparing simultaneous estimates of drug serum level with pharmacodynamic effects. In the present paper we have contrasted the effects of clinically equipotent doses of lorazepam, alprazolam, and diazepam on the performance of tracking and digit symbol substitution tasks. Eight young males were tested for 12 h after ingesting the drug. The three benzodiazepines and placebo were administered to each subject according to a balanced double-blind Latin square design. A model is presented that describes the relationship between drug concentration and the degree of impairment across time after the final peak effect. Exponential rate constants were determined for each drug using a Marquardt nonlinear fit of the pooled data. Basically, the constants relate offset serum drug values to the impairment curves at a time when serum-brain equilibrium is assumed to have occurred. The values indicate markedly rapid acute tolerance for alprazolam and diazepam but relatively little acute tolerance for lorazepam. Whether these constants reflect adaptation or differential association-dissociation receptor rate constants cannot be determined, but they do highlight the need to consider receptor kinetics as an important factor in benzodiazepine pharmacodynamics.

In vivo stereological assessment of caudate volume in man: Effect of normal aging

Using intermediate weighted magnetic resonance imaging (MRI) and a systematic sampling stereological method in 39 normal volunteers aged 24-79 years old, we demonstrated a marked age-associated decline in caudate nuclei volume (r = -0.69, p less than 0.0001). The mean absolute volume of the caudate nuclei in this study (9.4 cm3) was almost identical to that reported in a previous autopsy study and further confirms the validity of this stereological technique for use with MR images. This technique will provide a method for measuring the caudate and other nuclei in vivo, from brain images and, as such, a research tool to correlate age-associated changes in cognitive, sensory and motor function with caudate nucleus volume and other brain regions.

Therapeutic effects of antidepressants in chronic pain

Depression and chronic pain syndromes are often associated. Over the last twenty years there has been a number of controlled and uncontrolled studies evaluating the efficacy of antidepressants in various pain problems. The administration of antidepressant medications in the management of chronic pain has become a commonly prescribed therapeutic modality in the treatment of this complex syndrome. This paper reviews the clinical studies in which antidepressants have been used to control chronic pain, summarizes the results of the clinical studies, and comments on the mechanism of action of antidepressants in chronic pain.