Peripheral dopaminergic system

Peripheral Dopaminergic System Dopamine is usually thought of as a neurotransmitter in the brain or as an intermediate in the production of norepinephrine and epinephrine in the periphery. It has been presumed tliat these sources account for the large amounts of dopamine and dopamine metabolites excreted in urine. The contribution of the brain to circulating levels and urinary excretion of dopamine metabolites is, however, now known to be relatively minor. Also, in sympathetic nerves and the adrenal medulla most dopamine is converted to norepinephrine. Therefore other sources and functions of dopamine in the periphery must be considered. Emerging evidence suggests the presence of a third peripheral catecholamine system, in which dopamine functions not as a neurotransmitter or circulating hormone, but as an autocrine or paracrine substance. ... 

DAT is predominantly expressed by dopaminergic brain neurons, NET by noradrenergic neurons in the central and peripheral nervous system, and SERT is restricted to the axons of serotonergic neurons, which originate in the raphe nuclei and innervate numerous higher brain regions therefore SERT is widely distributed in the brain. Outside the brain, 5HT transport can be measured on non-neuronal cells (e.g. platelets, lympho-blastoid cells and smooth muscle cells) most of the 5HT appearing in the circulation is taken up by platelets. 

L-dopa is effective in the treatment of Parkinson s disease, a disorder characterised by low levels of dopamine, since L-dopa is metabolised into dopamine. However, this biosynthesis normally occurs in both the peripheral nervous system (PNS) and the central nervous system CNS. The related drug carbidopa inhibits aromatic L-amino acid decarboxylase only in the periphery, since it does not cross the blood-brain barrier. So, when carbidopa is given with L-dopa, it reduces the biosynthesis of L-dopa to dopamine in the periphery and, thus, increases the bioavailability of L-dopa for the dopaminergic neurons in the brain. Hence, carbidopa increases the clinical efficacy of L-dopa for Parkinsonian patients. 

Fung YK, Schmid MJ, Anderson TM, Lau YS (1996) Effects of nicotine withdrawal on central dopaminergic systems. Pharmacol Biochem Behav 53 635-640 Gilbert DG, Mehska CJ, Williams CL, Jensen RA (1992) Subjective correlates of cigarette smoking-induced elevations of peripheral beta-endorphin and cortisol. Psychopharmacology 106 275-81... 

The effects on sleep result from the psychostimulant and sympathomimetic actions of these drugs. They enhance noradrenergic, dopaminergic and serotonergic transmission in the central and peripheral nervous system mainly by increasing transmitter release and also inhibitory uptake. 

BDNF brain derived neurotrophic factor is a member of the nerve growth factor family of trophic factors. In the brain, BDNF has a trophic action on retinal, cholinergic, and dopaminergic neurons, and in the peripheral nervous system it acts on both motor and sensory neurons. (From Kendrew, The Encyclopedia of Molecular Biology, 1994). 

Hence, the demonstration of discrete dopaminergic receptors (Figure 14) opens up a whole new field of investigation to explore the role of dopamine in the central and peripheral nervous system with respect to mental, cardiovascular, and neurological disturbances. 

Levodopa can pass the blood-brain barrier (unlike dopamine), where it is converted into dopamine, and thus acts by topping up the CNS dopaminergic system. Levodopa is most usually given with carbidopa or benser-azide (dopa-decarboxylase inhibitors), which prevent the wasteful peripheral metabolism of levodopa. This allows lower doses of levodopa to be given, which results in fewer adverse effects. 

The dopamine precursor l-DOPA (levodopa) is commonly used in TH treatment of the symptoms of PD. l-DOPA can be absorbed in the intestinal tract and transported across the blood-brain barrier by the large neutral amino acid (LNAA) transport system, where it taken up by dopaminergic neurons and converted into dopamine by the activity of TH. In PD treatment, peripheral AADC can be blocked by carbidopa or benserazide to increase the amount of l-DOPA reaching the brain. Selective MAO B inhibitors like deprenyl (selegiline) have also been effectively used with l-DOPA therapy to reduce the metabolism of dopamine. Recently, potent and selective nitrocatechol-type COMT inhibitors such as entacapone and tolcapone have been shown to be clinically effective in improving the bioavailability of l-DOPA and potentiating its effectiveness in the treatment of PD. 

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