Morphine-dependent rats: blockade of precipitated abstinence by tetrahydrocannabinol.

Male rats were implanted subcutaneously with a pellet containg 75 milligrams of morphine base or placebo, and naloxone hydrochloride (4 milligrams per kilogram of body weight) was administered 72 hours later. Treatment with delta-9-tetrahydrocannabinol (2, 5, or 10 milligrams per kilogram) 1 hour before maloxone administration significantly reduced the intensity of abstinence; the two higher doses blocked the appearance of wet shakes and escapes, diarrhea, and increased defecation. delta-9-Tetrahydrocannabinol did not induce abstinence itself, and prior treatment with cannabidiol was ineffective in reducing naloxoneprecipitated abstinence in animals with morphine pellets. These data suggest that delta-9-tetrahydrocannabinol may be of value in facilitating narcotic detoxification.

Tritiated imipramine binding sites are decreased in the frontal cortex of suicides.

Binding characteristics of tritiated imipramine were determined in the frontal cortex of suicides and well-matched controls. Maximal binding was significantly lower in brains from the suicides. This finding is consistent with reports of decreased tritiated imipramine binding in the platelets of patients diagnosed as having a major affective disorder.

Dopamine synthesis: stimulation by a hypothalamic factor.

The effect of treatment with the factor that inhibits the release of melanocyte stimulating hormone (MSH) identified as 1-prolyl-1-leucylglycinamide (MIF) on brain catecholamine synthesis was examined in normal and hypophysectomized rats. The tripeptide induced a dose-related increase in striatal dopamine synthesis in slices obtained from treated normal animals but not in hypophysectomized animals. Hypothalamic norepinephrine synthesis was unaltered by MIF treatment in normal as well as in hypophysectomized rats. In addition, dopamine and norepinephrine syntheses were depressed in untreated hypophysectomized animals, as compared to normal controls. These results constitute the first direct demonstration of a central neurochemical effect of a hypothalamic factor.

Mental symptoms in Huntington's disease and a possible primary aminergic neuron lesion.

Monoamine oxidase activity was higher in the cerebral cortex and basal ganglia of patients dying from Huntington's disease than in controls. Enzyme kinetics and multiple substrate studies indicated that the increased activity was due to elevated concentrations of monoamine oxidase type B. Concentrations of homovanillic acid were increased in the cerebral cortex but not in the basal ganglia of brains of patients with Huntington's disease. These changes may represent a primary aminergic lesion that could underlie some of the mental symptoms of this disease.

Parachlorophenylalanine reversal of tranylcypromine effects in depressed patients.

Hospitalized bipolar and unipolar endogenously depressed patients who showed an antidepressant response to the monoamine oxidase (MAO) inhibitor, tranylcypromine sulfate, relapsed (ie, depression returned) when relatively small doses of parachlorophenylalanine (PCPA) were added for brief periods. Considered together with our findings that PCPA similarly reversed the antidepressant effects of the tricyclic drug, imipramine hydrochloride, implications are (1) serotonergic mechanisms are likely involved in the antidepressant effects of both the tricyclic drugs and MAO inhibitors in man and (2) this indolamine may also play a role in the endogenous clinical state of depression.

Psychoactive drugs in mania. A controlled comparison of lithium carbonate, chlorpromazine, and haloperidol.

Lithium carbonate, haloperidol, and chlorpromazine hydrochloride were compared in a double-blind controlled study with severely ill hospitalized manics. Lithium carbonate and haloperidol produced a highly significant improvement of manic symptoms without sedation. Although producing considerable sedation, chlorpromazine did little to alter the underlying mania qualitatively. Qualitative differences between lithium carbonate and haloperidol indicate that, while haloperidol has a more dramatically rapid impact on behavior-motor activity, lithium carbonate acted more evenly on the entire manic picture, with total normalization realized during active treatment. The majority of lithium carbonate-treated patients met discharge criteria at study termination, but not the patients receiving either neuroleptic drug. The rating scales are not sensitive enough to monitor manic psychopathology; this accounts for the lack of statistically significant differences among drug groups at treatment termination, despite the widely disparate discharge rates.

Correlation between plasma and cerebrospinal levels of imipramine.

