Madepalli K. Lakshmana

Chronic phenytoin induced impairment of learning and memory with associated changes in brain acetylcholine esterase activity and monoamine levels

Groups of adult, male, Wistar rats were administered phenytoin (DPH) at 5, 12.5, 25, 50, or 75 mg/kg i.p. for 21 days. The learning and memory of these rats were assessed using the T-maze and passive avoidance tests. The plasma DPH levels, acetylcholine esterase (AChE) activity in different brain regions, and the levels of monoamines in the hippocampus were measured. The results indicate that DPH below the therapeutic plasma level did not significantly impair learning and memory. Correspondingly, no changes were noted in the brain 5-HT or AChE activity. However, DPH, at therapeutic plasma concentrations (i.e., 10.5 micrograms/ml in the dosage range of 50 and 75 mg/kg, respectively), significantly impaired learning and memory in rats. The impaired learning and memory functions were associated with increased 5-HT levels and decreased AChE activity in the hippocampus. With a dose of 75 mg/kg DPH, there was a reduction in the AChE activity in the striatum, in addition to hippocampus. It is conjectured that the neurochemical changes brought about by DPH at therapeutic plasma levels may account for the impairment of learning, memory, and cognitive functions in epilepsy.

Chronic (-) deprenyl administration increases dendritic arborization in CA3 neurons of hippocampus and AChE activity in specific regions of the primate brain

The mechanism by which (-) deprenyl enhances cognitive function in Alzheimers disease (AD) is not yet understood. (-) Deprenyl (0.2 mg/kg/day) was administered intramuscularly to adult male monkeys (n = 6) for 25 days. Control monkeys (n = 6) received physiological saline by the same route. The activity of acetylcholinesterase (AChE) in different brain regions and the dendritic arborization in CA3 pyramidal neurons of hippocampus were analysed. (-) Deprenyl-treated monkeys showed a significant increase in the AChE activity by 43% (p < 0.001) in the frontal cortex, by 39% (p < 0.025) in the motor cortex, by 66% (p < 0.001) in the hippocampus and by 26% (p < 0.05) in the striatum compared to controls. The branching points and the intersections of both apical and basal dendrites of CA3 hippocampal pyramidal neurons were also significantly increased in (-) deprenyl-treated monkeys. Enhanced AChE activity may increase dendritic arborization in the hippocampus and it may also play a role in improving cognitive functions observed in AD, following (-) deprenyl treatment.

Chronic (−) deprenyl administration alters dendritic morphology of layer III pyramidal neurons in the prefrontal cortex of adult Bonnett monkeys

Chronic (-) deprenyl (0.2 mg/kg, b.wt; for 25 days) treatment induced alterations in the dendritic morphology of prefrontal cortical neurons in adult Bonnett monkeys were evaluated in the present study. The branching points and intersections in apical and basal dendrites were studied up to a distance of 400 and 200 micrometers, respectively, in Golgi impregnated layer III pyramidal neurons of the prefrontal cortex. Our results revealed a significant (p<0.001) increase in the number of branching points and intersections in both apical and basal dendrites in (-) deprenyl treated monkeys compared to controls. Such an enriched dendritic arborization in prefrontal cortical neurons may be responsible for the enhancement of cognitive functions in Alzheimer disease patients following (-) deprenyl treatment.

Changes in Learning and Memory, Acetylcholinesterase Activity and Monoamines in Brain After Chronic Carbamazepine Administration in Rats

Summary Groups of adult male Wistar rats were administered carbamazepine (CBZ) in doses of 5, 10, 20, 40, or 80 mg/kg/day intraperitoneally (i.p.) for 21 days. The learning and memory of the rats were assessed by the T‐maze and passive avoidance tests. The CBZ plasma levels, the activity of acetylcholinesterase (AChE) in different brain regions, and the levels of monoamines in the hippocampus were also measured. None of the administered doses of CBZ impaired learning and memory. Rats with CBZ plasma levels of 2.5 and 4.5 μg/ml corresponding to the doses of 20 and 40 mg/kg, learned significantly better than controls. AChE activity was decreased in hippocampus and pyriform cortex (19%) in these groups. Simultaneously, an increase in the serotonin (5‐HT) (36%) and dopamine (137%) levels in the hippocampus was noted in the 20‐mg/kg CBZ group. 5–Hydroxyindole acetic acid (5‐HIAA) and homovanillic acid (HVA) levels were increased at 10‐, 20‐, and 40‐mg/kg CBZ doses. However, a dose of 80‐mg/kg caused no change in learning performance as compared with that of controls. Correspondingly, no changes were evident in the AChE activity or monoamine levels. We postulated that the decreased AChE activity caused by CBZ in the therapeutic range may lead to increased ACh levels in brain, thus producing improvement in learning and memory. The increased turnover of 5‐HT and dopamine (DA) in the hippocampus may play a role in long‐term potentiation and improvement in memory.

