Timothy T. Soncrant

Memory improvement without toxicity during chronic, low dose intravenous arecoline in Alzheimer's disease

Arecoline, a cholinergic agonist, administered at low doses by continuous intravenous infusion for up to 2 weeks, significantly and replicably improved memory in five of nine subjects with mild-moderate Alzheimers disease. During dose finding, performance on a verbal memory task improved with an inverted U-shaped relation to dose. Six of nine subjects were classified as responders. During blinded, placebo-controlled, individualized optimal dosing for 5 days, verbal memory again improved in five of six responders but not in any non-responder. No adverse drug effects occurred. Arecoline, and possibly other cholinergic agonists, can safely improve memory in Alzheimers disease at doses much lower than previously studied.

Haloperidol and Cerebral Metabolism in the Conscious Rat: Relation to Pharmacokinetics

Abstract: The time course and distribution of alterations in cerebral metabolic activity after haloperidol administration were evaluated in relation to the pharmacokinetics of haloperidol and the topography of the dopaminergic system in the brain. Local cerebral glucose utilization was measured, using the 2‐deoxyglucose technique, in awake rats after i.p. administration of the dopamine antagonist haloperidol (0.5 or 1 mg/kg). Haloperidol significantly reduced glucose utilization in 60% of 59 brain regions examined, but produced a large increase in the lateral habenula. The regional distribution of changes in glucose utilization was not closely related to the known anatomy of the brain dopaminergic system. The time course of the effect of haloperidol on cerebral metabolism was different for the two doses studied (0.5 and 1 mg/kg), and was not simply related to estimated brain concentrations of haloperidol. However, a linear relation between the metabolic effect and the time‐integrated brain concentration was demonstrated. These results show that haloperidol has an effect on CNS metabolic activity that is more widespread than would be predicted from the topography of the dopaminergic system; this may be due to indirect propagation of the primary effects of haloperidol. The metabolic response to haloperidol depends on brain concentration and duration of exposure to the drug.

Arecoline-induced elevations of regional cerebral metabolism in the conscious rat

Local cerebral glucose utilization (LCGU) was measured, using the quantitative [14C]2-deoxy-D-glucose ([14C]DG) method, at 3 min after administration to 3-month-old, awake Fischer rats of the muscarinic agonist arecoline (AREC) 0.05, 0.5, 5, 15 or 50 mg/kg or saline i.p. Animals were pretreated with methylatropine (a cholinergic antagonist which does not enter the brain and has no effect on cerebral metabolism) 4 mg/kg s.c. to prevent parasympathomimetic side-effects of AREC. Tremor produced by AREC was rated subjectively. Intensity of tremor was dose-related, peaked at 2-5 min after AREC, and abated within 30 min. Elevations in LCGU (measured after [14C]DG injection during peak behavior) in extrapyramidal regions, which mediate tremor, were related to the intensity of tremor. The lowest dose of AREC selectively increased LCGU in the hippocampus and median raphe; higher doses produced more generalized metabolic enhancement. In the hippocampus and cortex, LCGU rose in layers in which cholinoceptive cells are located. Regions of the auditory pathway and superficial neocortical layers (I-III) were generally unaffected by AREC, but LCGU did not decrease in any region. The selective increase in LCGU produced by low doses of AREC in the hippocampus presumably is due to a specific action of AREC, and demonstrates the high sensitivity of this region to cholinomimetic stimulation.

Covariance Analysis of Functional Interactions in the Brain Using Metabolic and Blood Flow Data

Proper behavioral performance depends on the interaction of particular brain regions with one another. To determine the functional relations between brain areas, neural data must be obtained simultaneously from multiple brain regions and the covariance of such data assessed. If, in a given group of subjects under specific experimental conditions, two brain regions are functionally associated, their activity will be highly correlated. As indicators of functional activity, the local rate of cerebral glucose utilization (LCGU), measured in humans using positron emission tomography (PET) with fluorodeoxyglucose (FDG) and in sub-human animals using autoradiography and 2-deoxyglucose (2-DG), or regional cerebral blood flow (rCBF), measured with PET and [15-O]water, are employed.

Clinical pharmacokinetics of arecoline in subjects with Alzheimer's disease

To study the pharmacokinetics and pharmacodynamics of intravenously administered arecoline in subjects with Alzheimers disease.

Clinical pharmacokinetics of physostigmine in patients with Alzheimer's disease

To study the pharmacokinetic and pharmacodynamic properties of physostigmine in subjects with Alzheimers disease.

