Agonizing over dopaminergic replacement therapy—lessons from animal models of Parkinson's disease

Pacific Parkinson's Research Centre, University of British Columbia, 2221 Wesbrook Mall, Vancouver, BC, Canada V6T 2B5.
Experimental Neurology (Impact Factor: 4.7). 10/2003; 183(1):1-3. DOI: 10.1016/S0014-4886(03)00184-5
Source: PubMed
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    ABSTRACT: For thousands of years, opioid drugs such as morphine have remained unsurpassed for their analgesic, sedative, antidiarrheal, and euphorigenic effects. The principal acute actions on neurons are to open K + channels, leading to membrane hyperpolarization, and to close Ca 2+ channels, leading to decreased influx of calcium into nerve terminals. Both effects result in inhibition of synaptic transmission. Continued occupation of the opioid receptor induces adaptive changes to oppose these actions. A rapid, homologous desensitization (acute tolerance) is due to uncoupling of the opioid receptor from intracellular effectors. The second adaptive response is a more slowly developing increase in the excitability of the opioid-sensitive neurons. These become depolarized and their excitatory synaptic inputs are enhanced. The adaptive hyperexcitability has two major consequences. First, it opposes the inhibitory actions, not only of morphine but of numerous other inhibitory agents, producing the nonspecific tolerance that is characteristic of humans who repeatedly self-administer morphine. Secondly, when the opioid is withdrawn, the adaptive hyperexcitability precipitates a constellation of withdrawal signs, revealing a state of dependence. Dependent individuals are motivated to re-administer the opioid, in part to alleviate the physiological disturbances of withdrawal. The prime determinant of drug-seeking behavior, however, is psychological dependence, based on the rewarding, euphorigenic effects of morphine. Opioids produce euphoria by disinhibition of dopaminergic neurons in natural reward pathways that project from the ventral tegmental area to the nucleus accumbens. The identification of specific neuronal circuits underlying opioid reward is essential in defining the neural basis of compulsive drug-seeking behavior.
    Principles of Medical Biology 01/1997; 8:1003-1012. DOI:10.1016/S1569-2582(97)80113-4
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    ABSTRACT: The in vivo equilibrium specific binding of d-threo-[3H]methylphenidate, a radioligand for the dopamine transporter (DAT), and +-alpha-[3H]dihydrotetrabenazine, a radioligand for the vesicular monoamine transporter (VMAT2), were examined in rat brain with and without prior administration of 5 mg/kg scopolamine. Drug-treated animals exhibited a 30% increase in d-threo-[3H]methylphenidate binding to the DAT in the striatum relative to controls. No changes in specific binding of +-alpha-[3H]dihydrotetrabenazine were observed in any brain region following scopolamine pretreatment. Cholinergic drugs thus differentially affect in vivo specific binding of DAT and VMAT2 radioligands, suggesting this should be a consideration in selection of in vivo markers for imaging studies of dopaminergic terminals in the brain of animals and humans.
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    ABSTRACT: Over the past two decades, positron emission tomography (PET) has provided valuable insights into the mechanisms of nigrostriatal degeneration in Parkinson's disease (PD). Furthermore, it allows the in vivo assessment of disease progression and the evaluation of treatment interventions. In this review, we shall discuss some of the issues and concerns that arise with the use of PET as a surrogate marker of disease progression in Parkinson's disease.
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