Transient enhancement of cholinergic neurochemical markers induced by NGF in aged F344 rats.

Two experiments were conducted to assess the durability of nerve growth factor (NGF) effects on cholinergic neurochemical markers. Artificial CSF or NGF was infused via osmotic pumps for 2 weeks into the lateral ventricles of young adult (3- to 6-month-old) and aged (22- to 26-month-old) Fischer 344 rats. Assessment of choline acetyltransferase (CAT) and acetylcholinesterase (AChE) within the cortex, striatum, and hippocampus was conducted either approximately 3 (experiment 1) or 12 (experiment 2) weeks after termination of treatment. A variety of age-related deficiencies were found in the two experiments with decreased marker levels within the dorsal hippocampus and striatum being most consistent. NGF increased cholinergic marker enzyme activity in experiment 1 only. Specifically, NGF (a) attenuated age-related CAT and AChE deficits within the dorsal hippocampus and striatum, (b) enhanced CAT activity within the frontal cortex and ventral hippocampus in aged animals, and (c) increased CAT activity within the dorsal hippocampus in young subjects. It is concluded that NGF may be beneficial in enhancing cholinergic neurochemical parameters, especially in aged animals, but such effects are most likely transient.

The acute effects of a rapid medical detoxification upon dysphoria and other psychopathology experienced by heroin abusers.

Self-reported dysphoria, personality disorder traits, and subjective opioid withdrawal symptoms were assessed in 30 opioid abusers before and after a rapid medical detoxification from heroin. Subject exclusion criteria reflected an effort to control for potential sources of affective change that were extraneous to the effect of detoxification. Subjects received few rehabilitative services during their 12-day inpatient hospitalization, and were not permitted visitors or off-ward privileges. At the preadmission assessment, they reported elevated levels of dysphoria and personality disorder traits, as well as opioid withdrawal symptoms. The results indicate that clinically significant declines in symptoms of dysphoria, opioid withdrawal symptoms, and personality disorder traits occur during the course of a rapid medical detoxification. Dysphoric and opioid withdrawal symptom abatement was most pronounced between the preadmission and admission assessments. These factors should be considered in the clinical diagnosis and treatment, as well as in research about psychiatric comorbidity of these substance abusers.

Cortical cholinergic markers in schizophrenia.

Cortical cholinergic deficits have been implicated in the cognitive deficits produced by a variety of neurodegenerative diseases including Alzheimer's disease (AD). Recent studies have suggested that many of the chronically institutionalized geriatric schizophrenic patients are also cognitively impaired. In this postmortem study we compared cholinergic marker activity in six different cortical regions derived from elderly controls, chronically institutionalized geriatric schizophrenic patients, and AD patients. All of the Alzheimer's disease cases met neuropathological criteria for AD, while none of the schizophrenic cases met criteria for AD. Cholinergic marker activity (choline acetyltransferase and acetylcholinesterase) was significantly diminished in the AD cohort but not in the schizophrenic cohort. Additionally, cortical choline acetyltransferase activity was significantly and negatively correlated with Clinical Dementia Rating scores (CDR), whereas no such correlations were evident in the schizophrenic cohort. These results suggest that cognitive deficits in geriatric schizophrenics are not due to diminished cortical cholinergic activity.

Induction of memory and cortical cholinergic neurochemical recovery with combine fetal transplantation and GM1 treatments in rats with lesions of the NBM.

Sixty-four Sprague-Dawley rats received ibotenic-acid-induced unilateral nucleus basalis of Meynert (nbM) lesions; 10 additional animals served as sham controls. Eight to ten days later, subjects with lesions received either fetal cholinergic transplants implanted within the ipsilateral (relative to the lesion) frontal cortex or control transplant surgeries. Lesioned animals with and without transplants were then treated with GM1 (20 mg/kg, i.p.) for either 0, 1 or 10 days and were then trained and tested for 72-hour retention of passive avoidance. Results indicated that the lesion produced a significant impairment on this task. Transplant therapy combined with GM1 for 10 days yielded a significant reversal of this deficit. GM1 injections continued once per week for 4 weeks for half the lesioned animals in the transplant and no-transplant 10-day conditions. During a 6-month period, all subjects were assessed on two additional memory tasks (complex spatial discrimination and delayed spatial alternation). In general, there was no indication of a lesion, transplant, GM1, or transplant X GM1 effect on these tasks. Approximately 7.5 months after transplants, subjects were sacrificed and their frontal cortices examined for choline acetyltransferase (CAT) and acetylcholinesterase (AChE) activity. Only lesioned subjects with transplants which were given sustained GM1 treatment (i.e., 10 days plus weekly injections for 4 weeks) showed significant attenuations of lesion-induced CAT and AChE depletions. These data suggest that a combined treatment strategy of fetal transplant plus GM1 is capable of reversing nbM lesion-induced memory and neurochemical deficits in an animal model of the cholinergic deficits in Alzheimer's disease.