This study measured the levels of imipramine hydrochloride and desipramine hydrochloride (desmethylimipramine) in the plasma and cerebrospinal fluid (CSF) in 11 depressed patients. The oral doses correlated significantly with the plasma levels irrespective of different diagnostic categories. The CSF levels varied significantly. In the endogenous depressive group the CSF levels were significantly higher in responders as compared to nonresponders. The CSF levels of the nonresponders in the endogenous depressive group, and of both responders and nonresponders in the schizo-affective groups, were similar.

The effects of hyperbaric and normobaric oxygen on cognitive impairment in the elderly.

Eighty-two elderly subjects with significant cognitive impairment were randomly assigned to treatment with either hyperbaric oxygen, hyperbaric air, normobaric oxygen, or normobaric air. Treatment consisted of two 90-minute sessions a day for 15 consecutive days. Subjects were evaluated on measures of memory and intellectual capacity, as well as on psychiatric symptom rating scales. Results immediately after treatment and at one, two, three, and eight weeks following treatment did not show enhanced cognitive functioning or significantly greater symptom reduction in experimental subjects who received either normobaric or hyperbaric oxygen as compared to controls who received hyperbaric or normobaric air. There was also no evidence of differential treatment effects as a function of initial severity of illness, sex, response to a CO2 loading test, or presumed evidence of cerebrovascular disease.

Prostaglandins, platelets, and schizophrenia.

Prostaglandin (PG) E1 enhances formation of 3H-adenosine-3',5'-cyclic monophasphate (3H-cAMP) in platelets pulse-labeled with 3H-adenine. This response was assessed as an index of receptor sensitivity and of PG function. Prostagladin E1-stimulated 3H-cAMP accumulation in paltelets from schizophrenics was significantly reduced compared with control subjects. Platelet incorporation of 3H-adenine and basal 3H-cAMP accumulation. We discuss the results in terms of the possible role of PGs in the etiopathology of schizophrenia and derivative implications for treatment.

Thiethylperazine; clinical antipsychotic efficacy and correlation with potency in predictive systems.

A one-to-one relationship between clinical antipsychotic potency and pharmacologic dopaminergic antagonism is implicit in the dopamine hypothesis of neuroleptic action. Thiethylperazine maleate, a classical antiemetic phenothiazine, displays dopaminergic antagonism in behavioral, neurochemical, and neuroendocrine systems, but is paradoxical insofar as it is thought not to possess clinical neuroleptic activity. In three tests of dopaminergic antagonism--elevation of levels of CSF homovanillic acid in monkeys, striatal dihydroxyphenylacetic acid in rats, and prolactin in man--as well as in a clinical trial of neuroleptic efficacy in schizophrenics, thiethylperazine was fully active and approximately three times as potent as chlorpromazine. Differences in efficacy between this and earlier clinical studies can be accounted for on the basis of dosage.

Increased cerebrospinal fluid glutamine levels in depressed patients.

BACKGROUND: There is increasing evidence for an association between alterations of brain glutamatergic neurotransmission and the pathophysiology of affective disorders. METHODS: We studied the association between cerebrospinal fluid (CSF) metabolites, including glutamine, in unipolar and bipolar depressed patients versus control subjects using a proton magnetic resonance spectroscopy technique. Cerebrospinal fluid samples were obtained from 18 hospitalized patients with acute unmedicated severe depression without medical problems and compared with those of 22 control subjects. RESULTS: Compared with the control group, the depressed patient group had significantly higher CSF glutamine concentrations, which correlated positively with CSF magnesium levels. CONCLUSIONS: These findings suggest an abnormality of the brain glial-neuronal glutamine/glutamate cycle associated with N-methyl-D-aspartate receptor systems in patients with depression.

Lithium-induced increases in red blood cell choline and memory performance in Alzheimer-type dementia.

To investigate the relationship between RBC choline and memory in Alzheimer-type senile dementia (SDAT), lithium carbonate was administered to 14 SDAT patients in doses of 400-600 mg/day for 5 weeks. A battery of memory tests was administered at baseline and at weekly intervals. Five patients with serum concentrations below 0.6 meq/liter developed neurotoxicity and were dropped from further analysis. For the remaining patients, Li+ with mean serum concentrations up to 0.6 meq/liter did not alter memory scores significantly. The dramatic increases in RBC choline during the study, however, suggest that RBC choline is not correlated with memory functioning in SDAT.

The importance of dietary control in metabolic studies of manic-depressive patients.

