Anthony C. Santucci

Excessive serotonin release, not depletion, leads to memory impairments in rats

Eight experiments compared and contrasted the effects of serotonin release and depletion on performance by rats in two tests of memory. Most experiments (Experiments 1-5) examined the effects of the serotonergic releasing/depleting agent p-chloroamphetamine on passive avoidance performance. Additional experiments explored p-chloroamphetamines effects on retention performance by animals trained in an 8-arm radial maze (Experiment 6), and the effects of dorsal raphe nucleus lesions on passive avoidance in animals treated with (Experiment 8) or not treated with (Experiment 7) p-chloroamphetamine. In general, acute increases in serotonin release produced consistent and extensive retention performance deficits in both passive avoidance and radial arm maze. Results from an ancillary control experiment indicated that the p-chloroamphetamine-induced passive avoidance impairment was not related to drug-induced alterations in pain sensitivity. Other experiments ruled out the possibility that p-chloroamphetamine was disrupting passive avoidance retention performance by affecting post-trial consolidation processes, producing state-dependent retention, having direct effects at postsynaptic receptors, or indirectly by affecting non-serotonergic neurotransmitter systems. Depletion of serotonin resulting from either the long-term residual effects of p-chloroamphetamine or lesions of the dorsal raphe nucleus failed to alter passive avoidance retention scores although it produced extensive depletion (45-85%) of serotonin and 5-hydroxyindoleacetic acid in the cortex and hippocampus. These data contribute to the growing body of literature indicating an important role of serotonin in cognitive processes by demonstrating that excessive release, but not depletion, of serotonin produces profound retention performance impairment.

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.

Chapter 35 Implications of multiple transmitter system lesions for cholinomimetic therapy in Alzheimer's disease

Publisher Summary This chapter discusses the implications of multiple transmitter system lesions for cholinomimetic therapy in Alzheimers disease (AD). Because of the profound cholinergic deficits in AD, most therapeutic and animal model studies have focused on this system. The cholinergic lesion-induced learning and memory deficits are found to be readily reversed by cholinomimetic agents. Low doses of physostigmine and other cholinomimetics have repeatedly been shown to reverse n. basalis Meynert (nbM) lesion-induced learning and memory deficits. The experiments described in the chapter are based on the hypothesis that the failure of all or some of the other transmitter systems affected in AD contributes to the symptoms of AD and possibly to the efficacy of cholinomimetics in exerting a beneficial effect. In addition to the cholinergic deficits, the noradrenergic, serotonergic, somatostatinergic, and corticotropin releasing factor (CRF) systems are among the most severely affected in AD. This chapter describes the necessity for treating AD as a multitransmitter system disease requires a multitransmitter approach toward its treatment.

Nucleus basalis lesions impair memory in rats trained on nonspatial and spatial discrimination tasks.

Ibotenic acid-induced lesions of the nucleus basalis of Meynert (nbM) in rats produced severe memory impairments when subjects were required to acquire a brightness discrimination and learn its reversal (Experiment 1). Lesion-induced impairments were also observed when a complex (30-choice) spatial discrimination task served as the assessment instrument (Experiment 2). The memory deficits observed in Experiment 2 were evident despite an approximate 4-month postoperative recovery period and prior brightness discrimination training. Identical nbM lesions failed to produce memory decrements when rats were trained and tested 24 hr later on a simple (2-choice) right vs. left spatial discrimination task. It is concluded that nbM lesions impair memory for both nonspatial and spatial tasks and that, at least with tests of spatial memory, task difficulty may be an important determinant of this impairment.

Pharmacological alleviation of combined cholinergic/noradrenergic lesion-induced memory deficits in rats

Summary: Data derived from a number of preclinical studies examining the effects of combined cholinergic and noradrenergic lesions in a rat model of Alzheimers disease are reviewed. Results from these studies indicated that a nucleus basalis of Meynert (nbM) lesion combined with a lesion of the ascending noradrenergic bundle (ANB) did not exacerbate 72‐h passive avoidance retention deficits beyond the degree of impairment produced by nbM lesions alone. However, the addition of an ANB lesion did block the efficacy of two cholinomimetics (physostigmine and oxotremorine) to reverse the lesion‐induced memory impairment. Memory in combined lesioned rats was restored when cholinomimetic therapy was administered in combination with low doses of clonidine. Studies investigating a number of Hoechst‐Roussel Pharmaceuticals compounds have produced memory‐enhancing effects in animals prepared with combined nbM/ANB lesions without the need for clonidine supplementation. These compounds include P128, P86‐7493, and P87‐8184. Moreover, these compounds have also been shown to be effective in reversing passive avoidance memory deficits in animals with nbM lesions and treated with the noradrenergic toxin DSP‐4. Implications for pharmacotherapeutic approaches for the treatment of Alzheimers disease are discussed.

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)

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.

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 studys 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.

Biochemical mechanisms of stress-induced impairment of rat T cell mitogenesis.

Splenic mononuclear cells isolated from rats exposed to two brief stressors (5 min of restraint or 2 min of footshock) showed a diminished response to the T cell mitogens, concanavalin A and phytohemagglutinin. Cells from these stressed animals also exhibited a diminished response to stimulation with the phorbol ester, tetradecanoylphorbol acetate (TPA), and/or the calcium ionophore, ionomycin. Since stimulation with these latter two agents mimics early signals generated by mitogen surface receptor binding including increased intracellular calcium and protein kinase C activation, the data indicate that stress-related defects in T cell proliferation occur at sites other than or in addition to these early events in cellular activation.

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