Cholinergic marker deficits induced by lesions of the nucleus basalis of Meynert are attenuated by nerve growth factor in young, but not in aged, F344 rats.

To investigate the efficacy of nerve growth factor (NGF) in promoting recovery from cholinergic damage, young (3-4 month old) and aged (22-23 month old) Fischer 344 rats received NMDA-induced unilateral lesions of the nucleus basalis of Meynert and subcutaneous osmotic pumps (2-week duration) connected to permanently implanted cannulas directed at the lateral ventricle ipsilateral to the lesion. Pumps were filled with either artificial CSF/rat serum albumin (the vehicle) or 5.0 micrograms of angiotensin-free, beta-NGF. Fourteen days after surgery, all subjects were sacrificed and their brains regionally dissected (frontal and occipital cortices, striatum, and dorsal and ventral hippocampi) and assayed for choline acetyltransferase (CAT) and acetylcholinesterase (AChE). Results indicated that the lesion decreased CAT and AChE levels within the frontal cortex of both young (29.8% and 39.4% depletion, respectively) and aged (30.5% and 34.8% depletion, respectively) animals. Only in young animals did NGF reduce these lesion-induced CAT (by 34.2%) and AChE deficits (by 65.5%). In fact, NGF exacerbated frontal cortical CAT depletions in aged animals in that percent depletion was 11.3% more following treatment (30.5% vs. 41.8% depletion in Aged/CSF and Aged/NGF groups, respectively). Lower CAT and AChE levels were found in the striatum of aged animals, an effect not reversed by NGF treatment. In contrast, NGF in young animals enhanced striatal CAT activity on the non-lesioned side by 22.2%.(ABSTRACT TRUNCATED AT 250 WORDS)

Organic mood syndrome associated with detoxification from methadone maintenance.

OBJECTIVE: The authors delineate the clinical characteristics of mood state changes that occur in stable opioid-dependent patients undergoing therapeutic detoxification from methadone maintenance treatment. METHOD: Twenty-four patients participated in a blinded protocol for gradual methadone dose reduction that included weekly assessments of affective state using the Profile of Mood States (POMS) as well as weekly assessments of signs and symptoms of opioid withdrawal. Data obtained before methadone dose reduction and during the 2-week period of maximal dysphoric symptoms were compared. Changes in affective and opioid withdrawal measures were compared in patients who differed in their success in completing the detoxification regimen. RESULTS: Sustained increases in POMS scores of greater than 20 points were observed in 12 of the 24 patients during the course of detoxification. The emergence of symptoms of dysphoria was accompanied by insomnia, loss of appetite, and somatic complaints consistent with symptoms of opioid withdrawal but only minimal levels of objective signs of withdrawal. Greater changes from baseline in mood state and opioid withdrawal measures occurred in patients who were unable to complete the detoxification regimen. CONCLUSIONS: The development of an organic mood syndrome is a common occurrence in patients undergoing slow detoxification from methadone maintenance treatment and is associated with a poor outcome.

The dysphoria of heroin addiction.

Levels of dysphoria and opioid dependence were assessed in 54 male patients with heroin addiction applying for drug treatment. During a period of naturalistic heroin use, symptom measures of dysphoria and of spontaneous opioid withdrawal reported by these patients were highly correlated. Upon admission to treatment, levels of dysphoria and opioid withdrawal were assessed before and after a pharmacological challenge with either 0.4 mg naloxone or placebo. Signs and symptoms of opioid withdrawal and symptoms of dysphoria increased in patients following naloxone, but not placebo administration. Naloxone-induced changes in symptoms of dysphoria were correlated with changes in opioid withdrawal as assessed by both subjective and objective measures. These findings suggest that dysphoric mood states in heroin addicts may be, in part, pharmacological sequelae of their drug dependence. Dysphoria due to opioid withdrawal may contribute to the initiation and maintenance of heroin use, and to the high rates of syndromal affective disorders reported in this population.

Clinical characteristics of naloxone-precipitated withdrawal in human opioid-dependent subjects.

