Dopamine autoreceptor

It is possible to deplete the brain of both DA and NA by inhibiting tyrosine hydroxylase but while NA may be reduced independently by inhibiting dopamine jS-hydroxylase, the enzyme that converts DA to NA, there is no way of specifically losing DA other than by destruction of its neurons (see below). In contrast, it is easier to augment DA than NA by giving the precursor dopa because of its rapid conversion to DA and the limit imposed on its further synthesis to NA by the restriction of dopamine S-hydroxylase to the vesicles of NA terminals. The activity of the rate-limiting enzyme tyrosine hydroxylase is controlled by the cytoplasmic concentration of DA (normal end-product inhibition), presynaptic dopamine autoreceptors (in addition to their effect on release) and impulse flow, which appears to increase the affinity of tyrosine hydroxylase for its tetrahydropteridine co-factor (see below). 

Markstein, R., and Lahaye, D. In vitro effect of the racemic mixture and the (-)enantiomer of N-n-propyl-3(3-hydroxyphenyl)-piperidine (3-PPP) on postsynaptic dopamine receptors and on a presynaptic dopamine autoreceptor. J. Neural Transm 58 43-53, 1983. 

Mulder, A.H. Draper, R. Sminia, P. Schoffelmeer, A.N.M. and Stoof, J.C. Agonist and antagonist effects of 3-PPP enantiomers on functional dopamine autoreceptors and postsynaptic dopamine receptors in vitro. jji J. Pharmacol 107 291 -297, 1985. 

Olive M. F., Seidel W. F., Edgar D. M. (1998). Compensatory sleep responses to wakefulness induced by the dopamine autoreceptor antagonist (-(DS121. J. Pharmacol. Exp. 7her. 285(3), 1073-83. 

The postsynaptic receptors on any given neuron receive information from transmitters released from another neuron. Typically, postsynaptic receptors are located on dendrites or cell bodies of neurons, but may also occur on axons or nerve terminals in the latter case, an axoaxonic synaptic relationship may cause increases or decreases in transmitter release. In contrast, autoreceptors are found on certain neurons and respond to transmitter molecules released from the same neuron. Autoreceptors may be widely distributed on the surface of the neuron. At the nerve terminal, they respond to transmitter molecules released into the synaptic cleft on the cell body, they may respond to transmitter molecules released by dendrites. Functionally, most autoreceptors appear to decrease further transmitter release in a kind of negative feedback loop. Autoreceptors have been identified for all the catecholamines, as well as for several other neurotransmitters. a2-adrenergic receptors are often found on noradrenergic nerve terminals of postganglionic sympathetic nerves, as well as on noradrenergic neurons in the CNS [36], and activation of these receptors decreases further norepinephrine release. Dopamine autoreceptors,... 

The second illustration of the interest of /V-monosubsti luted carbamates is in prodrugs of (-)-3-(3-hydroxyphenyl)-N-propylpiperidine, also known as (-)-3-PPP [163], This presynaptic dopamine autoreceptor agonist readily crosses the blood-brain barrier but is orally poorly bioavailable. The bioavailability of the drug was not improved in the majority of a large and structurally very diverse series of prodrugs. However, a few /V-(subsli luted phe-nyl)carbamates stood out as remarkable exceptions. While the AT-phenylcar-bamate and AT-(4-chlorophenyl)carbamates were poorly bioavailable, the iV-(4-isopropylphenyl)carbamate (8.129), AT-(4-ethoxyphenyl)carbamate, and iV-(3,4-dimethoxyphenyl)carbamate each exhibited good bioavailability. Pro-... 

S. O. Thorberg, S. Berg, J. Lundstrom, B. Pettersson, A. Wijkstrom, D. Sanchez, P. Lind-berg, J. L. G. Nilsson, Carbamate Ester Derivatives as Potential Prodrugs of the Pre-synaptic Dopamine Autoreceptor Agonist (-)-3-(3-Hydroxyphenyl)-A-propylpiperidine J. Med. Chem. 1987, 30, 2008-2012. 

Svensson, K. (1986) Thesis Dopamine autoreceptor antagonists A new class of central stimulants. University ofGoteborg, Gdteborg, Sweden, ISBN 91-7900-078-9. Nedelec, L., Guillaume, J. and Dumont, C. (1976) Fr. Patent 76-3933 (1977) Chem. Abstr. 87, 152038. 

In addition to these two subtypes, there is also evidence that the release of dopamine is partially regulated by feedback inhibition operating via the dopamine autoreceptor. 

In addition to the posts)maptic receptors, dopamine autoreceptors also exist on the nerve terminals, dendrites and cell bodies. Experimental studies have shown that stimulation of the autoreceptors in the somatodendritic region of the neuron slows the firing rate of the dopaminergic neuron while stimulation of the autoreceptors on the nerve terminal inhibits both the release and the synthesis of the neurotransmitter. Structurally, the autoreceptor appears to be of the D2 type. While several experimental compounds have been developed that show a high affinity for the autoreceptors, to date there is no convincing evidence for their therapeutic efficacy. 