Cerebral Glucose Utilization in Rats is Not Altered by Hindlimb Restraint or by Femoral Artery and Vein Cannulation

The effects of immobilization and femoral artery and vein cannulation on resting rates of local cerebral glucose utilization (LCGU) were measured in 35 brain regions of awake rats by using the quantitative, autoradiographic [14C]2-deoxy-D-glucose ([14C]DG) technique. Three groups of rats were cannulated on the previous day, and LCGU was measured under conditions of no restraint, 4 h of hindlimb restraint, or acute, four-limb immobilization. A fourth group represented the conventional preparation for [14C]DG experiments, with same-day cannulation followed immediately by 4 h of hindlimb restraint. Plasma catecholamines, corticosterone, and glucose concentrations were measured in all groups; all were elevated significantly above values in unrestrained animals only during four-limb immobilization. LCGU was unchanged by same-day surgery, hindlimb restraint, or both. During four-limb immobilization, LCGU was reduced by 25% in the dorsal hippocampus, and to a lesser extent in the anteroventral thalamic nucleus. It was increased only in the lateral habenula (42%). We conclude that two stressors of the experimental preparation (same-day surgery and hindlimb restraint) do not influence LCGU measurements by the [14C]DG method. More severe, acute stress selectively alters LCGU in a few rat brain regions.

The pattern of functional coupling of brain regions in the awake rat.

The functional interactions among many regions of the rat brain were characterized simultaneously by using a new method for analyzing regional cerebral metabolic rates for glucose (rCMRglc). Regional CMRglc, a measure of regional functional activity, was determined in 68 brain regions of 24 awake, male, 3-month-old Fischer rats by the quantitative autoradiographic [14C]deoxyglucose technique. Because rCMRglc for each region varies among subjects, the functional coupling of two regions can be assessed by determining whether their metabolic rate change in a coordinated manner from rat to rat. Positive coupling arises if, for each rat, higher rCMRglc in one region is accompanied by a higher metabolic rate in another area; likewise, regions whose metabolic rates vary inversely are negatively coupled. A pairwise coupling can be quantified by calculating the linear correlation coefficient for points whose coordinates represent rCMRglc values for the two regions in each of the 24 rats. Correlation coefficients were calculated for each possible region pair among the 68 areas studied. The technique of partial correlation was used to weight equally the contribution of each rat to the correlation coefficient, regardless of its overall mean CMRglc. In general, highly positive couplings (R greater than 0.5) were found between adjacent or nearby regions, whereas distant region pairs often were coupled negatively (R less than -0.5). A large number of positive couplings were found between left-right homologous regions and between neocortical areas. Similar findings in humans, obtained by positron emission tomography, have been reported. This technique uses inter-animal variation in rCMRglc to demonstrate functional interactions among brain areas, thus providing a method to explore anatomical-functional linkages in a given experimental state.

Time-course and regional distribution of the metabolic effects of bromocriptine in the rat brain.

Local cerebral glucose utilization (LCGU) and motor behavior were examined in awake Fischer-344 rats after administration of the dopaminergic agonist bromocriptine (BROMO). LCGU was measured using the [14C]2-deoxyglucose technique in 63 brain regions at 1,2,3 or 4 h after BROMO 20 mg/kg, and at 4 h after BROMO 100 mg/kg i.p. At 2 h, LCGU was reduced significantly in 13% of the 63 regions examined. The affected regions are related to the topographical distribution of dopaminergic innervation in the brain. At 3-4 h, LCGU remained depressed in some of the above dopaminergic regions, but was elevated significantly in regions which are involved in sensorimotor function. BROMO also produced two behavioral effects depending on time after administration. Locomotor activity was depressed at 1-2 h, and stereotyped behavior appeared at 3-4 h. The time-dependent effects of BROMO may reflect progressively increasing brain concentrations of the drug or of its active metabolites. The coincidence of locomotor depression and reduction of LCGU in dopaminergic regions suggests a role of dopamine autoreceptors in regulation of motor function. Metabolic stimulation of many non-dopaminergic regions when stereotypy is evident suggests that circuit(s) involving these areas may contribute to stereotypy.

Selective Changes in Local Cerebral Glucose Utilization Induced by Phenobarbital in the Rat

Alterations in cerebral metabolic activity were measured after different doses of phenobarbital. Local cerebral glucose utilization was determined in 58 brain regions with the use of the [14C]deoxyglucose technique in 3-month-old Fischer 344 rats, at 1 h after the ip administration of saline or of phenobarbital. Whole brain glucose utilization declined in a dose-related manner by 4%, 13%, 33%, 35%, and 56% after phenobarbital 18, 60, 180, 300, and 600 mg/kg, respectively. The number of regions significantly affected (P < 0.05) increased from 7 to 95% of the regions examined between doses of 18 to 600 mg/kg. Metabolism decreased in all significantly affected regions except the interpeduncular nucleus, where it was increased. In a separate group of rats, the number of falls per 5 min from a constantly rotating cylinder was measured at subanesthetic doses of phenobarbital. Doses of drug that affected performance on the rotating cylinder (18 and 60 mg/kg) reduced glucose utilization in brain regions involved with motor performance, including the red nucleus, vestibular nucleus, substantia nigra, and deep layers of the superior colliculus, whereas cerebral cortical regions were not altered significantly. The results demonstrate that phenobarbital reduces cerebral glucose utilization, in a dose-dependent manner, in most brain regions and affects subcortical regions of the motor system significantly before reducing metabolism in the cerebral cortex.