Studies were conducted to investigate the clinical characteristics of naloxone-precipitated withdrawal in human opioid-dependent subjects. Each of 20 male patients stabilized on 24 mg of methadone daily received two i.v. pharmacological challenges: one with naloxone (0.05, 0.10, 0.15 and 0.20 mg; five patients each dose), and one with saline placebo. Measures of opioid withdrawal, affective state, cognitive performance and changes in autonomic parameters were assessed after each pharmacological challenge. Naloxone produced dose-dependent increases in opiate withdrawal scale scores and in symptoms of dysphoria as measured by the Profile of Mood States. Differences within subjects between naloxone and placebo infusions in Profile of Mood States scores were highly correlated with differences in opioid withdrawal as assessed by both subjective and objective rating scales. Naloxone also produced substantial increases in pulse, systolic and diastolic blood pressure and respiratory rate, as well as a small decrease in temperature. However, naloxone-induced changes from base-line values in these autonomic parameters correlated only modestly with other measures of opioid withdrawal. No differences between infusions were observed in two measures of cognitive performance (Stroop Color and Word Test, Digit Span Test). The results indicate that dysphoric mood states reflecting a broad range of affective experience must be considered as integral components of the naloxone-precipitated opioid withdrawal syndrome.

Levels of opioid physical dependence in heroin addicts.

The levels of opioid physical dependence in a group of long-term heroin addicts were ascertained by measuring the severity of the opioid withdrawal syndrome before and after pharmacological challenge with either 0.4 mg naloxone or placebo. Prior to challenge, patients manifested some subjective symptoms but few objective signs of opioid withdrawal. Patients who received placebo (n = 18) showed a significant increase in the mean score on one of three rating scales used to assess opioid withdrawal. Patients who received naloxone (n = 58) showed significant increases in mean scores on all three rating scales, but this was due primarily to increases observed in a minority of patients. Sixty-one percent of patients failed to manifest clinically significant changes in subjective symptoms, and 74% of patients failed to manifest clinically significant changes in objective signs of opioid withdrawal following naloxone administration. The results suggest that a substantial subgroup of heroin addicts are able to use opioids regularly while maintaining relatively low levels of physical dependence.

Platelet phospholipid synthesis in Alzheimer's disease.

The rates of incorporation of [3H]choline and [3H]ethanolamine into membrane phospholipids of platelets from 22 drug-free Alzheimer's disease patients and 18 normal elderly controls were compared. No significant differences between groups were found. If alterations in lipid metabolism are involved in the pathophysiological processes underlying Alzheimer's disease, such alterations are not manifest in measures of radiolabeled base incorporation into platelet phospholipids.

Fetal transplant-induced restoration of spatial memory in rats with lesions of the nucleus basalis of Meynert.

Bilateral lesions of the nucleus basalis of Meynert (nbM) in rats produced mnemonic deficits when subjects were tested on tests of spatial memory over a period of 3 to 7.5 months postoperatively. The transplantation of cholinergic-rich, fetal ventral forebrain tissue to either two or four frontoparietal cortical sites normalized performance on the spatial memory tasks. However, which transplant condition yielded recovery depended upon the nature of the task and/or posttransplantation interval. When assessed 8 months following transplant surgery, cortical choline acetyltransferase and acetylcholinesterase activity levels in both transplant groups were comparable to those values found in sham-operated animals. These data indicate that fetal transplants can reverse the mnemonic deficits and restore cortical cholinergic neurochemical activity to near-normal levels in rats with nbM lesions.

Frontal cortex as the site of action of physostigmine in nbM-lesioned rats.

The administration of a variety of cholinomimetic agents to nucleus basalis of Meynert-lesioned rats has been shown to alleviate their lesion-induced memory deficits. This experiment attempted to determine whether the frontal cortex was the site of the memory enhancing action of the cholinomimetic physostigmine. Different groups of rats received excitotoxic lesions of the basal forebrain, the frontal cortex or both. Immediately after one trial passive avoidance training, these rats were injected with either saline or a 0.06 mg/kg dose of physostigmine. Physostigmine enhanced the 72-hour retention test performance of sham-operated and basal forebrain-lesioned rats, but failed to affect the performance of rats with cortical lesions. These data were interpreted as consistent with the hypothesis that the memory-enhancing effects of physostigmine are at least partially mediated by the frontal cortex.

Restoration of cholinomimetic activity by clonidine in cholinergic plus noradrenergic lesioned rats.

The effects of combined lesions of forebrain cholinergic and noradrenergic systems on memory and responsivity to the memory enhancing effects of cholinomimetics were investigated in rats. Forebrain noradrenergic deficits produced by the injection of 6-hydroxydopamine into the ascending noradrenergic bundle (ANB) blocked the ability of cholinomimetics such as physostigmine and oxotremorine to enhance retention test performance in nucleus basalis of Meynert lesioned rats. Low doses of the noradrenergic receptor agonist clonidine, when administered in conjunction with cholinomimetics reversed this blockade. These results suggest that combined cholinergic/noradrenergic therapy may be of value in the treatment of some Alzheimer's disease patients.