However, experimental studies of the 5-HT3 antagonists on dopamine autoreceptors may eventually offer new leads to the development of novel antipsychotic drugs. 

Fedele E, Andrioli GC, Ruelle A, et al Release-regulating dopamine autoreceptors in human cerebral cortex. Br J Pharmacol 110 20-22, 1993 Feder R Lithium augmentation of clomipramine. J Clin Psychiatry 49 458, 1988 Feighner JP Busporine in the long-term treatment of generahsed anxiety disorder. J Chn Psychiatry 48 (suppl) 3-6, 1987... 

Kellner CH, Beale MD, Pritchett JT, et al Electroconvulsive therapy and Parkinson s disease the case for further study. Psychopharmacol Bull 30 495-500, 1994 Kellner M, Wiedemann K, Kiieg J-C, et al Effects of the dopamine autoreceptor agonist roxindole in patients with depression and panic disorder (abstract). Neuropsychopharmacology 10 1018, 1994... 

Muscat R, Towell A, Willner P Changes in dopamine autoreceptor sensitivity in an animal model of depression. Psychopharmacology 94 545-550, 1988 Muscat R, Papp M, Willner P Antidepressant-hke effects of dopamine agonists in an animal model of depression. Biol Psychiatry 31 937-946, 1992... 

Presynaptic Dopamine Autoreceptors Modulation of Dopamine Release.292... 

Dopamine autoreceptors play a role in Parkinson s disease, schizophrenia and drug addiction. Dopamine heteroreceptors affecting the release of acetylcholine and of amino acid neurotransmitters in the basal ganglia are also relevant for Parkinson s disease. Peripheral dopamine heteroreceptors on postganglionic sympathetic terminals influence heart rate and vascular resistance through modulation of noradrenaline release. 

Our knowledge of presynaptic dopamine and serotonin receptors dates back to the 1970s (Famebo and Hamberger 1971). Presynaptic histamine receptors were discovered in 1983 (Arrang et al. 1983). Presynaptic dopamine receptors occur as autoreceptors, i.e., on dopaminergic axon terminals, and as heteroreceptors on nondopaminergic axon terminals. By analogy the same holds true for presynaptic histamine and serotonin receptors. The early days of the dopamine autoreceptors were stormy, but the controversies were finally solved (see Starke et al. 1989). The main function that presynaptic receptors affect is transmitter release, which in this article means Ca2+-dependent exocytosis. However, some receptors discussed in... 

The main effect mediated by presynaptic dopamine autoreceptors is modulation of exocytotic release of dopamine (Table 1) however, the receptors in addition subserve other functions (Table 2). 

Table 2 Functions of presynaptic dopamine autoreceptors other than modulation of release ( increase, J, decrease in function). Receptor classification as by the authors cited. Designation as Didike or D2-like where no differentiation between Di and D5, or between D2, D3 and D4, was made.

Presynaptic dopamine autoreceptors are rapidly desensitized by dopamine but not other agonists auch as apomorphine or roxindole (Arbilla et al. 1985 Seyfiried and Bartoszyk 1994 see also Kim et al. 2005). The reason for the difference is unknown. 

A large receptor reserve - i.e., receptors in excess of those necessary to produce a maximum response - has been described for release-modulating dopamine autoreceptors in rat striatum (Yokoo et al. 1988). No reserve exists for the autoreceptors in human neocortex (Loffler et al. 2006). 

As mentioned above, presynaptic dopamine autoreceptors subserve functions in addition to modulation of dopamine release. They are summarized in Table 2. 

Dopamine neurons are involved in several neuropsychiatric disorders such as Parkinson s disease, schizophrenia, and psychotropic drug abuse. It seems likely that dopamine autoreceptor function is affected in these disorders as well as by their drug treatment. 

Like presynaptic dopamine autoreceptors, presynaptic histamine autoreceptors are activated by the released endogenous transmitter to inhibit further histamine release, as shown by the increase in histamine release caused by antagonists at H3 receptors a definite piece of physiology. Evidence has been presented recently that cardiac postganglionic sympathetic neurons of the guinea pig synthesize and release histamine as a co-transmitter (Li et al. 2003 2006). These noradrenaline-histamine neurons possess H3 autoreceptors which, when activated, depress the release of both noradrenaline and histamine - unlike the D2-like autoreceptors of dopamine-neurotensin neurons which modulate the release of the two cotransmitters in opposite direction (see Section 2.2). It would be of interest to see whether, conversely, activation of ot2-autoreceptors inhibits the release of histamine in the guinea pig heart. 

Blockade of dopamine autoreceptors increased the extent of H3 receptor-mediated inhibition of dopamine release in mouse striatal slices this another example of an autoreceptor/heteroreceptor interaction (Schlicker et al. 1993 compare Sections 2.4, 3.3, 4.3). 

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