Dopamine storage

GHB temporarily inhibits the release of dopamine in the brain. This may cause increased dopamine storage, which is followed by increased dopamine release when the GHB influence wears off. This effect could account for the middle-of-the-night awakenings common with use of higher GHB doses, and the general feelings of increased well-being, alertness, and arousal the next day. 

It was thus concluded that D2R has a major role in regulating the size of the terminal arbor in dopamine neurons projecting from the SNpc to the CPu. This is consistent with the role of the D2 autoreceptor in regulating the delivery of dopamine. It suggests that this regulation is not only confined to dopamine storage, synthesis and turnover in the terminals but is also manifested in the density of dopamine terminals. 

Piperidine-like alkaloid from Indian tobacco (Lobelia inflata). Partial agonist at nACh receptors and alters dopamine storage and release. 

The dopamine is then concentrated in storage vesicles via an ATP-dependent process. Here the rate-limiting step appears not to be precursor uptake, under normal conditions, but tyrosine hydroxylase activity. This is regulated by protein phosphorylation and by de novo enzyme synthesis. The enzyme requites oxygen, ferrous iron, and tetrahydrobiopterin (BH. The enzymatic conversion of the precursor to the active agent and its subsequent storage in a vesicle are energy-dependent processes. 

The transporters for 5HT, noradrenaline and dopamine, biogenic monoamines, are genetically related, exist as single isoforms and are expressed on the surface of nerve cells, which use monoamines as (or convert them into) their cognate neurotransmitter. The single-isoform monoamine transporters fulfil all three fundamental functions (reuptake, limiting synaptic transmission, and control of the extracellular neurotransmitter concentration). Inactivation of DAT, NET, or SERT results in an increased extracellular lifetime and level of monoamine neurotransmitter, but decreased intracellular storage and evoked release (Fig. 3). 

There are numerous transmitter substances. They include the amino acids glutamate, GABA and glycine acetylcholine the monoamines dopamine, noradrenaline and serotonin the neuropeptides ATP and NO. Many neurones use not a single transmitter but two or even more, a phenomenon called cotransmission. Chemical synaptic transmission hence is diversified. The basic steps, however, are similar across all neurones, irrespective of their transmitter, with the exception of NO transmitter production and vesicular storage transmitter release postsynaptic receptor activation and transmitter inactivation. Figure 1 shows an overview. Nitrergic transmission, i.e. transmission by NO, differs from transmission by other transmitters and is not covered in this essay. 

The sites of action of drugs affecting the dopamine synapse are indicated in Fig. 7.3. Those modifying the synthesis, storage, release, uptake and metabolism of DA have been covered above in the appropriate sections on neurochemistry. The actions and uses of agonists and antagonists are outlined in Table 7.4 and covered in detail in appropriate chapters. Their structures are given in Fig. 7.6. 

The pathway for synthesis of the catecholamines dopamine, noradrenaline and adrenaline, illustrated in Fig. 8.5, was first proposed by Hermann Blaschko in 1939 but was not confirmed until 30 years later. The amino acid /-tyrosine is the primary substrate for this pathway and its hydroxylation, by tyrosine hydroxylase (TH), to /-dihydroxyphenylalanine (/-DOPA) is followed by decarboxylation to form dopamine. These two steps take place in the cytoplasm of catecholaminereleasing neurons. Dopamine is then transported into the storage vesicles where the vesicle-bound enzyme, dopamine-p-hydroxylase (DpH), converts it to noradrenaline (see also Fig. 8.4). It is possible that /-phenylalanine can act as an alternative substrate for the pathway, being converted first to m-tyrosine and then to /-DOPA. TH can bring about both these reactions but the extent to which this happens in vivo is uncertain. In all catecholamine-releasing neurons, transmitter synthesis in the terminals greatly exceeds that in the cell bodies or axons and so it can be inferred... 

Reserpine inhibits the synaptic vesicular storage of the monoamines dopamine, serotonin and noradrenaline. As a result they leak out into the cytoplasm where they are inactivated by monoamine oxidase this causes their long-lasting depletion. The resulting low levels of dopamine underlie the antipsychotic actions of reserpine (Chapter 11), whereas the reduced noradrenaline levels underlie its antihypertensive actions. Finally, the resulting low levels of serotonin and noradrenaline mean that reserpine also induces depression. These severe side effects mean that reserpine is no longer used clinically as a treatment for schizophrenia (Chapter 11). 

