Addiction mechanisms

Figure 14.7 General Michael addiction mechanism for polymer functionalization. Enolate of carbonyl compound (labeled as Michael donor) will add to an a,3-unsaturated carbonyl compound (indicated as Michael acceptor) to give 1,4-addiction product. Carbon atoms involved in this step are labeled with numbers 1—5.

Morphine and its salts are very valuable analgesic drugs but are highly addictive. In addition to suppression of pain, morphine causes constipation, decreases pupillary size and depresses respiration. Only the (-l-)-stereoisoraer is biologically active. They appear to produce their effects on the brain by activating neuronal mechanisms normally activated by... 

Nonnarcotic Antitussives. The most centrally active, noimarcotic antitussive is dextromethorphan [125-71-3] (39). It is similar to codeine in terms of potency and mechanism of action, ie, it is a direct depressant of the cough center. It is unique in that even though it is stmcturaHy related to codeine, it is not addictive. 

Cocaine and desipramine inhibit the reuptake of monoamine neurotransmitters whereas amphetamine, which is a phenylalkylamine - similar in structure to the catecholamines, see Fig. 4 - competes for uptake and more importantly, evokes efflux of the monoamine neurotransmitters. All of them exert antidepressant effects. Cocaine and amphetamine are addictive whereas tricyclic antidepressants and their modern successors are not. The corollaty of the addictive properties is interference with DAT activity. Blockade of DAT by cocaine or efflux elicited by amphetamine produces a psychostimulant effect despite the different mechanisms even the experienced individual can hardly discern their actions. Because of the risk associated with inhibiting DAT mediated dopamine clearance the antidepressant effects of psychostimulants has not been exploited. 

Caffeine binds to adenosine receptors in the brain, preventing adenosine from inducing sleep or opening blood vessels. Caffeine also increases levels of dopamine, the neurotransmitter associated with pleasure. This is the chemical mechanism for addiction. The response to adenosine competition causes increased adrenaline flow. 

Littleton J, Zieglgansberger W Pharmacological mechanisms of naltrexone and acamprosate in the prevention of relapse in alcohol dependence. Am J Addict 12 (suppl 1) S3-S11,2003... 

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Somoza EC, Winhusen TM, Bridge TP, et al An open-label pilot study of methylpheni-date in the treatment of cocaine-dependent patients with adult attention deficit/ hyperactivity disorder. J Addict Dis 23 77—92, 2004 Sora 1, Wichems C, Takahashi N, et al Cocaine reward models conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice. Proc Natl Acad Sci U S A 95 7699-7704, 1998 Soral, Hall FS, Andrews AM, etal Molecular mechanisms of cocaine reward combined dopamine and serotonin transporter knockouts eliminate cocaine place preference. Proc Nad Acad Sci U S A 98 5300-5305, 2001 Spear J, Alderton D Psychosis associated with prescribed dexamphetamine use 0etter). 

McLellan AT, Kushner H, Metzger D, et al The fifth edition of the Addiction Severity Index. J Subst Abuse Treat 9 199—213, 1992 Mechanic JA, Maynard BT, Holloway FA Treatment with the atypical antipsychotic, olanzapine, prevents the expression of amphetamine-induced place conditioning in the rat. Prog Nemopsychopharmacol Biol Psychiatry 27 43—54, 2003... 

Covey LS, Classman AH A meta-analysis of double-blind placebo controlled trials of clonidine for smoking cessation. Br J Addict 86 991—998, 1991 Covey LS, Classman AH, Stetner F Naltrexone effects on short-term and long-term smoking cessation.] Addict Dis 18 31 0, 1999 Covey LS, Sullivan MA, Johnston A, et al Advances in non-nicotine pharmacotherapy for smoking cessation. Drugs 39 17-31, 2000 Dani JA, De Biasi M Cellular mechanisms of nicotine addiction. Pharmacol Biochem Behav 70 439 46, 2001... 

It is well established that NF-kB signaling plays a critical role in inflammation and immunity. Understanding the mechanism of NF-kB involvement in opioid receptor activation and chemokine expression may provide a vital key to understanding this complex signaling network. However, the elucidation of molecular mechanisms following activation of the opioid receptor family could aid in the development of future therapeutics for immune system-related and inflammatory diseases, drug addiction and HIV infection. 

Recently much interest has centred on a very specific toxin for DA neurons. This is 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP). It was discovered when a student, who was addicted to pethidine, tried to manufacture l-methyl-4-phenyl-4-propionoxy-piperidine (MPPP) but took a short-cut in synthesis and produced MPTP. When he administered this to himself he developed Parkinsonism. MPTP destroys DA neurons. Again this process depends on the neuronal uptake mechanism, since MPTP itself is not the active material. It needs to be deaminated to MPP+ which is then taken up by DA nerve terminals. 

Traditional psychodynamic therapy in the treatment of addiction often fails however, the principles of psychodynamic therapy are still valuable and important for a clinician in order to understand the patient and help him or her work through his or her mechanisms of defense, attachment difficulties, processing grief, and coping with internal and external drives.32 Among the validated and thoroughly studied approaches are the following ... 

Consistent with these observations, there is some evidence that caffeine may act, in part, on dopaminergic fibers that project into the medial forebrain bundle. Other psychostimulants also appear to act on this system, which may be at least one of the neural mechanisms involved in the development of dependence.271 Further work has suggested a parallel between caffeine and another highly addictive drug, alcohol. Many of the same factors that enter into the development of alcoholism may also influence the development of dependence on caffeine.272... 

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Simantov, R., Chronic morphine alters dopamine transporter density in the rat brain possible role in the mechanism of drug addiction, Neurosci. Lett., 163, 121, 1993. 

Pidoplichko, V.I., Noguchi, J., Areola, O.O. et al. Nicotinic cholinergic synaptic mechanisms in the ventral tegmental area contribute to nicotine addiction. Learn. Mem. 11 60, 2004. 

Kelley, A.E. Memory and addiction shared neural circuitry and molecular mechanisms. Neuron. 44 161, 2004. 

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