ABSTRACT
The present experiment was designed to elucidate whether chronic dietary treatment with nimodipine (3 months, 1000 ppm) enhances water maze spatial navigation, passive avoidance behavior and locomotor activity, and whether such a treatment with nimodipine would interact with the therapeutic effect of acute metrifonate treatment. In young medial septum-lesioned rats, nimodipine had no effect by its own on cognitive or motor behavior, and did not enhance the water maze and passive avoidance behavior improving action of metrifonate (3 and 10 mg/kg. p.o.). Nimodipine treatment of aged rats did not markedly affect the deficit in motor performance. Single and combined nimodipine and metrifonate (3 and 10 mg/kg, p.o.) treatment of aged rats resulted in shorter escape distance values to the hidden water maze escape platform compared to those of control aged rats. The passive avoidance performance of aged rats was more effectively facilitated by a combined nimodipine and metrifonate treatment than by either of the drugs on their own. Following a washout period of 2.5 months the rats that were treated previously with nimodipine no longer performed better than aged controls in the water maze test. Furthermore, after the washout period metrifonate 10 mg/kg was no longer effective in improving the water maze behavior of the now 26-month-old rats irrespective of their chronic pretreatment. Taken together, these findings indicate that chronic nimodipine and acute metrifonate treatment may more effectively stimulate cognitive functioning than either of the treatments on their own.
Subject(s)
Avoidance Learning/drug effects , Calcium Channel Blockers/pharmacology , Cholinesterase Inhibitors/pharmacology , Nimodipine/pharmacology , Space Perception/drug effects , Trichlorfon/pharmacology , Animals , Brain Chemistry/drug effects , Male , Maze Learning/drug effects , Motor Activity/drug effects , Rats , Rats, WistarABSTRACT
We investigated the effects of acute p.o. pretraining treatment with an indirect acetylcholinesterase inhibitor, metrifonate, on water maze spatial navigation and passive avoidance behavior. Metrifonate (10-100 mg/kg, orally, p.o.) did not improve the water maze or passive avoidance performance of young intact rats. However, in young rats metrifonate over a broad dosage range (10-100 mg/kg, p.o.) was able to alleviate the adverse effects of scopolamine (a muscarinic acetylcholine receptor antagonist; 0.4 and 2.0 mg/kg in water maze and passive avoidance study, respectively) and medial septum-lesioning on spatial reference and working memory and passive avoidance performance. In old (23-month-old) rats, a defect of water maze and passive avoidance behavior was observed. In old rats, metrifonate improved spatial reference memory function in the water maze and also passive avoidance at 10-30 mg/kg, but the 3 mg/kg dose was ineffective. Very old (27-month-old) rats had a more severe impairment of water maze performance than old rats, and metrifonate 3-30 mg/kg did not improve their spatial navigation. These results show that metrifonate may over a wide range of doses stimulate cognitive functioning, but during advanced aging neurobiological defects develop that may mask some of the therapeutic effects of metrifonate in rats.
Subject(s)
Aging/physiology , Avoidance Learning/drug effects , Cholinesterase Inhibitors/pharmacology , Motor Activity/drug effects , Scopolamine/pharmacology , Trichlorfon/pharmacology , Animals , Male , Rats , Rats, WistarABSTRACT
The present study was designed to investigate the interactions between alpha 1-adrenoceptors and NMDA receptors in modulating spatial navigation and passive avoidance behavior in rats. Pretraining treatment with prazosin, and alpha 1-adrenoceptor antagonist, at 2 mg/kg i.p., impaired acquisition performance in a water maze navigation test and had no effect on passive avoidance behavior. Posttraining and pretest injections of prazosin had no effect on water maze or passive avoidance behavior. Pretraining treatment with ((+/-))-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), a competitive NMDA receptor antagonist, does dependently (3 and 10 mg/kg) impaired passive avoidance and water maze behavior. Posttraining treatment with CPP had no effect on water maze and passive avoidance behavior. A pretraining combination of subthreshold doses of CPP (1 mg/kg) and prazosin (1 mg/kg) impaired water maze behavior. A combination of subthreshold doses of CPP (3 mg/kg) and prazosin (1 mg/kg) injected posttraining or pretest had no marked effect on water maze or passive avoidance performance. A control experiment showed that CPP 3 mg/kg or CPP 1 mg/kg and prazosin 1 mg/kg injected pretraining had no effect on cue navigation to a clearly visible platform, but CPP 10 mg/kg markedly impaired performance. The present results indicate that alpha 1-adrenoceptors and NMDA receptors may synergistically regulate acquisition of spatial navigation performance. Therefore, it would be interesting to study the effects of combined stimulation of alpha 1-adrenoceptors and NMDA receptors on age-related memory defects.
Subject(s)
Adrenergic alpha-Antagonists/pharmacology , Avoidance Learning/drug effects , Convulsants/pharmacology , Piperazines/pharmacology , Prazosin/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Computers , Dose-Response Relationship, Drug , Drug Combinations , Male , Memory/drug effects , Rats , Rats, WistarABSTRACT
The present study was designed to investigate the hypothesis that nicotine may act via thalamic and basal forebrain nicotinic acetylcholine receptors to suppress neocortical high voltage spindling and slow waves in awake rats. Loca microinfusions of a nicotinic acetylcholine receptor agonist (nicotine 3, 10 and 30 micrograms) or antagonist (mecamylamine 10 micrograms) into the vicinity of the basal forebrain cholinergic projection neurones of the nucleus basalis had no effect on cortical EEG waves. However, nicotine (3, 10 and 30 micrograms) microinfusions into the thalamus decreased high voltage spindles and desynchronized non-spindling EEG waves in the cortex. This suggests that nicotinic acetylcholine receptor active drugs may modulate thalamocortical oscillations and desynchronize EEG waves via brain stem cholinergic projections at the thalamus.
Subject(s)
Electroencephalography/drug effects , Nicotine/pharmacology , Substantia Innominata/drug effects , Thalamus/drug effects , Animals , Cerebral Cortex/drug effects , Dose-Response Relationship, Drug , Male , Rats , Rats, WistarABSTRACT
We examined the role of anterior and posterior cingulate cortical muscarinic receptors in water maze spatial learning and passive avoidance. Pretraining and posttraining trial scopolamine (a mixed a muscarinic acetylcholine antagonist) infusions into the anterior cingulate cortex dose dependently (3 no effect; 10 and 30 micrograms impaired) impaired passive avoidance performance. Pretesting infusion into the anterior cingulate had no effect on passive avoidance. Scopolamine infusion into the anterior cingulate did not impair spatial navigation. On the contrary, scopolamine (3 micrograms no effect, 10 and 30 micrograms impaired) infusions into the posterior cingulate before daily training trials impaired water maze navigation to a hidden platform, but did not affect navigation to a visible escape platform or passive avoidance. Posttraining and pretesting infusion into the posterior cingulate did not impair WM spatial navigation. The present results indicate that muscarinic acetylcholine receptor antagonist may modulate passive avoidance performance via cholinergic receptors located in anterior cingulate cortex and the ability to develop a spatial navigation strategy via muscarinic receptors located in posterior cingulate.
