Michael E. Ragozzino

Glucose enhancement of memory in patients with probable senile dementia of the Alzheimer's type

Attempts to attenuate the severe memory deficits in patients with SDAT have been largely unsuccessful, particularly in patients at advanced stages of the disease. Recent evidence indicates that glucose administration enhances memory in generally healthy aged rodents and humans. The present experiment demonstrates that glucose administration improves memory in moderately to severely demented patients with probable SDAT. Glucose ingestion significantly enhanced performance on several tests including orientation, word recognition and recall, narrative prose, and face recognition after glucose ingestion. Thus, the results extend enhancement of memory with glucose from generally healthy rodent and human populations to patients with probable SDAT.

The contribution of the rat prelimbic-infralimbic areas to different forms of task switching.

The experiments examined the effects of prelimbic-infralimbic inactivation in rats on the acquisition and reversal learning of different discrimination tasks: 2- or 4-choice odor discrimination in Experiments 1 and 2, the shift from 2-choice odor discrimination to 2-choice place discrimination in Experiment 3, and the shift from 2-choice place to 2-choice odor discrimination in Experiment 4. Infusions of 2% bupivacaine did not impair performance in the odor discrimination tests. Prelimbic-infralimbic inactivation did not impair acquisition but did impair the shift from an odor to a place discrimination and vice versa. Analysis of the errors revealed that the deficit was due to perseveration of the previously learned strategy. The selective deficits observed in the odor-place tests suggest that the prelimbic-infralimbic areas enable behavioral flexibility when conditions demand inhibiting the use of one type of attribute information and learning a new type of attribute information.

Spontaneous alternation and inhibitory avoidance impairments with morphine injections into the medial septum. Attenuation by glucose administration

Peripheral glucose administration attenuates impairments produced by peripheral injections of the opioid agonist, morphine, on spontaneous alternation. Injections of opioid agonists directly into the medial septum also impair memory. The present experiments examined whether systemic and intraseptal glucose injections could attenuate deficits on spontaneous alternation and inhibitory avoidance in rats treated with intraseptal morphine. Morphine (3.95 nmol) injected into the medial septum significantly impaired performance on spontaneous alternation and inhibitory avoidance tasks. Both systemic (100 mg/kg, i.p.) and intraseptal (18.33 nmol) injections of glucose, administered concomitantly with intraseptal morphine, attenuated the morphine-induced impairments on these tasks in rats. These findings suggest that one brain region where glucose may act is the medial septum, possibly by releasing opioid inhibition of cholinergic activity.

The Parafascicular Thalamic Nucleus Concomitantly Influences Behavioral Flexibility and Dorsomedial Striatal Acetylcholine Output in Rats

Recent evidence suggests that a circuit involving the centromedian–parafascicular (Pf) thalamus and basal ganglia is critical for a shift away from biased actions. In particular, excitatory input from the Pf onto striatal cholinergic neurons may facilitate behavioral flexibility. Accumulating evidence indicates that an endogenous increase in dorsomedial striatal acetylcholine (ACh) output enhances behavioral flexibility. The present experiments investigated whether the rat (Rattus norvegicus) Pf supports flexibility during reversal learning, in part, by modifying dorsomedial striatal ACh output. This was determined first by examining the effects of Pf inactivation, through infusion of the GABA agonists baclofen and muscimol, on place acquisition and reversal learning. Additional experiments examined Pf inactivation on dorsomedial striatal ACh output during reversal learning and a resting condition. Behavioral testing was performed in a cross-maze. In vivo microdialysis combined with HPLC/electrochemical detection was used to sample ACh from the dorsomedial striatum. Pf inactivation selectively impaired reversal learning in a dose-dependent manner. A subsequent study showed that an increase in dorsomedial striatal ACh efflux (∼30% above basal levels) during reversal learning was blocked by Pf inactivation, which concomitantly impaired reversal learning. In the resting condition, a dose of baclofen and muscimol that blocked a behaviorally induced increase in dorsomedial striatal ACh output did not reduce basal ACh efflux. Together, the present findings indicate that the Pf is an intralaminar thalamic nucleus critical for behavioral flexibility, in part, by directly affecting striatal ACh output under conditions that require a shift in choice patterns.

Glucose attenuates a morphine-induced decrease in hippocampal acetylcholine output: an in vivo microdialysis study in rats

Systemic injections of morphine impair performance in memory tests. Glucose administration ameliorates memory deficits produced by morphine treatment. The memory impairments induced by morphine may be related to opioid inhibition of acetylcholine release with reversal of this effect by glucose. The present experiment determined whether: (1) systemic morphine treatment decreases acetylcholine output in the hippocampal formation; and (2) systemic glucose administration attenuates the effect of morphine treatment. Employing microdialysis, samples were collected at 12-min intervals and assayed for acetylcholine using HPLC with electrochemical detection. Morphine (10 mg/kg)/saline injections resulted in an immediate decrease in acetylcholine output (20-35%) that was observed up to the third postinjection sample (36 min). Glucose (100 mg/kg) administered concurrently with morphine attenuated the reduction in acetylcholine output in the second and third samples. These findings suggest that glucose may attenuate morphine-induced memory impairments by reversing a decrease in acetylcholine output produced by morphine.