Mercuric chloride-induced alterations of levels of noradrenaline, dopamine, serotonin and acetylcholine esterase activity in different regions of rat brain during postnatal development

Wistar rats were fed mercuric chloride, 4 mg/kg body weight per day chronically from postnatal day 2 to 60 by gastric intubation. Mercury consumption was then discontinued until 170 days to allow time for recovery. Since mercury caused reduction in body weight, an underweight group was also included besides the normal saline group. Levels of noradrenaline (NA), dopamine (DA), 5-hydroxy-tryptamine (5-HT) and the activity of acetylcholine esterase (AChE) were assayed in various brain regions in different age groups. By 60 days of age, the mercury group showed elevations of NA levels in olfactory bulb (OB), visual cortex (VC) and brain stem (BS) but not in striatum-accumbens (SA) and hippocampus (HI). DA levels were also increased in OB, HI, VC and BS but not in SA. AChE activity was decreased in the mercury group only in HI and VC at 20 days of age. The Mercury group showed no behavioural abnormality outwardly; however, operant conditioning revealed a dificiency in performance. Nevertheless, all these changes disappeared after discontinuation of mercury intake. Thus the changes occurring in the brain at this level of oral mercuric chloride intake seem to reflect adaptive neural mechanisms rather than pathological damage.

Role of Monoamine Oxidase Type A and B on the Dopamine Metabolism in Discrete Regions of the Primate Brain

The role of monoamine oxidase (MAO) type A and B on the metabolism of dopamine (DA) in discrete regions of the monkey brain was studied. Monkeys were administered (–)-deprenyl (0.25 mg/kg) or clorgyline (1.0 mg/kg) or deprenyl and clorgyline together by intramuscular injections for 8 days. Levels of DA and its metabolites, dihydroxy phenylacetic acid (DOPAC) and homovanillic acid (HVA) were estimated in frontal cortex (FC), motor cortex (MC), occipital cortex (OC), entorhinal cortex (EC), hippocampus (HI), hypothalamus (HY), caudate nucleus (CN), globus pallidus (GP) and substantia nigra (SN). (–)-Deprenyl administration significantly increased DA levels in FC, HY, CN, GP and SN (39–87%). This was accompanied by a reduction in the levels of DOPAC (37–66%) and HVA (27–79%). Clorgyline administration resulted in MAO-A inhibition by more than 87% but failed to increase DA levels in any of the brain regions studied. Combined treatment of (–)-deprenyl and clorgyline inhibited both types of MAO by more than 90% and DA levels were increased (57–245%) in all brain regions studied with a corresponding decrease in the DOPAC (49–83%) and HVA (54–88%) levels. Our results suggest that DA is metabolized preferentially, if not exclusively by MAO-B in some regions of the monkey brain.

Levels of dopamine and noradrenaline in the developing retina — effect of light deprivation

The effect of light deprivation on the levels of dopamine and noradrenaline was studied in the developing rat retina. These transmitters were estimated in three groups of rats: (i) cycling light reared; (ii) dark reared since birth; and (iii) dark reared since birth, but exposed to cycling light for 1 day prior to the estimation of catecholamines. Our results show that (1) there is a progressive decrease in the levels of dopamine and noradrenaline in the cycling light and dark reared rats during postnatal development; (2) dark rearing further reduces the content of dopamine and noradrenaline; and (3) restoration of physiological (light) stimulus in the dark‐reared rats during the early postnatal period results in the recovery of noradrenaline to a greater extent than that of dopamine. This study demonstrates a progressive decrease in the plasticity of dopaminergic system during retinal development, while such a decrease is not apparent in the noradrenergic system.

Phenobarbital in the anticonvulsant dose range does not impair learning and memory or alter brain AChE activity or monoamine levels

The learning and memory in adult, male Wistar rats were assessed using the T-maze and passive avoidance tests after chronic administration of phenobarbital (PB) at 5, 15, 30, 60, or 75 mg/kg intraperitoneally (IP) for 21 days. The PB levels in plasma, the acetylcholine esterase (AChE) activity in the motor cortex, pyriform cortex, olfactory bulb, striatum, septum, and hippocampus and the levels of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) levels in the hippocampus were measured. There was no significant change in learning and memory, AChE activity, or monoamine levels at plasma PB levels of 1.5, 6.0, 9.0, and 25 micrograms/ml (corresponding to doses of 5, 15, 30, or 60 mg/kg PB, respectively). However, at a plasma level of 55 micrograms/ml (75 mg/kg), PB caused impairment in learning and memory. It was associated with an increase in AChE activity and 5-HT levels in the hippocampus. The results indicate that chronic PB administration may not be linked to impaired learning and memory functions at doses used in anticonvulsant therapy.

Increased acetylcholinesterase activity in selected regions of rat brain after chronic (−)-deprenyl administration

Abstract(−)-Deprenyl, 0.05, 1.0, 2.0, and 10.0 mg/kg body weight, was administered intraperitonially to Wistar rats for 30 days. The activity of acetylcholinesterase, and monoamine oxidase A and B were assayed in different brain regions. After the experimental period acetyl cholinesterase activity was found to be significantly increased in frontal cortex [P<0.001] and hippocampus [P<0.001] but not in striatum and brainstem at 0.1, 1.0, and 2.0 mg/kg dose, the maximum increase being at 0.1 mg/kg dose. Monoamine oxidase B activity was inhibited by more than 90% at 1.0, 2.0, and 10.0 mg/kg dose while 0.05 and 0.1 dose inhibited only about 55% and 70% respectively. Monoamine oxidase A activity was inhibited to more than 70% at 1.0 mg dose and to more than 90% at 2.0 and 10.0 mg/kg dose. At 0.05 and 0.1 mg/kg dose monoamine oxidase A activity was not significantly altered.