Diet control of electrolyte intake appears to diminish day to day variation of urinary electrolyte output. Urine sodium concentration is more affected by diet control than potassium, possibly due to the greater variation in sodium ingestion on uncontrolled diets. The coefficient of variation of urinary sodium excretion on the controlled diet was not significantly greater than the variation in sodium ingestion. These experimental results suggest that controlled diets reduce random variation in sodium and potassium excretion and therefore enhance the possibility of observing illness-related biological changes.

Chronic myo-inositol increases rat brain phosphatidylethanolamine plasmalogen.

BACKGROUND: Oral myo-inositol (12--18 g/day) has shown beneficial effect in placebo-controlled studies of major depression, panic disorder, and obsessive compulsive disorder, and preliminary data suggest it also may be effective in bipolar depression. Evidence linking antidepressant activity to membrane phospholipid alterations suggested the examination of acute and chronic myo-inositol effects on rat brain membrane phospholipid metabolism. METHODS: With both (31)P nuclear magnetic resonance (NMR) and quantitative high-performance thin-layer chromatography (HPTLC; hydrolysis) methods, rat brain phospholipid levels were measured after acute (n = 20, each group) and chronic myo-inositol administration (n = 10, each group). With (31)P NMR, we measured myo-inositol rat brain levels after acute and chronic myo-inositol administration. RESULTS: Brain myo-inositol increased by 17% after acute myo-inositol administration and by 5% after chronic administration, as compared with the control groups. Chronic myo-inositol administration increased brain phosphatidylethanolamine (PtdEtn) plasmalogen by 10% and decreased brain PtdEtn by 5%, thus increasing the ratio PtdEtn plasmalogen (PtdEtn-Plas)/PtdEtn by 15%. Phosphatidylethanolamine plasmalogen levels quantified by (31)P NMR and HPTLC were highly correlated. The validity and reliability of the (31)P NMR method for phospholipid analysis were demonstrated with phospholipid standards. CONCLUSIONS: The observed alteration in the PtdEtn-Plas/PtdEtn ratio could provide insights into the therapeutic effect of myo-inositol in affective disorders.

Brain lithium concentrations in bipolar disorder patients: preliminary (7)Li magnetic resonance studies at 3 T.

BACKGROUND: This study was conducted to investigate the feasibility of human brain (7)Li MRS investigations at a high magnetic field (3 T), and to further explore the relationship between brain and serum lithium measures in lithium-treated bipolar patients. METHODS: Eight bipolar disorder type I patients (5 males, 3 females; mean age +/- SD = 33 +/- 9 years) were studied. A 3-T scanner, using a dual-tuned ((1)H and (7)Li) echoplanar imaging (EPI) compatible radiofrequency (RF) birdcage coil was used. (7)Li magnetic resonance spectroscopy (MRS) signal was acquired at the frequency of 49.64 MHz using an imaging selective in vivo spectroscopy (ISIS) sequence (TR = 15 sec, 128 averages), and quantitation was obtained in reference to an external standard. RESULTS: The mean +/- SD oral lithium dose was 1265 +/- 442 mg/day, and the mean +/- SD 12-hour serum level was 0.69 +/- 0.19 mEq/L. The measured brain lithium concentrations varied from 0.23 to 0.55 mEq/L (mean +/- SD = 0.35 +/- 0.11 mEq/L). The brain-serum ratios varied from 0.30 to 0.80 (mean +/- SD = 0.52 +/- 0.16). Subjects on single daily doses of lithium at bedtime (n = 5) had higher brain-serum lithium ratios compared with those on twice-a-day schedules (n = 3) (0.61 +/- 0.12 and 0.37 +/- 0.07, respectively; Mann--Whitney U test, Z = -2.24, p =.03). CONCLUSIONS: This study demonstrated for the first time the feasibility of (7)Li MRS human studies at 3 T. Future studies should examine a possible role for this methodology in investigations of lithium refractoriness and prediction of treatment outcome in bipolar patients.

Measurement of cholinergic drug effects on memory in Alzheimer's disease.

Double-blind, placebo-controlled investigations of scopolamine, physostigmine, arecoline, and tetrahydroaminoacridine (THA) in normal adults and in dementia of the Alzheimer-type (DAT) were reviewed to determine the relative sensitivity of various assessment procedures in the measurement of drug effects. In normal adults, word list learning techniques have been most widely employed and have been sensitive to drug effects. In DAT, a wide variety of assessment procedures have been employed. Based on the limited number of possible comparisons across studies, two procedures appear to be useful: word list learning tasks that generate an index of intrusion errors, and visual recognition tasks. The lack of standardized assessments limits the ability of investigators to replicate studies, to compare relative efficacy of various drugs, or to address a number of other questions that are fundamental to the development of effective cholinergic treatments for DAT.