The answers are 318-d, 319-c, 320-a. (Hardman, pp 120-1220 Norepinephrine is synthesized from dopamine by dopamine-p-oxidase, which hydnoxylates the p-carbon This enzyme is localized in the amine storage granules. Norepinephrine is found in adrenergic fibers, the adrenal medulla, and in neurons in the locus ceruleus and lateral ventral tegmental fields of the CNS. 

Ordinarily, low concentrations of catecholamines are free in the cytosol, where they may be metabolized by enzymes including monoamine oxidase (MAO). Thus, conversion of tyrosine to l-DOPA and l-DOPA to dopamine occurs in the cytosol dopamine then is taken up into the storage vesicles. In norepinephrine-containing neurons, the final P-hydroxylation occurs within the vesicles. In the adrenal gland, norepinephrine is N-methylated by PNMT in the cytoplasm. Epinephrine is then transported back into chromaffin granules for storage. 

Several of the neurotransmitters are small-molecule amines such as dopamine, serotonin, epinephrine, and norepinephrine. These neurotransmitters are synthesized in the cytoplasm of the axon terminal and subsequently transported into and stored within the synaptic vesicles. The amino acids glycine and glutamic acid are normal constituents of proteins and are present in abundance in the axons. These are also stored in synaptic vesicles. Each electrical impulse that arrives at the presynaptic side of a synapse will cause only a small minority of the synaptic vesicles to fuse with the plasma membrane and discharge their contents. The remaining synaptic vesicles remain, waiting for subsequent electrical impulses. At the same time, neurotransmitter synthesis continues, as does their storage in synaptic vesicles. This tends to restore the full complement of amine neurotransmitters at the axon terminal. 

The noradrenaline normally contained in the storage granules can be partly or completely replaced by structurally related sympathomimetic amines, either by injection of the amine itself, or of suitable precursors such as a-methyl-DOPA or a-methyl-w-tyrosine. These amines can be depleted from the heart by guanethidine in the same way as the noradrenaline which they had replaced. a-Methylnoradrenaline [337] and metaraminol [338] are depleted less readily than noradrenaline from rabbit or rat hearts, whereas dopamine, octopamine and w-octopamine are depleted more readily than noradrenaline [339]. The more rapid depletion of these last three compounds was attributed to weaker binding in the storage granules [339], but could equally well be due to their greater susceptibility to destruction by monoamine oxidase, since both a-methyl-noradrenaline and metaraminol are resistant to attack by monoamine oxidase. 

In the CNS, inhibition of MAO affects neuronal storage not only of NE but also of dopamine and serotonin. 

Reserpine, an alkaloid from the Rauwolfia plant, abolishes the vesicular storage of biogenic amines (NE, dopamine = DA, serotonin = 5-HT) by inhibiting an ATPase required for the vesicular amine pump. The amount of NE re-Liillmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. 

Conventionally called adrenergic neuron blockers, the last group of adrenoblockers are drugs that suppress synthesis, storage, and release of biogenic amines (norepinephrine, dopamine, or serotonin) in nerve endings. 

Adrenergic neuron blockers cause degradation of biogenic amines in neuron endings. These drugs can interfere with the synthesis, storage and release of norepinephrine, dopamine, and serotonin. 

Since the main clinical use for antisympathotonics is in the treatment of essential hypertension, such drugs will be discussed in Chapter 20 in more detail. The alkaloid reserpine from Rauwolfia serpentina was the first drug used clinically to reduce sympathetic tone. Reserpine reduce the ability of storage and release of various transmitters (adrenaline, noradrenaline, serotonine and dopamine) by an irreversible destruction of the axonal vesicle membranes. The duration of the reserpine effect is actually determined by the de novo synthesis of these structure. Beside various central side effects like sedation, depression, lassitude and nightmares the pattern of unwanted effects of reserpine is determined by the shift of the autonomic balance towards the parasympathetic branch myosis, congested nostrils, an altered saliva production, increased gastric acid production, bardycardia and diarrhea. As a consequence of the inhibition of central dopamine release, reserpine infrequently shows Parkinson-like disturbances of the extrapyramidal system. 

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