Presynaptic dopamine

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). 

The neuroehemical sites for psyehomotor stimulant reward are likely to be the presynaptic dopamine terminals located in the region of the nucleus aeeumbens, frontal cortex, and other forebrain structures that originate in the ventral tegmental area. Note, however, that intraeranial self-administration of eoeaine is elicited from the frontal cortex, but not from the nucleus aeeumbens (Goeders and Smith 1983). Thus, eoneomitant activation of structures other than the nucleus accumbens may be an important part of the circuitry involved in initiation of cocaine intravenous self-administration, as has been hypothesized for the opiates (Smith and Lane 1983 Smith et al. 1982). 

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. 

Chen, J., Paredes, W., Li, J., Smith, D., Lowinson, J., and Gardner, E.L., In vivo brain microdialysis studies of A9-tetrahydrocannabinol on presynaptic dopamine efflux in nucleus accumbens of the Lewis rat, Psychopharmacology, 102, 156, 1990. 

Chen J, Paredes W, Li J, Lowinson J and Gardner EL (1990b). A9-tetrahydrocannabinol enhances presynaptic dopamine efflux in medial prefrontal cortex. European Journal of Pharmacology, 190, 259-262. 

It is now possible to image not only postsynaptic, but pre-synaptic and intrasynaptic neurotransmission (Fig. 58-5). Presynaptic sites, such as the dopamine transporter and the serotonin transporter the presynaptic dopamine vesicular transporter (VMAT-2) and the acetylcholine transporter extrasynaptic sites such as the enzymes which break down neurotransmitters, e.g. MAO A and MAO B with radioligands that bind to post or pre-synaptic sites, i.e. dopamine competing with radioligands such as UC raclopride (see Fig. 58-9) (PET (Fig. 58-10) can be measured under basal conditions or following drugs which either decrease (e.g. AMPT) or increase (e.g. intravenous amphetamine) intrasynaptic dopamine. 

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-... 

In addition to the effects on seretonin, buspirone demonstrates moderate affinity for presynaptic dopamine D2 receptors (Hiner et ah, 1988 Hardman et al., 1996 Chouinard et ah, 1999). The effect on the D2 receptors allows buspirone to reverse neuroleptic-induced catalepsy (Cole and Yonkers, 1995 Baldessarini, 1996). The clinical significance of the action of buspirone on the Dj autoreceptors is unknown (Jann, 1988). 

Kiuchi K, Hirata Y, Minami M, et al Effect of 7- 3-[4-(2,3-dimethylphe-nyl)piperazinyl]propoxy -2(lH)-quinolinone (OPC-4392), a newly synthesized agonist for presynaptic dopamine D2 receptor, on tyrosine hydroxylation in rat striatal slices. Life Sci 42 343-349, 1988 Lehman AF, Lieberman JA, Dixon LB, et al Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry 161 (suppl 2) 1-56, 2004... 

On the dopamine side of the equation, one of the most promising agents in late clinical development is aripiprazole, theoretically a presynaptic D2 autoreceptor agonist. This compound is postulated to exert its antipsychotic actions in a manner far different from serotonin-dopamine antagonism that is, it may shut off the presynaptic dopamine terminal and stop dopamine release in the mesolimbic dopamine pathway by stimulating presynaptic D2 receptors. The agents Cl-1007 and DAB-... 

The most commonly used agents to enhance attention in attention deficit disorder are the stimulants methylphenidate and ( -amphetamine. Other effective stimulants are not as widely used, pemoline because of liver toxicity and methamphetamine because of its greater abuse potential. Methylphenidate and ( -amphetamine act predominantly by releasing dopamine from presynaptic dopamine terminals (Figs. 12— 2 and 12—3). These agents not only block the dopamine transporter but may actually... 

FIGURE 12-3. When (/-amphetamine binds to the presynaptic dopamine transporter on the dopamine neuron, it not only blocks dopamine reuptake but actually causes dopamine release. There may be a preference or selectivity for cortical over striatal dopamine presynaptic terminals by (/-amphetamine, so lower doses may have preferential effects on attention rather than on motor activity. Methylphenidate has a similar action, which is not quite as rapid but longer-lasting in many patients. 

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

Presynaptic dopamine, histamine and serotonin receptors are involved in various (patho)physiological conditions. Examples are the following ... 

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... 

Presynaptic dopamine receptors modulate the release of a variety of neurotransmitters. When looking at Table 1 one may be impressed by the number of studies and the number of neuron systems studied. It is clear that, overall, Di-like presynaptic receptors are facilitatory, whereas D2-like presynaptic receptors are inhibitory in the case of the few exceptions, the reason often remains unclear. 

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 1 Tissues in which neurotransmitter release is increased (f) or decreased (J.) by presynaptic dopamine receptor activation. Receptor classification (except with superscript11) as by the authors cited. Designation as D -like or D2-like where no differentiation between D 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. 

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

Although noradrenergic terminals normally contain too little dopamine for presynaptic dopamine heteroreceptors to become activated, and despite the fact that the hippocampus is only sparsely innervated by dopaminergic fibers (Bischoff et al. 1979), the release of [3H]-noradrenaline in rabbit (Jackisch et al. 1985) and rat (Monnet 2002) hippocampus was inhibited by endogenous dopamine as shown by the facilitatory effect of D2 antagonists. Voltage-sensitive calcium channels seem to play a role in the dopaminergic inhibition of noradrenaline release (Monnet 2002). 

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