| Drug addiction remains one of the most serious threats to our nation's public health in terms of lost lives and productivity. Addiction can be defined as the loss of control over drug use, or the compulsive seeking and taking of drug regardless of the consequence. Cocaine is among the most commonly abused psychostimulants and inhibits all three monoamine transporters-dopamine (DA), serotonin, and norepinephrine, especially for dopamine transporter (DAT), thereby potentiating monoaminergic transmission. Underlying mechanism of cocaine addiction is not yet fully understood, however, substantial evidence indicates that several circuits in mesocorticolimbic systems, are known to mediate the addicting actions of cocaine. Most attention has been given to the nucleus accumbens (NAc) and its dopaminergic input from the ventral tegmental area (VTA) of the midbrain as key substrates for the drug effects. Other brain regions interact with the circuit, including the amygdala, prefrontal cortex (PFC) and other limbic regions. DA and glutamate (Glu) are the most important neurotransmitiers in both the induction and the expression of cocaine sensitization. Available treatments for addiction remain inadequately effective for most individuals. Consequently, there is intense interest in better understanding the neurobiology of addiction in the hope that such knowledge will lead eventually to more effective treatments.ATP sensitive potassium (KATp) channels were first described by Akinori Noma in the membrane of cardiac myocytes in 1983. Now it is known that KATP channels are widely expressed in many cell types including neurons. KATp channels consist of two types of subunits: aninwardly rectifying K+ channel subunit (termed Kir) and a sulfonylurea receptor subunit (SUR), which is a member of the family of ATP-binding cassette transporter proteins. Up until now, two members of the Kir6 family, Kir6.1 and Kir6.2, and two SUR isoforms, SUR1 and SUR2, have been identified. The Kir is thought to confer ATP inhibition and determine conductance, whereas the SUR is considered the primary target for sulfonylureas, KATP channels opener (KCO), and nucleotide diphosphonate (NDP). The open probability of KATP channels directly depends on the intracellular ATP/ADP levels allowing the channels to directly couple the metabolic state of a cell to its electrical activity. KATP channels are distributed widely in brain and may play a critical role in neuroprotection as well as the regulation of DA and Glu transmission.We developed a new compound iptkalim hydrochloride, which has been demonstrated to be a novel KATP channel opener by pharmacological, electrophysiological and biochemical studies, and receptor binding test. Notably, IPT is the only one of KCOs that can pass through blood-brain-barrier, which makes it possible to investigate its effects systematically. Previous studies in our lab have indicated that IPT was relevant to the regulation of DA and Glu release, the very two neurotransmitters playing a critical role in cocaine addiction. But there is no report on the relationship between KATP channels and cocaine addiction hitherto. In the present study, behavioral experiment, determination of neurotransmitters and molecular biology experiment were employed to investigate the correlation between KATP channels and cocaine addiction so as to obtain the basic evidence to develop IPT into a safe and effective therapeutic drug.Part I. Effect of IPT on acute and chronic cocaine-induced enhancement of locomotor activity of mice and changes of DA and Glu levels in rat brain1. Effect of IPT on acute cocaine-induced change of locomotor activity of miceAim: To investigate the effect of IPT on acute cocaine induced change of locomotor activity. Methods and Groups: Mice of either sex were divided into four groups: 1) control: saline 20 ml/kg ip; 2) cocaine group: cocaine 30 mg/kg ip; 3) IPT group: IPT 0.75mg/kg ip; 4) IPT plus cocaine group: IPT 0.75mg/kg 5 min later followed by cocaine 30 mg/kg ip. Behavioral activity w...
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