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1.  Inhibition of aldehyde dehydrogenase-2 suppresses cocaine seeking by generating THP, a cocaine use–dependent inhibitor of dopamine synthesis 
Nature medicine  2010;16(9):1024-1028.
There is no effective treatment for cocaine addiction despite extensive knowledge of the neurobiology of drug addiction1–4. Here we show that a selective aldehyde dehydrogenase-2 (ALDH-2) inhibitor, ALDH2i, suppresses cocaine self-administration in rats and prevents cocaine- or cue-induced reinstatement in a rat model of cocaine relapse-like behavior. We also identify a molecular mechanism by which ALDH-2 inhibition reduces cocaine-seeking behavior: increases in tetrahydropapaveroline (THP) formation due to inhibition of ALDH-2 decrease cocaine-stimulated dopamine production and release in vitro and in vivo. Cocaine increases extracellular dopamine concentration, which activates dopamine D2 autoreceptors to stimulate cAMP-dependent protein kinase A (PKA) and protein kinase C (PKC) in primary ventral tegmental area (VTA) neurons. PKA and PKC phosphorylate and activate tyrosine hydroxylase, further increasing dopamine synthesis in a positive-feedback loop. Monoamine oxidase converts dopamine to 3,4-dihydroxyphenylacetaldehyde (DOPAL), a substrate for ALDH-2. Inhibition of ALDH-2 enables DOPAL to condense with dopamine to form THP in VTA neurons. THP selectively inhibits phosphorylated (activated) tyrosine hydroxylase to reduce dopamine production via negative-feedback signaling. Reducing cocaine- and craving-associated increases in dopamine release seems to account for the effectiveness of ALDH2i in suppressing cocaine-seeking behavior. Selective inhibition of ALDH-2 may have therapeutic potential for treating human cocaine addiction and preventing relapse.
doi:10.1038/nm.2200
PMCID: PMC3191463  PMID: 20729865
2.  A selective ALDH-2 inhibitor reduces anxiety in rats 
CVT-10216 is a highly selective, reversible inhibitor of ALDH-2 that reduces excessive alcohol drinking. Anxiety plays a role in alcoholism. The present study asks whether CVT-10216 has anxiolytic properties, as reflected in social interaction behavior in four unrelated rodent models: endogenous anxiety-like behavior in naïve Fawn-Hooded rats, repeated alcohol-withdrawal-induced anxiety, restraint stress-induced anxiety and drug-induced anxiety. CVT-10216 counteracted anxiety in all models except that produced by the 5-HT2C agonist, mCPP. CVT-10216 exhibited both acute and prophylactic inhibitions of repeated alcohol-withdrawal-induced anxiety. Importantly, anxiogenic behavior induced by the benzodiazepine receptor inverse agonist, DMCM, was counteracted dose-dependently by CVT-10216. Thus, a non-addictive selective inhibitor of ALDH-2 has both anxiolytic and antidipsotropic properties, which may be dependent, in part on the involvement of the GABA–benzodiazepine system.
doi:10.1016/j.pbb.2009.09.004
PMCID: PMC2859712  PMID: 19747934
ALDH-2 inhibitor; Social interaction test; Fawn-Hooded rats; Anxiogenic behavior; Ethanol withdrawal; DMCM; mCPP; Restraint stress
3.  Ranolazine Attenuates Behavioral Signs of Neuropathic Pain 
Behavioural pharmacology  2009;20(8):755-758.
Ranolazine modulates the cardiac voltage-gated sodium channel (Nav 1.5) and is FDA-approved for the treatment of ischemic heart disease. Ranolazine also targets neuronal (Nav 1.7, 1.8) isoforms that are implicated in neuropathic pain. Therefore, we determined the analgesic efficacy of ranolazine in a pre-clinical animal model of neuropathic pain. Both i.p. and oral administration of ranolazine dose-dependently inhibited the mechanical and cold allodynia associated with spared nerve injury, without producing ataxia or other behavioral side effects. These data warrant clinical investigation of the potential use of ranolazine in the treatment of neuropathic pain.
doi:10.1097/FBP.0b013e3283323c90
PMCID: PMC2975014  PMID: 19773645
spared nerve injury; hyperalgesia; allodynia; rat; Nav 1.7; Nav 1.8
4.  Dopamine and Ethanol Cause Translocation of εPKC Associated with εRACK: Cross-talk Between PKA and PKC Signaling Pathways 
Molecular pharmacology  2008;73(4):1105-1112.
Previously we found that neural responses to ethanol and the dopamine D2 receptor (D2) agonist NPA involve both epsilon protein kinase C (εPKC) and cAMP-dependent protein kinase A (PKA). However, little is known about the mechanism underlying ethanol- and D2-mediated activation of εPKC and the relationship to PKA activation. In the present study, we used a new εPKC antibody, 14E6, that selectively recognizes active εPKC when not bound to its anchoring protein εRACK (receptor for activated C-kinase), and PKC isozyme-selective inhibitors and activators, to measure PKC translocation and catalytic activity. We show here that ethanol and NPA activated εPKC and also induced translocation of both εPKC and its anchoring protein, εRACK to a new cytosolic site. The selective εPKC agonist, pseudo-εRACK, activated εPKC but did not cause translocation of the εPKC/εRACK complex to the cytosol. These data suggest a step-wise activation and translocation of εPKC following NPA or ethanol treatment where εPKC first translocates and binds to its RACK and subsequently the εPKC/εRACK complex translocates to a new subcellular site. Direct activation of PKA by Sp-cAMPS, PGE1 or the adenosine A2A receptor is sufficient to cause εPKC translocation to the cytosolic compartment in a process that is dependent on PLC activation and requires PKA activity. These data demonstrate a novel cross-talk mechanism between εPKC and PKA signaling systems. PKA and PKC signaling have been implicated in alcohol rewarding properties in the mesolimbic dopamine system. Cross-talk between PKA and PKC may underlie some of the behaviors associated with alcoholism.
doi:10.1124/mol.107.042580
PMCID: PMC2692587  PMID: 18202306
5.  Phospholipase C activation is required for cardioprotection by ethanol consumption 
Regular alcohol consumption decreases the incidence of myocardial infarction (MI) and improves post-MI survival. It has previously been reported that chronic ethanol exposure induces long-term protection against cardiac ischemia/reperfusion injury, which improves myocardial recovery after MI. Chronic cardioprotection by ethanol requires the activation of myocyte adenosine A1 receptors and sustained intramyocyte translocation of epsilon protein kinase C. A1 receptors activate phospholipase C (PLC). In the present paper, the role of PLC in mediating ethanol’s protective effect against ischemia/reperfusion injury is investigated. Isolated hearts from guinea pigs fed 2.5% ethanol in their water for four months were subjected to ischemia/reperfusion. Hearts from ethanol-treated animals showed improved recovery of left ventricular developed pressure compared with controls (61% versus 38% of baseline, respectively; P<0.05) and decreased necrosis, assessed by the release of creatine kinase (263±18 U/mL × g dry weight versus 360±24 U/mL × g dry weight, respectively; P<0.05). Ethanol protection was abolished by the PLC antagonist, U-73122 (50 nM). These findings suggest that PLC activation is required for ethanol cardioprotection against ischemia/reperfusion injury.
PMCID: PMC2719158  PMID: 19649218
Ethanol; Heart; Phospholipase C; Preconditioning; U-73122

Results 1-5 (5)