Interactions of forebrain cholinergic and somatostatinergic systems in the rat.

The neurochemical, behavioral and pharmacological effects of forebrain cholinergic and somatostatinergic deficits were assessed in adult rats. Brain somatostatinergic activity was manipulated by the systemic administration of different doses of cysteamine. Forebrain cholinergic systems were lesioned by the infusion of ibotenic acid into the nucleus basalis of Meynert (nbM). Forebrain cholinergic lesions did not affect forebrain somatostatin-like-immunoreactivity (SLI). Depletion of forebrain SLI by cysteamine did not significantly affect forebrain cholinergic marker activity. The combination of forebrain cholinergic deficits with forebrain somatostatinergic deficits did not lead to any greater impairment of mnemonic function than that produced by lesions alone, nor did SLI deficits hamper the efficacy of physostigmine to enhance memory in sham operated or nbM-lesioned rats. These results suggest that although forebrain cholinergic and somatostatinergic systems do interact at some levels, this interaction is a minor one with respect to neurochemical, behavioral or pharmacological variables.

Infusion of NMDA into the nucleus basalis of Meynert, frontal cortex or lateral ventricle in rats: effect on memory and cholinergic brain neurochemistry.

The present study's aim was to examine the behavioral and neurochemical effects of damage limited to intrinsic neurons of the frontal cortex in rats. Specifically, it was of interest to evaluate the effects of N-methyl-D-aspartic acid-induced lesions of discrete frontal cortical loci on passive avoidance memory and on cortical cholinergic neurochemical markers (choline acetyltransferase--CAT and acetylcholinesterase--ACHE). The present study also compared the behavioral and neurochemical effects produced by frontal cortical damage with those effects produced by lesions of the nucleus basalis of Meynert (nbM). Results indicated that nbM lesions and lesions to a rostral frontal cortical site produced severe passive avoidance memory impairments when subjects were tested 72 hours after training. Cortical, but not hippocampal, levels of CAT and ACHE were depleted in nbM animals only. These data were interpreted as providing support for the view that intrinsic frontal cortical neurons contribute to memory.

Attenuation of nucleus basalis of Meynert lesion-induced cholinergic deficits by nerve growth factor.

Nerve growth factor (NGF) was administered into either the lateral ventricle or into the basal forebrain of n. basalis of Meynert (nbM) lesioned rats. Rats received either continuous infusion of 5 micrograms of 7S NGF per day for 28 days, or 5 micrograms of 7S NGF on 4 occasions distributed evenly during the first two post-lesion weeks. The administration of NGF reduced lesion-induced cortical cholinergic marker deficits by approximately 50%, irrespective of the locus or mode of NGF administration. Thus NGF is able to attenuate lesion-induced cholinergic deficits across a range of treatment and lesion conditions.

Cyclic-AMP production by polymorphonuclear leukocytes in psychiatric disorders.

The cyclic adenosine monophosphate (cAMP) responses to histamine, prostaglandin-E1, and isoproterenol in polymorphonuclear leukocytes from drug-free normal controls and patients with schizophrenia or major depressive disorder were compared. These three groups of subjects did not differ in their cAMP responses to receptor activation. Exacerbated and remitted patients with either schizophrenia or major depressive disorder did not differ in their cAMP responses. The data indicate that in polymorphonuclear leukocytes, the cAMP responses to activation of histamine H2, prostaglandin-E1, or beta-adrenergic receptors are neither state-independent nor state-dependent markers for schizophrenia or major depressive disorder.

Effect of physostigmine on memory consolidation and retrieval processes in intact and nucleus basalis-lesioned rats.

The efficacy of physostigmine on memory enhancement in rats trained on a passive avoidance task was investigated. In experiment 1, the effect of posttraining injections of physostigmine (0.03 mg/kg) in subjects tested at either short (1.25 h or 72 h) or long (3 weeks or 5 weeks) retention intervals was explored. Results indicated drug-induced enhancement of memory at only the two short intervals. Experiment 2 examined the mnemonic consequences of pretest administration of physostigmine. Administration of physostigmine (0.015 mg/kg and 0.03 mg/kg) shortly prior to testing led to a significant potentiation of memory retrieval. The aim of experiment 3 was to determine whether or not an intact cholinergic system is necessary for pretest physostigmine to enhance memory retrieval. Results from this experiment indicated that physostigmine (0.03 mg/kg) was effective in enhancing memory in rats prepared with ibotenic acid-induced lesions of the nucleus basalis of Meynert. Together, these data provide further empirical support for the importance of the cholinergic system in memory processes.