Reverse Pharmacology on Corydalis yanhusuo: Dehydrocorybulbine, Analgesia and Antipsychosis And Methionine-induced Animal Models of Schizophrenia

In the first part of the dissertation, a traditional Chinese medicine, Corydalis yanhusuo, which is widely used for pain treatment, was systematically evaluated in three standardized pain assays and its mechanism of action in terms of antinociceptive effects was further studied. The results show that Corydalis yanhusuo extract effectively attenuates acute nociceptive pain, persistent inflammatory pain and chronic neuropathic pain, without causing tolerance. The effects on acute and neuropathic pain but not inflammatory pain are at least partially mediated through dopamine D2 receptor antagonism.By applying pharmacological approach which is used to identify compounds acting at G protein-coupled receptors, one compound, dehydrocorybulbine (DHCB) was identified from Corydalis yanhusuo extact. DHCB was synthesized and it is shown displaying weak μ-opioid receptor agonist and moderate dopamine receptor antagonist activities. DHCB is effective at alleviating thermally induced acute pain. By using selective pharmacological compounds and dopamine receptor knockout mice, the results show that the antinociceptive effect relies upon DHCB’s antagonist activity at the dopamine D2 receptor but not on its agonist activity at μ-opioid receptor. DHCB is further demonstrated to be effective against inflammatory pain and injury-induced neuropathic pain and furthermore causes no antinociceptive tolerance.Moreover, the antipsychotic effects of DHCB were evaluated by using apomorphine and MK-801 induced schizophrenia-like symptoms in mice and the extended pharmacological profile of DHCB was screened through radioligand receptor binding assays. DHCB is shown effectively attenuating positive, negative and cognitive symptoms in apomorphine and MK-801 induced animal models of schizophrenia. These effects are thought to be mediated through dopamine receptor antagonism but also other receptor activities such as serotonin-7 and sigma-1 receptors.In the second part of the dissertation, administration of l-methionine to adult mice for 7 days induces behavioral responses that reflect three types of schizophrenia-like symptoms. These responses are differentially reversed by typical and atypical antipsychotics in ways that parallel their effects in schizophrenics. Further, the male offspring from the prenatal l-methionine treatment exhibit behavioral responses that reflect three types of schizophrenia-like symptoms. Moreover, these mice show reduced excitatory synaptic connection and dysregulated expression of several neuronal activity-regulated genes that are known to be involved in the neurodevelopment, synaptic plasticity and learning and memory function