Philip D. Kanof

Pharmacological alleviation of cholinergic lesion induced memory deficits in rats

The cholinergic cells of the nucleus basalis of Meynert (nbM) have recently been found to degenerate in Alzheimers disease and are thought to be at least partly responsible for the cognitive deficits which are characteristic of this disease. These experiments explored the behavioral effects of bilateral excitotoxic lesions of the nbM in adult rats. The first experiment showed that nbM lesions lead to a substantial deficit in the 24 hour retention of the habituation to a novel environment without affecting general exploratory behavior. The second experiment showed that this retention deficit is a general phenomenon reflected in the 72 hour retention of a one trial passive avoidance task. These retention deficits could be reversed by the postacquisition administration of the acetylcholinesterase inhibitor, physostigmine. These results support the hypothesis that central cholinergic systems are involved in the retention of learned responses, and suggest that cholinergic lesion induced retention deficits can be reversed by pharmacological means.

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 Alzheimers disease patients.

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 druginduced 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.

Platelet [3H]Imipramine binding in psychiatric disorders

The Bmax and Kd values for [3H]imipramine binding were measured in platelets from drug-free normal controls and schizophrenic and depressive patients. No differences among groups were found. Exacerbated and remitted patients with either schizophrenia or depression did not differ in platelet [3H]imipramine binding parameters. No correlations were observed between platelet [3H]imipramine binding parameters and measures of symptom severity among actively ill patients with either schizophrenia or depression.

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.

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

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.

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.

Effects of indomethacin on plasma homovanillic acid concentration in normal subjects: a study of prostaglandin-dopamine interactions

In laboratory animals, prostaglandins have been shown to act as endogenous neuromodulators of central dopamine (DA) activity. To examine the interaction between prostaglandins and DA in man, the effect of a prostaglandin synthesis inhibitor, indomethacin, was studied on plasma concentrations of the DA metabolite, homovanillic acid (pHVA). Indomethacin (150 mg PO) as compared to placebo significantly elevated mean pHVA concentrations in eight normal subjects. Results of this study support the hypothesis that, as in animals, inhibition of prostaglandin synthesis increases central DA turnover in man.

Serotonergic Modulation of Cholinergic Systems Involved in Learning and Memory in Rats

Rats received either N-methyl- D -aspartic-acid-induced bilateral lesions (50 nmol/l µl/side) of a major forebrain cholinergic nucleus (nucleus basalis of Meynert, nbM) or sham operat