Autoreceptors dopamine

Methylphenidate like cocaine largely acts by blocking reuptake of monoamines into the presynaptic terminal. Methylphenidate administration produces an increase in the steady-state (tonic) levels of monoamines within the synaptic cleft. Thus, DAT inhibitors, such as methylphenidate, increase extracellular levels of monoamines. In contrast, they decrease the concentrations of the monoamine metabolites that depend upon monoamine oxidase (MAO), that is, HVA, but not catecholamine-o-methyltransferase (COMT), because reuptake by the transporter is required for the formation of these metabolites. By stimulating presynaptic autoreceptors, methylphenidate induced increase in dopamine transmission can also reduce monoamine synthesis, inhibit monoamine neuron firing and reduce subsequent phasic dopamine release. 

At low doses, both psychostimulants could theoretically stimulate tonic, extracellular levels of monoamines, and the small increase in steady state levels would produce feedback inhibition of further release by stimulating presynaptic autoreceptors. While this mechanism is clearly an important one for the normal regulation of monoamine neurotransmission, there is no direct evidence to support the notion that the doses used clinically to treat ADHD are low enough to have primarily presynaptic effects. However, alterations in phasic dopamine release could produce net reductions in dopamine release under putatively altered tonic dopaminergic conditions that might occur in ADHD and that might explain the beneficial effects of methylphenidate in ADHD. 

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). 

As with many neurons (e.g. NA) there are presynaptic autoreceptors on the terminals of dopamine neurons whose activation attenuate DA release. Although most of these receptors appear to be of the D2 type, as found postsynaptically, D3 receptors are also found. It is possible that in addition to the short-term control of transmitter release they may also be linked directly to the control of the synthesising enzyme tyrosine hydroxylase. It seems that autoreceptors are more common on the terminals of nerves in the nigrostriatal (and possibly mesolimbic) than mesocortical pathway. 

The inhibition of firing of catecholamine neurons resulting from amphetamine administration is likely due to activation of somatodendritic autoreceptors. This causes a hyperpolarization of the somatodendritic membrane of both locus coeruleus noradrenergic and substantia nigra dopamine neurons, probably as a consequence of an increase in potassium conductance (Lacey et al. 1987 Williams et al. 1985). 

The activation of presynaptic autoreceptors, as revealed by changes in terminal excitability, suggests that amphetamine releases dopamine at every tested dose. This observation is consistent with recent direct demonstrations using... 

ANSWER I think it is very clear that there is a population of autoreceptors at the axonal end, but there is no population of autoreceptors in the axon that passes through the medial forebrain level. The antidromic stimulation is up there, and it looks as if amphetamine and related dopamine agonists cause a decrease in excitability of the terminal field in the same way that they cause a decrease in excitability in the cell body. 

COMMENT I would favor the view that lethargy and fatigue of postamphetamine withdrawal during the withdrawal phase would be consistent with the shutting off of the dopamine neuron. Still, it is hard to imagine how that would be. First, the amphetamine-induced release is not regulated by the autoreceptor. And, as you say, if it would be impulse related, however weak, it would be regulated. But we do know that after a period of amphetamine intoxication, an individual is supersensitive behaviorally. 

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. 

Cragg S., Greenfield S. (1997). Differential autoreceptor control of somatodendritic and axon terminal dopamine release in substantia nigra, ventral tegmental area and striatum. J. Neurosci 17, 5738-46. 

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,... 

Dopamine acts on G-protein-coupled receptors belonging to the D1 -family of receptors (so-called D1-like receptors , or DlLRs, comprised of Dl- and D5-receptors), and the D2-family of receptors ( D2-like receptors , or D2LRs comprised of D2-, D3- and D4-receptors). Dl LRs stimulate adenylate cyclase activity and, possibly, also phosphoinosit-ide hydrolysis, while D2LRs reduce adenylate cyclase activity. In the striatum, DlLRs are predominately associated with medium spiny neurons of the direct pathway, while D2LRs have been found as autoreceptors on dopaminergic terminals, as heteroreceptors on cholinergic interneurons, and on indirect pathway neurons. In the SNr, DlLRs are located on terminals of the direct pathway projection, while D2LRs appear to function as 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. 

Andersen SL, Gazzara RA. 1994. The development of D2 autoreceptor-mediated modulation of K(-I-)-evoked dopamine release in the neostriatum. Brain Res Dev Brain Res... 

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. 

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