Neurotransmitter depletion

The Rauwolfia alkaloids, including reserpine, are now little used. They act by depleting neurotransmitter stores of catecholamines and reducing sympathetic nervous activity, but their effects are non-specific, and nervous system adverse effects (depression, drowsiness, tiredness, confusion) are prominent. There is also a troublesome incidence of diarrhea, hjrperprolactinemia, gynecomastia, and a possible withdrawal syndrome. 

Finally, there is the process of neurotransmitter "waste management." Certain enzymes operate to biologically degrade neurotransmitters—a necessary process. Yet in some circumstances this process gets out of hand Excessive enzymatic activity may abnormally deplete neurotransmitters. This is the case in some forms of clinical depression, in which the enzyme monoamine oxidase (MAO) can cause a significant inactivation of necessary neurotransmitters. 

One limitation of this method is that the specific activity of the radiolabel is progressively diluted as the radiolabelled transmitter is released from neurons and replaced by that derived from unlabelled substrate. This method also assumes that there is no compartmentalisation of the terminal stores, yet there is ample evidence that newly synthesised acetylcholine and monoamines are preferentially released. An alternative approach is to monitor the rate at which the store of neurotransmitter is depleted after inhibition of its synthesis (Fig. 4.1). However, the rate of release of some neurotransmitters (e.g. 5-HT) is partly governed by their rate of synthesis and blocking synthesis blunts release. 

Figure 4.1 Turnover of classical neurotransmitters. At normal rates of neuronal activity, endogenous stores of neurotransmitter are maintained at constant (steady-state) levels, indicating that the supply of new neurotransmitter (through synthesis) meets the demand (determined by release and metabolism). Consequently, the rate of the depletion (A) of the endogenous store of transmitter after inhibition of its synthesis indicates turnover rate and is described by the equation ...

Effects in Laboratory Animals. As highlighted in other chapters, the central toxicities during and after repeated stimulant bingeing may be related to neuronal or terminal destruction and/or depletion of neurotransmitter in the brain. In monkeys and cats, the report by Duarte-Escalante and Ellinwood (1970) of neuronal chromatolysis associated with decreased catecholamine histofluorescence following chronic METH intoxication has been followed by extensive neurochemical demonstrations of damage to the monoamine pathways by chronic stimulants (Seiden and Ricaurte 1987). 

Neurotransmitter depletion has been attempted in at least 90 studies and has been the subject of a number of systematic reviews, the most recent and comprehensive of which is a metaanalysis conducted by a research team at the University of Amsterdam.24 The hypotheses of these studies were based on the premise that lowered monoamine levels cause depression, in which case depletion of these neurotransmitters ought to trigger depression in people who are not depressed. Here is what actually happens. Experimentally lowering the level of available serotonin, or of norepinephrine and dopamine, in healthy volunteers who have never been depressed does not affect their mood in the slightest. 

The biochemical theory of depression is in a state of crisis. The data just do not fit the theory. The neurotransmitter depletion studies that I described earlier in this chapter show that lowering serotonin or norepinephrine levels does not make most people depressed. When administered as antidepressants, drugs that increase, decrease or have no effect on serotonin all relieve depression to about the same degree. And the effect of anti-depressants, which was the basis for proposing the chemical-imbalance theory in the first place, turns out to be largely a placebo effect. 

Although few Ecstasy users die from taking MDMA, the majority experience psychobiological problems in the days afterward these occur during the period of serotonergic depletion that follows the drug-induced boost in neurotransmitter... 

FIGURE18-4 Neuropeptides and conventional neurotransmitters are released from different parts of the nerve terminal. A neuromuscular junction containing both large dense-core vesicles (containing the neuropeptide SCP) and also small synaptic vesicles (containing acetylcholine) was stimulated for 30 min at 12 Hz (3.5 s every 7 s). Depletion of the small clear vesicles at the muscle face and of the peptide granules at the nonmuscle face of the nerve terminal was observed. After stimulation, there was an increase in the number of large dense-core vesicles within one vesicle diameter of the membrane. (Adapted from reference [37].)... 

In other examples, the amount of peptide available for release can be depleted by repeated firing of a terminal since new peptide must arrive by axonal transport, while new conventional neurotransmitters are synthesized or recaptured locally and transported into small synaptic vesicles. 

It blocks reuptake of catecholamine neurotransmitters and causes a depletion of brain dopamine. 

Desipramine has been used to facilitate withdrawal from chronic PCP use. The rationale is that PCP depletes norepinephrine concentrations in brain, and that this tricyclic antidepressant is the most selective blocker of norepinephrine uptake. Consequently, some of the deficiency of the neurotransmitter could be remedied. A dose of 25 to 50 mg was said to reduce craving for several hours. Six of eight patients treated with this drug were successfully withdrawn, while none of the eight offered other types of programs were successful (45). 

The Rauwolfia alkaloid reserpine, due to its strong central component of activity, is excluded from this review, even though it has the peripheral effect of releasing norepinephrine from storage sites where it can be metabolized by monoamine oxidase. This results in neurotransmitter depletion and it appears that good blood pressure control would be achieved by a drug which has this peripheral mechanism but lacks the central component. The Mead-Johnson compound MJ-10459-2 (LXI) shows activity in... 

Reserpine blocks vesicular storage of monoamines, prolonging their presence in cytoplasm. There they are degraded by MAO, leading to a depletion of monoamines in synaptic terminals of central and peripheral neurons, so that little or no neurotransmitter is released when the neuron depolarizes (Oates 1996). Reversal of this process requires synthesis of new vesicles, which occurs over a period of days to weeks after discontinuation of the drug. 

The excitatory neurotransmitter in brain, glutamate, is synthesised from glutamine in a reaction catalysed by the enzyme glntaminase. This enzyme is inhibited by a high concentration of ammonia, which could lead to a chronic depletion of this excitatory neurotransmitter. 

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