Philip J. Langlais

A corticosteroid/dopamine hypothesis for psychotic depression and related states

In recent years, considerable data have emerged that psychotic (delusional) depression is characterized by pronounced increases in hypothalamic-pituitary-adrenal (HPA) axis activity and positive responses to combined treatment with tricyclic antidepressants and antipsychotic (dopamine-blocking) agents. Recently, a number of observations in several species, including man, point to glucocorticoids increasing dopamine activity in a variety of tissues and this effect is particularly marked in rat brain mesolimbic dopamine systems. We propose that glucocorticoids enhancement of dopaminergic activity may explain the development of psychosis/delusions in the context of the depressive episode. Data in support of the hypothesis are presented and the identification of possible enzymatic risk factors are discussed. These interactions also have implications for understanding the biology of corticosteroid-induced psychoses in medical patients and some of the psychiatric complications of Cushings Disease.

The effects of a single acute dose of dexamethasone on monoamine and metabolite levels in rat brain.

Twenty male Sprague-Dawley rats were injected intraperitoneally with either 20 micrograms of dexamethasone or an equivalent volume of saline. The rats were then sacrificed at either one or four hours after the injections and their brains analyzed for monoamine and metabolite content using High Performance Liquid Chromatography with Electrochemical Detection. Significant effects were seen in dopaminergic and serotonergic systems, but these effects varied depending on the area of rat brain studied. Significant increases in dopamine (DA) levels were seen in the hypothalamus and nucleus accumbens of the dexamethasone treated rats when compared with saline treated rats. There was no significant effect of dexamethasone on DA levels in frontal or striatal brain areas. In the dexamethasone treated rats a significant increase in serotonin (5-HT) was observed in the hypothalamus; a significant decrease in 5-HT was observed in the frontal cortex. Biological and clinical implications of these findings are discussed.

Late‐onset Hallervorden‐Spatz disease presenting as familial parkinsonism

We studied a 68-year-old man who died after 13 years of progressive dementia, rigidity, bradykinesia, mild tremor, stooped posture, slow and shuffling gait, dystonia, blepharospasm, apraxia of eyelid opening, anarthria, aphonia, and incontinence. At autopsy, he had generalized brain atrophy with large deposits of iron pigment in the globus pallidus, caudate, and substantia nigra. Axonal spheroids were found in the globus pallidus, substantia nigra, medulla, and spinal cord. The neurochemical analysis of the brain revealed marked loss of dopamine in the nigral-striatal areas, with relative preservation of dopamine in the limbic areas. This is the oldest case of familial Hallervorden-Spatz disease reported and the first with neurochemical analysis of the brain.

Dexamethasone increases plasma free dopamine in man

In man, unconjugated plasma DA is normally undetectable or present in minute amounts. Twelve medication-free volunteers received a 1 mg dose of dexamethasone which produced pronounced increases of plasma free DA but not of other catecholamines. Mean plasma free dopamine levels after dexamethasone at 8 a.m. (155 +/- 102 pg/ml) and 4 p.m. (163 +/- 70 pg/ml) were significantly higher (p less than 0.001) than those at 8 a.m. (50 +/- 18 pg/ml) and 4 p.m. (42 +/- 7 pg/ml) before dexamethasone. Although the mechanism of increased dopaminergic activity after a dose of dexamethasone remains for future research, the data presented in this paper may explain the observations that corticosteroids lower prolactin levels and may induce psychiatric disturbances, as well as the finding that depressed patients with high postdexamethasone cortisol levels are frequently psychotic.

Behavioral impairments, brain lesions and monoaminergic activity in the rat following recovery from a bout of thiamine deficiency

Learning impairments were measured in rats following recovery from a subacute bout of thiamine deficiency. Behavioral training was carried out in an automated T-maze, beginning with paired run spatial delayed non-matching to sample (PR-1), then light-dark discrimination (LD), light-dark discrimination reversal (LD-R), spatial discrimination (SD), spatial discrimination-reversal (SD-R), and finally retraining on the original paired run task (PR-2). Comparable deficits were observed for PR-1 and PR-2, thus demonstrating long-lasting impairment on delayed non-matching to sample. Experimentals performed as well as controls on LD and LD-R. Two experimental animals were unable to perform above chance on the simple SD task. The remaining 15 experimental animals were equivalent to controls on several measures of SD and SD-R performance (errors to criterion, number of animals reaching criterion, correct responses in last 60 trials) although they were significantly worse than controls on both PR-1 and PR-2. Taken together, these results indicate an impairment of representational memory (PR-1, PR-2) with a spared capacity for dispositional memory (LD, LD-R, SD, SD-R) as defined by Thomas and Spafford (Behav. Neurosci., 1984, 98: 394-404). Histological analyses of left hemispheres revealed a high incidence (94%) of thalamic lesions, specifically within the intralaminar nuclei and ventral parts of the mediodorsal nucleus; and an absence of detectable changes in other structures, including the mammillary bodies, hippocampus, cortex, and locus coeruleus. In the right hemispheres, assays of monoamines and metabolites in 17 brain regions showed significant reduction only for norepinephrine in entorhinal cortex. All animals that were selectively impaired on the paired-run task had both the medial thalamic lesions and reduction in entorhinal norepinephrine.