Pyruvate Infusions Into the Septal Area Attenuate Spontaneous Alternation Impairments Induced by Intraseptal Morphine Injections

Glucose infusions into the medial septal area attenuate memory impairments produced by concurrent intraseptal morphine injections. One possible explanation for these effects of glucose on memory is that the treatment modulates regional energy metabolism. As a test of this hypothesis, the present experiment determined whether intraseptal pyruvate injections could attenuate a spontaneous alternation impairment seen after intraseptal morphine injections. Intraseptal injections of morphine (4.0 nmol) 30 min prior to testing produced spontaneous alternation scores significantly lower than those in control groups. Morphine injections near, but outside, the septal region did not impair spontaneous alternation performance. The morphine-induced impairment was similarly reversed by coadministration of either glucose (18 nmol) or pyruvate (18 nmol) into the septum. These findings suggest that glucose may act through the tricarboxylic acid cycle by increasing the availability of ATP, augmenting the synthesis of certain neurotransmitters, or both.

Glucose attenuates the effect of combined muscarinic-nicotinic receptor blockade on spontaneous alternation.

Glucose administration reverses the effects of both muscarinic and nicotinic cholinergic receptor antagonists on memory and other measures. In experiment 1, we found that glucose attenuated impairments on spontaneous alternation after muscarinic (scopolamine, 0.5 mg/kg) or nicotinic (mecamylamine, 5.0 mg/kg) receptor blockade. In experiment 2, we examined whether glucose could reverse the spontaneous alternation impairments produced by combined muscarinic-nicotinic receptor blockade. Scopolamine (0.1 mg/kg) and mecamylamine (2.5 mg/kg) when administered separately did not modify alternation performance, but when coadministered they decreased spontaneous alternation scores. This decrease was attenuated by glucose at 100, 300, 500 and 3000 mg/kg. These findings suggest that glucose may attenuate the behavioral impairment by enhancing cholinergic activity and/or other neurotransmitter systems.

Naloxone modulates the behavioral effects of cholinergic agonists and antagonists.

Peripheral glucose administration enhances memory in rodents and humans. Recent findings suggest that glucose may affect behavior, in part, by augmenting central cholinergic functions and by attenuating central opiate functions. The present experiments examined interactions between an opiate antagonist, naloxone, and cholinergic agents to determine whether the effects would parallel those found with glucose. Three behavioral measures were assessed: tremors, hyperactivity, and spontaneous alternation. Naloxone (1 mg/kg) significantly augmented tremors elicited by physostigmine (0.3 mg/kg). Naloxone (1 mg/kg) also attenuated increases in locomotor activity and impairments in spontaneous alternation performance elicited by scopolamine (1 and 3 mg/kg for activity and alternation measures, respectively). Thus, across three diverse measures, naloxone produced effects similar to those previously reported for glucose. These findings are consistent with the hypothesis that release of cholinergic activity from opiate inhibition may contribute to glucose effects on behavior.

Behavioral effects of neural transplantation.

Considerable evidence suggests that transplantation of fetal neural tissue ameliorates the behavioral deficits observed in a variety of animal models of CNS disorders. However, it is also becoming increasingly clear that neural transplants do not necessarily produce behavioral recovery, and in some cases have either no beneficial effects, magnify existing behavioral abnormalities, or even produce a unique constellation of deficits. Regardless, studies demonstrating the successful use of neural transplants in reducing or eliminating behavioral deficits in these animal models has led directly to their clinical application in human neurodegenerative disorders such as Parkinsons disease. This review examines the beneficial and deleterious behavioral consequences of neural transplants in different animal models of human diseases, and discusses the possible mechanisms by which neural transplants might produce behavior recovery.

Glucose effects on mecamylamine-induced memory deficits and decreases in locomotor activity in mice.

Peripheral glucose administration attenuates the effects of muscarinic cholinergic antagonists on several measures, including spontaneous alternation, inhibitory avoidance, and locomotor activity. The present study examined glucose interactions with mecamylamine, a nicotinic cholinergic antagonist, on these measures. Mecamylamine (5 mg/kg, sc) significantly impaired spontaneous alternation performance. Glucose (100 mg/kg, ip) administered with mecamylamine attenuated the impairment. Treatment with hexamethonium (5 and 10 mg/kg, sc), a peripheral nicotinic blocker, did not impair performance. Pretraining treatment with mecamylamine, but not hexamethonium, significantly reduced later retention latencies on inhibitory avoidance tests. Glucose, administered with mecamylamine prior to training, significantly attenuated the impaired test performance. Mecamylamine, but not hexamethonium, significantly decreased locomotor activity. In contrast to the attenuating effects of glucose on the other measures above, glucose administered with mecamylamine potentiated the decreased locomotor activity. These findings demonstrate that glucose influences the behavioral effects of a nicotinic cholinergic antagonist in a manner generally similar to that of muscarinic cholinergic antagonists, and supports previous evidence that circulating glucose interacts with central cholinergic functions.