Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is evidence that dependence on opiates occurs in neurones bearing their specific receptors, whose activation inhibits the neurone. Thus, incubation of guinea pig ileum with an opiate induces in the final cholinergic motoneurone of the myenteric plexus a dependence that closely resembles in basic characteristics opiate dependence in whole animals. A comparable, but distinct dependence can be induced by incubating the ileum with clonidine. Since adenosine also inhibits the final cholinergic motoneurone, by activating a specific purine receptor, we have tested whether it, too, can induce a distinct dependence in this neurone. To demonstrate dependence, we challenged the ileum by removing drug or by adding the selective purine receptor antagonist, 8-phenyltheophylline, which does not substantially inhibit phosphodiesterase, or caffeine. We found that incubation of the ileum with adenosine, or with the more potent derivative, 2-chloroadenosine, induced a novel form of drug dependence, made manifest by withdrawal of inducing drug, but not by antagonists of opiates or clonidine.
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PMID:Novel form of drug-dependence--on adenosine in guinea pig ileum. 668 83

Using CHO cells stably transfected with rat mu-opioid receptor cDNA, we show that the mu-agonists morphine and [D-Ala2,N-methyl-Phe4,Gly-ol5]enkephalin are negatively coupled to adenylylcyclase and inhibit forskolin-stimulated cAMP accumulation. Chronic exposure of cells to morphine leads to the rapid development of tolerance. Withdrawal of morphine or [D-Ala2,N-methyl-Phe4,Gly-ol5]enkephalin following chronic treatment (by wash or addition of the antagonist naloxone) leads to an immediate increase in cyclase activity (supersensitization or overshoot), which is gradually reversed upon further incubation with naloxone. Phosphodiesterase inhibitors do not affect the overshoot, indicating that it results from cyclase stimulation rather than phosphodiesterase regulation. Morphine's potency to inhibit cAMP accumulation is the same before and after chronic treatment, suggesting that the apparent tolerance results from cyclase activation, rather than from receptor desensitization. The similar kinetics of induction of tolerance and overshoot support this idea. Both the overshoot and acute opioid-induced cyclase inhibition are blocked by naloxone and are pertussis toxin-sensitive, indicating that both phenomena are mediated by the mu-receptor and Gi/G(o) proteins. The supersensitization is cycloheximide-insensitive, indicating that it does not require newly synthesized proteins. This is supported by the rapid development of supersensitization. Taken together, these results show that mu-transfected cells can serve as a model for investigating molecular and cellular mechanisms underlying opiate drug addiction.
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PMID:Adenylylcyclase supersensitization in mu-opioid receptor-transfected Chinese hamster ovary cells following chronic opioid treatment. 853 Mar 63

Development of drug addictive behaviors is modulated by both genetic and environmental risk factors. However, the molecular mechanisms remain unknown. To address the role of adolescent stress in the development of drug addiction, we combined a transgenic mouse model in which a putative dominant-negative form of DISC1 under expressional control of the prion protein promoter is used as a genetic risk factor and adolescent social isolation stress as a gene-environmental interaction (GXE). Repeated cocaine exposure induced greater locomotion in the GXE group than in the other groups. In a conditioned place preference (CPP) test, GXE mice exhibited a significant place preference to the cocaine-conditioned area compared with the other groups. In the nucleus accumbens (NAc) of GXE mice, we found increased enzyme activity of phosphodiesterase-4 (PDE4), predominantly located in NAc D2-receptor-expressing neurons, and enhanced effects of the PDE4 inhibitor rolipram, but not the D1 agonist SKF81297, on the phosphorylation of DARPP-32 and GluA1 at PKA sites. Rolipram injection before cocaine exposure completely inhibited cocaine-induced hyperlocomotion and CPP in the GXE group. These results indicate that GXE enhances sensitivity to repeated cocaine exposure via an increase in PDE4 activity in NAc D2-recptor-expressing neurons, leading to the development of cocaine addictive behaviors.
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PMID:Adolescent psychosocial stress enhances sensitization to cocaine exposure in genetically vulnerable mice. 3083 Nov 36