Cerebrospinal fluid levels of angiotensin- converting enzyme, acetylcholinesterase, and dopamine metabolites in dementia associated with Alzheimer's disease and Parkinson's disease: A correlative study☆

Mean levels of the two hydrolases angiotensin-converting enzyme (ACE) and acetylcholinesterase (AChE), the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and total protein concentration were examined in cerebrospinal fluid (CSF) samples from a group of patients with dementia of the Alzheimers type, a group of comparably demented patients with Parkinsons disease, and a neurologically healthy elderly control group. Both pathological groups exhibited a significant decrease in the mean levels of ACE activity and DOPAC per milliliter and were distinguishable from one another based on mean CSH HVA levels. Unlike the Parkinsons disease group, whose mean concentration of HVA was lower than, but not significantly different from that of the control group, the mean HVA concentration of the Alzheimers disease group was significantly elevated. In contrast, comparisons of the mean CSF AChE activity (expressed per milliliter or per milligram of protein) and CSF total protein concentration did not reveal significant differences for any of the groups. Independent of CSF protein concentration, ACE activity per milliliter exhibited a positive correlation with AChE activity per milliliter within the control and Parkinsons disease groups, whereas a statistically significant correlation for these CSF hydrolases was not observed within the Alzheimers disease group. Thus, the CSF profiles for patients with mild dementias associated with Alzheimers or Parkinsons disease differed by at least two neurochemical criteria. Based on the levels of ACE activity, DOPAC, and HVA per milliliter of CSF, two discriminant functions were derived and resulted in the correct classification of 71% of all subjects (n = 38) into Alzheimers disease, Parkinsons disease, and neurologically healthy control groups.

Neurochemical pathology in Korsakoff's psychosis Implications for other cognitive disorders

There seems to be an anatomic correspondence between pathways of monoamine-containing neurons and the brainstem and diencephalic lesions associated with Korsakoff s psychosis. In 25 patients with Korsakoff s disease, we found that CSF levels of metabolites of norepinephrine, dopamine, and serotonin were significantly lower than in controls. Norepinephrine metabolite levels were reduced more consistently and extensively than those of dopamine and serotonin. The 25 patients had circumscribed cognitive deficits, but were not demented. We argue that norepinephrinecontaining neurons are selectively damaged in Korsakoff s psychosis and that lesions of brain monoamine-containing neurons cause specific cognitive impairments, not global dementia.

Psychotic and nonpsychotic depressions: I. Comparison of plasma catecholamines and cortisol measures.

Unconjugated plasma catecholamines and cortisol were measured before and after a 1 mg dose of dexamethasone in 22 medication-free depressed patients and 6 healthy, medication-free control subjects. Plasma dopamine (DA) levels in the psychotically depressed subgroup (n = 4) were significantly higher both before and after dexamethasone than those in the nonpsychotic depressed group and higher before dexamethasone than in the control group. Similarly, the psychotically depressed group exhibited significantly higher cortisol levels both before and after dexamethasone than the nonpsychotic depressed group or the control group. In contrast, the psychotically depressed group had significantly lower postdexamethasone plasma norepinephrine levels compared to the nonpsychotic depressed group. In both patients and controls, plasma DA was significantly higher after dexamethasone administration than before, but the magnitude of the increase was 10 times greater in controls than in patients.

Monoamines and metabolites in cortex and subcortical structures: normal regional distribution and the effects of thiamine deficiency in the rat.

The present study measured the concentration of monoamines, metabolites and estimates of turnover rate in eighteen separate brain regions from controls and a rat model of Korsakoffs disease induced by a two week bout of pyrithiamine and thiamine deficient diet (PTD). A behaviorally tested control (n = 12) and PTD (n = 17) group, and a non-behaviorally tested PTD group (n = 8) were sacrificed 7 months after recovery from treatment. The brains were dissected into nine cortical areas and nine subcortical regions. In behaviorally tested PTD animals, a significant reduction of NE was observed in entorhinal cortex. Diminished norepinephrine (NE) concentration was also observed in entorhinal, hippocampal, septal and olfactory areas of the non-behaviorally tested PTD group. Serotonin and 5-hydroxyindoleacetic acid (5-HIAA) levels were increased in several brain areas, particularly midbrain-thalamus, striatum, of both groups of recovered PTD animals. These findings are discussed with respect to results and hypotheses presented in our previous study of this animal model. Significant differences in monoamine, metabolite and turnover estimates were also observed among cortical areas of the control animals. Entorhinal cortex contained the highest concentration of NE and 5-hydroxytryptamine (5-HT), while DA was highest in somatosensory cortex. The distribution of 5-HT and 5-HIAA were more homogeneous and displayed a rostral-caudal decline in concentration.

Long-Lasting Changes in Regional Brain Amino Acids and Monoamines in Recovered Pyrithiamine Treated Rats

Rats were subjected to a severe bout of thiamine deficiency induced by daily pyrithiamine +a thiamine deficient diet, reversed by thiamine administration and allowed to recover. Pyrithiamine treated animals demonstrated impaired retention of a 24 h recall of passive avoidance. Regional brain concentration of norepinephrine, dopamine, serotonin, 3,4-dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid, GABA, glutamate, aspartate, glutamine, and glycine were determined after 2 and 9 weeks of nutritional recovery. A significant increase in NE content of cerebellum from the pyrithiamine treated animals was observed at both 2 and 9 week recovery periods. The concentrations of serotonin and its metabolite were signifciantly elevated in midbrain-thalamus and striatum. Significant reductions of GABA and glutamate were also observed in midbrain-thalamus. Amino acid levels in all other brain areas were unchanged from pair-fed controls. These results suggest regionally specific, chronic alterations in GABA, glutamate, serotonin, and norepinephrine activity following recovery from an acute bout of pyrithiamine-induced thiamine deficiency. The absence of a permanent reduction of cortical norepinephrine similar to that observed in an earlier study is discussed.