Dopamine receptor autoreceptors

J.L.G. 3-PPP, a new centrally acting dopamine receptor agonist with selectivity for autoreceptors. I ife Sci 28 1225-1238,... 

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. 

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... 

Helmreich I, Reimann W, Hertting G, Starke K (1982) Are presynaptic dopamine autoreceptors and postsynaptic dopamine receptors in the rabbit caudate nucleus pharmacologically different Neuroscience 7 1559-66... 

Figure 4. Representation of the classification of the dopamine receptor based on its coupling with adenylate cyclase activity. DA+ receptors (left) are coupled to adenylate cyclase through the Ns GTP-binding protein (91) with secondary activation of adenylate cyclase. DA. receptors (middle) are coupled through the Ni GTP-binding protein, thus resulting in inhibition of cyclic AMP formation. DA0 receptors (right) are those uncoupled to cyclic AMP formation, the example being possibly some autoreceptors on nigrostriatal dopaminergic neurons.

Dopamine induces biochemical and physiological effects in the mammalian neostriatum. The occurrence of a D-l dopamine receptor (in the classification scheme of Kebabian and Caine) accounts for the ability of dopamine to enhance cyclic AMP formation. The occurrence of a D-2 dopamine receptor accounts for the ability of dopamine to inhibit cyclic AMP formation brought about by stimulation of a D-l dopamine receptor. Dopamine receptors mediate the regulation of (1) the release or turnover of acetylcholine (postsynaptic dopamine receptor) and (2) the release or turnover of dopar mine (presynaptic autoreceptor). Both receptors can be classified as D-2 dopamine receptors. Indications for the occurrence of dopamine receptors affecting the release or turnover of GABA, glutamate, serotonin and several neuropeptides are evaluated. 

The dopamine-containing nigro-neostriatal dopaminergic neurons possess receptors for dopamine. These dopamine receptors occur on both the nerve terminals within the neostriatum (pre-synaptic autoreceptors) as well as on the soma and dendrites (soma-dendritic autoreceptors). Stimulation of either category of autoreceptor can regulate the synthesis, turnover and release of dopamine in the neostriatum but by different mechanisms. 

Systemical or intranigral application of dopamine receptor agonists depresses the firing of nigrostriatal dopamine cells by stimulating soma-dendritic autoreceptors in the zona compacta, an effect again antagonized by neuroleptics (110, 111, 112). ... 

Many of these effects can still be observed after pretreatment with kainic acid in the neostriatum (113). This treatment degenerates the neostriatal efferent pathways and by consequence also the neostriatal efferent part(s) of the nigrostriatal loop. Apparently postsynaptic dopamine receptors, if located on these striatonigral neurons play only a minor role in the regulation of dopamine synthesis and turnover in dopaminergic neurons and the major role has to be attributed to dopaminergic autoreceptors. 

Fig. 3. Locomotor hyperactivity to drugs activating forebrain dopamine systems (schematic illustration of response). A. Moderate doses of amphetamine induce progressive dose-dependent increases in counts recorded in automated activity chambers. B. At higher dose, amphetamine induces stereotypy which competes with the expression of locomotion resulting in a suppression of activity counts at peak dose. C. Competing stereotypy yields an inverse U function in the dose response curve (total activity over 2 h test). D. The dopamine receptor agonist apomorphine also increases activity at moderate doses which is blocked by competing stereotypy at high dose, but this drug also inhibits activity at the lowest doses, believed to be due to selective action at presynaptic autoreceptors (see text).

Figures 5.1A-C show that compounds 11, 80, and 12 act as dopamine D2 receptor agonists, because they all induce a decrease in the release of dopamine in the striatum. R-(-)-ll-hydroxyaporphine (79) (Figure 5.ID) induces, in a dose of 1 pmol/kg, a small significant decrease in the release of dopamine in the striatum. This lack of biochemical activity of compound 79 was not expected from a structure-activity point of view. However, Schaus et al.261 already published that R-(-)-ll-hydroxyaporphine (79) acts as a partial agonist at the dopamine D2 receptor. This would explain our findings that this compound has a very weak effect on the dopamine D2 autoreceptor.

I DA release is under inhibitory autoreceptor feedback regulation by the presynaptic D2 and/or D3 dopamine receptor, activation of these receptors results in tte inhibition of DA release (Fig. 1.8). 

Pramipexole, a dopamine receptor agonist with activity at both autoreceptors and postsynaptic receptors, has shown efficacy in aifimal models of parkinsonism. 

Dopamine autoreceptor agonists. The discovery of 3-(3-hydroxyphenyl)-A -/i-propyl piperidine (( )-3-PPP), a centrally acting dopamine receptor agonist with selectivity for dopaminergic autoreceptors, offers a potential alternative to neuroleptics in the treatment of schizophrenia. The structure of ( )-3-PPP (Fig. 14.31) can be considered as resulting from a disjunctive approach applied to pergolide. Surprisingly, an increase in the... 

Typioal antipsyohotic drugs act in both extrapyramidal and limbio brain regions at D2-type dopamine receptors that can be located postsynaptically (on cell bodies, dendrites, and nerve terminals of other neurons) as well as presynaptioally on dopamine neurons. Dopamine reoeptors looated presynaptically on dopamine cell bodies and nerve terminals are called autoreceptors and aot to negatively modulate neuronal firing and dopamine synthesis and release (Fig. 22.3) (24). Low concentrations of oertain ... 

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