Question:

Dopamine activates adenylyl cyclase via D1 receptors and inhibits activity by D2. 6-OHDA, a neurotoxin, results in cell atrophy and increased dopamine signaling in surviving neurons, at least in the nigrostriatal pathway. Cause or effect in CR?  Biochem Pharmacol. 1992 Jul 7;44(1):73-82.  Related Articles, Links   Dissociation of the striatal D-2 dopamine receptor from adenylyl cyclase following 6-hydroxydopamine-induced denervation. Thomas KL, Rose S, Jenner P, Marsden CD. Parkinson’s Disease Society Experimental Research Laboratories, King’s College London, U.K. Intracellular cyclic AMP accumulation following exposure to dopamine (DA) agonists and and antagonists was measured in striatal slices from rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway and which showed contralateral circling to apomorphine. Both DA (10-320 microM) and the D-1 agonist SKF 38393 (0.1-32 microM) increased cyclic AMP accumulation in striatal slices from the lesioned and intact hemispheres. The EC50 for DA to increase cyclic AMP accumulation in slices was greater in the 6-OHDA-lesioned striata compared to the intact striatum, but the EC50 for SKF 38393 was not affected. The D-1 antagonist SCH 23390 (10 microM) completely inhibited the ability of DA and SKF 38393 to increase cyclic AMP accumulation in striatal slices from both denervated and intact sides of the brain. In slices from the intact hemisphere the increase in DA-induced cyclic AMP accumulation was enhanced by the D-2 antagonist (+/-)-sulpiride (50 microM) but (+/-)-sulpiride had no effect on the DA response in slices from the lesioned side. Similarly, the ability of SKF 38393 to enhance cyclic AMP accumulation was blocked by the D-2 agonist quinpirole (10 microM) in striatal slices from the intact hemisphere but not in tissue from the lesioned side. The density of striatal D-1 and D-2 receptors assessed by [3H]SCH 23390 and [3H]spiperone binding did not differ between the hemispheres although there was an increase in the affinity of D-1 receptors for [3H]SCH 23390 in the lesioned striatum. After striatal deafferentiation there appears to be an uncoupling of the "inhibitory" D-2 receptor from the D-1 receptor-associated adenylyl cyclase. PMID: 1321630 [PubMed - indexed for MEDLINE] Tim

Response:

The age-related loss of the D2 dopamine receptor is considered a very robust biomarker of aging. Ann Neurol. 1998 Jul;44(1):143-7.  Related Articles, Links   Parallel loss of presynaptic and postsynaptic dopamine markers in normal aging. Volkow ND, Wang GJ, Fowler JS, Ding YS, Gur RC, Gatley J, Logan J, Moberg PJ, Hitzemann R, Smith G, Pappas N. Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA. Aging of the human brain is associated with a decline in dopamine (DA) function, generally interpreted as reflecting DA cell loss. Positron emission tomography studies revealed that in healthy individuals, the age-related losses in DA transporters (presynaptic marker) were associated with losses in D2 receptors (postsynaptic marker) rather than with increases as is known to occur with DA cell loss. This association was specific for DA synaptic markers, because they were not correlated with striatal metabolism. Furthermore, the association was independent of age, suggesting that a common mechanism regulates the expression of receptors and transporters irrespective of age. Publication Types: Clinical Trial PMID: 9667606 [PubMed - indexed for MEDLINE] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&… http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&… http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&… Tim

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