Effects Of Physostigmine On Behavioral Sensitization And Changes Of Electroencephalogram Induced By Morphine In Rats

Behavioral sensitization was defined as an increased (behavioral) response to a given dose of drug or a response of a similar magnitude upon treatment with a lower dose of drug after repeated treatment with drugs of abuse. The "incentive sensitization theory of addiction" pointed out that behavioral sensitization induced by repeated administration to drugs of abuse plays a key role in certain aspects of drug addiction such as compulsive drug-seeking behavioral and represents the sensitization of motivation and reward system. There are two mechanisms of the behavioral sensitization induced by morphine: dopamine (DA)-dependent and non dopamine-dependent. Previous study indicated that chronic administration of morphine increased extracelular DA release in the rat nucleus acumbens (NAc) in the process of behavioral sensitization. When morphine withdrawal precipitated by naloxone and withdrawal symptom was detectable, extracelular DA release decreased in the NAc. These results suggested that high DA level in NAc may correlate with morphine reward, and low DA level with aversion. Acetylcholine (Ach) changes were opposite with DA in the NAc: extracellular Ach level was low in response to morphine and high during abstinence or withdrawal precipitated by naloxone. Thus, Ach in the NAc have a special relationship to morphine reinforcement.This study based upon the "incentive sensitization theory of addiction" and the above results, and used the behavioral sensitization as an animal model, in- vestigated the effects of the physostigmine , a cholinergic agonist of centre nerve system, on the morphine or the morphine plus the surroundings clues or the surroundings clues inducing or challenging behavioral sensitization and examined the relationship between these effects of the physostigmine and the dopaminergic function in NAc, by using the methods of record Locomotor Activity (LA), High Performance Liquid Chromatography (HPLC), Microinjection (MJ). The effect of the physostigmine on the changes of electrocorticogram (ECoG) induced by the morphine were also examined. Main results of the study are listed as follows:1 Administration of the anticholinestrase physostigmine (0.2mg/kg, i.p) inhibited significantly the morphine (10mg/kg, i.p)-induced the development of behavioral sensitization, intra-shell of NAc administration of the physostigmine (8ug/rat) blocked the development of behavioral sensitization induced by the morphine (10mg/kg) plus the surroundings clues. These results suggested that morphine-induced and the morphine plus the surroundings clues induced behavioral sensitization is related with the reducing of the cholinergic function of the centre nerve system.2 The surroundings clues could challenge the expression of behavioral sensitization induced by the morphine (10mg/kg, i.p) plus the surroundings clues. The physostigmine, whether i.p (0.2mg/kg) or intra-shell of NAc (8ug/rat), could also inhibit the evocative role of the surroundings clues to the morphine-induced behavioral sensitization. Thus, the evocative role of the surroundings clues to the behavioral sensitization induced by the morphine plus the surroundings clues is related to the cholinergic function of the centre nerve system to some extent.3 Intra-shell of NAc administration of the dopaminergic agonist SKF-82958 (8ug/rat, co-administration with 8ug/rat-physostigming) reversed the physostigmine-induced inhibition of the morphine (10mg/kg, i.p) response. Therefore, the effects of the physostigmine on the morphine-induced sensiti- zation are related to the interaction of the cholinergic system and thedopaminergic system in NAc.4 Acute administration of the morphine (10mg/kg, i.p) reduced significantlythe α and β wave of the EEG on the cortex in rats. Administration of thephysostigmine (i.p, 0.2mg/kg) reversed these changes of the EEG. As a result,the changes of EEG induced by the morphine are also related to thecholinergic function of the centre nerve system.Taking the above results together, the morphine or the morphine plus thesurroundings clues or the surroundings clues inducing or challengingbehavioral sensitization and the changes of EEG induced by the morphine arerelated with the reducing of the cholinergic function of the centre nerve system.The cholinesterase inhibitors such as physostigmine could be approached aspotential therapeutic agents for patients who abuse drugs.