Multiple, single-dose naltrexone administrations fail to effect overall cognitive functioning and plasma cortisol in individuals with probable Alzheimer's disease.

A double-blind placebo-controlled study was conducted in 10 individuals with probable Alzheimer's disease to assess the effects of varying doses of Naltrexone (0, 25, 50 and 100 mg) on cognitive functioning and on plasma cortisol. Each individual participated in four separate sessions at least three days apart. Naltrexone was found to improve performance in only one of the six psychometric tasks employed (Token Test). However, enhancement of Token Test performance was limited to the 25 mg Naltrexone dose and was mainly the result of an improvement on the part of the two most severely impaired patients. In contrast to the previous reports of elevations of plasma cortisol following administration of opiate antagonists to younger, non-demented subjects, Naltrexone administration failed to produce any significant increase in plasma cortisol in Alzheimer's patients.

Correlation of behavioral and cerebrovascular functions in the aging rat.

Regional cerebral blood flow (rCBF), maze performance and the influence of environmental enrichment on these parameters were studied in Sprague-Dawley rats aged 6, 12 and 24 months. Learning ability in a complex sequential T-maze (Stone maze) progressively declined with increasing age in rats which were normally housed in standard caging. Environmental enrichment significantly improved maze performance but did not prevent the age-dependent impairment. Following completion of the learning studies, rCBF was measured in each of 13 brain regions in conscious, unrestrained, resting animals. In the absence of any significant change in cardiac output over the entire age range, rCBF was lower in all brain regions by an average of 16% in 12-14 month old rats and 8% in aged rats (24-26 months old); the occipital cortex, inferior and superior colliculi and hypothalamus were particularly affected regions in both age groups. The sharp reduction of rCBF that occurred between 6 and 12 months of age did not reflect, and probably preceded the progressive decline in maze performance. Such highly significant age-related changes in rCBF were not affected, however, by environmental enrichment procedures. This contrasts with the substantial influence of enrichment on maze performance. Finally, mean brain blood flow and mean cortical blood flow correlated inversely and significantly with average daily numbers of errors made by 24 month old rats during Stone maze acquisition.

Cerebrovascular permeability and cognition in the aging rat.

Regional cerebrovascular permeability-capillary surface area products (rPS) and brain vascular space (BVS) were measured in aging, conscious, unrestrained Sprague-Dawley rats. Three groups of animals were examined: young-mature (6 months), middle-aged (12-14 months), and old (24-26 months) rats. Complex maze learning had been previously characterized in these same animals. Maze learning declined with age. Brain vascular space did not differ significantly with age in any brain region. However, small, but significant age-dependent decreases in rPS (25-33%) were observed. These decreases occurred mainly in the old animals in the basal ganglia and parietal cortex, and in the middle-aged and old rats in the olfactory bulbs. Significant and unexpected positive average correlations between brain permeability-capillary surface area products (PS) and learning errors occurred primarily in young rats and were attributable mainly to changes in 5 of 14 brain regions; hypothalamus, hippocampus, parietal cortex, septal area and superior colliculus. The higher correlations between maze learning errors and PS in young animals may indicate dynamic regulation of this cerebrovascular parameter which is lessened with aging. Average correlations between PS and cerebral blood flow also were determined and found to be generally small and not significant for most brain regions and age groups.

Central amine metabolism in Alzheimer's disease: in vivo relationship to cognitive deficit.

Levels of the amine metabolites homovanillic acid (HVA) and methoxyhydroxyphenylglycol (MHPG) were measured in the cerebrospinal (CSF) fluid of drug-free patients with Alzheimer's disease and compared to levels in a group of controls. No significant differences were found in CSF HVA and MHPG, although the Alzheimer's group was severely demented. Platelet monoamine oxidase (MAO) enzyme kinetics were measured and did not differ between controls and Alzheimer patients. The degree of dementia did not show any significant correlation with the levels of HVA or MHPG. It was concluded that, unlike previous reports in the literature, the dementia of Alzheimer's disease was not related to changes in central catecholamine metabolism nor was it associated with increased platelet MAO activity.