Neurological Mechanisms Underlying Physiological Withdrawal And Craving Induced By Repeated Morphine Administration:Behavioral And Neuroimage Studies

Chronic/repeated use of opioids can induce addictive behaviors that are followed by the emergence of physiological withdrawal and craving behaviors during abstinence. This thesis aims to elucidate the neural basis of the physiological withdrawal and look for effective ways to suppress drug-seeking behaviors in animal models of repeared morphine adminsitration.In the first study, manganese-enhanced magnetic resonance imaging (MEMRI) was used to map activated areas during the spontaneous withdrawal period after repeated morphine injection. The following studies used different behavioral protocols to investigate the effects of glutamate antagonism and olfactory deprivation on development and expression of addiction-related behaviors. The goals of these studies are to:1) elucidate the neural substrates of morphine-induced withdrawal reaction;2) test whether glutamate antagonism will attenuate the expression of psychological craving behaviors; and3) investigate whether olfactory deprivation intranasal instillation of zinc sulfate would affect the development and expression of morphine-induced behavioral sensitization and conditioned place preference.In chapter1, the basic theory, mainstream hypotheses and major research approachs in addiction research are introduced. The principles of MEMRI and its applications in neuroscience reseaches are reviewed.In chapter2, MEMRI was used to map activated/deactivated brain regions during the spontaneous withdrawal period after repeated morphine injection. The results showed that multiple brain regions were involved in the expression of withdrawal reactions, including the cingulate cortex (Cg), motor cortex, insular cortex, hippocampus, striatum, retrosplenial cortex (RS), accumbens nucleus (NAc), amygdale (Amy), peduncular part of lateral hypothalamus (PLH), ventral tegmental area (VTA) and central nucleus of inferior colliculus (CIC) etc. These results indicated that multiple brain systems; such as the motivation system, the reward system and the executive system are involved in mediating reactions to morphine withdrawal.In chapter3, hyperfunction of glutamatic system was found during the relapse after morphine administration. To investigate the role of the glutamate system in the addiction process, the combined action of a small dose of MK-801(0.05mg/kg, i.p.), an NMDAR antagonist, and ceftriaxone (25mg/kg, i.p.), an inducer of glutamate transporter subtype-1(GLT-1) expression (ceftriaxone), were used to measure their combine effect on morphine CPP during different phases. Neither a small dose of MK-801(0.05mg/kg, i.p.) nor ceftriaxone (25mg/kg, i.p.) were found to effectively impair CPP behaviors. However, the combined action of a small dose of MK-801(0.05mg/kg, i.p.) and ceftriaxone (25mg/kg, i.p.) together reduced the acquisition of morphine-induced CPP and completely inhibited morphine reinstatement. The combination also notably impaired the CPP extinction of the morphine CPP. Taken together, these results indicated that the combined action of a small dose of NMDA receptor antagonists (MK-801) and GLT-1activation (ceftriaxone) can effectively affect the different phases of CPP behaviors. This finding may pave the way in the development of new drugs and/or cocktails for the treatment of addicted patients.In Chapter4and5, nasal perfusion of zinc sulfate (ZnE) was applied to mice to induce the olfactory deprivation. ZnE treatment was found to be able to affect the development and relapse of addiction behaviors. Results showed that pretreatment by ZnE was found to attenuate the development of morphine-induced sensitization and morphine-induced conditioned place preference (CPP) behaviors. Additionally, the expression of FosB-like proteins, transcription factors associated with behavioral alterations, in the nucleus accumbens of the brain was attenuated in the ZnE-treated morphine-conditioned mice. On the other hand, ZnE treatment after development of addiction-behaviors eliminated behavioral sensitization and reinstatement of CPP. In brain circuitry regions involved in drug reinstatement the expression of c-Fos was found to be inhibited in ZnE treated animals when contrasted with the saline-treated treated (Sa1E) ones. Altogether, these results demonstrated that olfaction impairments caused by ZnE could disturbe the development of addiction behaviors and eliminate already established addiction-related behaviors in mice. It is suggested that olfactory stimulus from environmental stimulation may be an important factor in develop and relapse of drug addiction.