Stimulants and acetylcholine

Stimulants And Acetylcholine

The substances referred to as stimulants are a variety of compounds that excite the central nervous system or alter the body’s metabolic activity. Some stimulants enhance alertness and increase energy whereas others affect emotions and oppose psychological depression.  One way in which chemical stimulants function is to mimic or enhance the effects of hormones that prepare animals for “fight or flight” when they are faced with threatening situations. They bring about an increased heart rate, increased blood pressure, and an increased rate of respiration. One way in which such hormones (or their imitators) prepare the body for sudden action is to increase the breakdown of glycogen and glucose in order to meet the increased demand for energy. The best examples of these hormones are the catecholamines (epinephrine, also known as adrenalin, and norepinephrine, also known as noradrenalin). The hormones bind to receptors on target muscle cell membranes and prompt formation of cyclic adenosine monophosphate (cAMP), known as a “second messenger” because it transmits a signal to many intracellular molecules involved in metabolism (epinephrine and norepinephrine being first messengers). In order for a subsequent message to be received (and for intracellular alterations related to fight or flight to be maintained), hormones and second messengers must be rapidly removed from cell surfaces once they have delivered their messages. An enzyme classified as a phosphodiesterase degrades cAMP to a form that is inactive. Some of the most common stimulants, such as caffeine and related compounds in tea and chocolate, inhibit the phosphodiesterase enzyme so that cAMP levels remain high enough to maintain the alerted state.

A second way in which stimulants exert their effects is by inhibiting the neurochemistry that involves the transmission of signals from one nerve cell to another. When a nerve cell receives a signal, that signal is propagated to the far end of the long nerve cell. In order for that signal to be transmitted to the next nerve cell, molecules called neurotransmitters are released into the spaces (synapses) between the cells. The neurotransmitters bind to specific receptors on the receiving cell, thus passing on the signal. In order to prepare for a new signal, neurotransmitters must be removed from the intercellular space through reuptake or degradation.

Cells can also recover from the signal for the fight or flight reaction by taking hormones that they have released back up into themselves. Cocaine interferes with the reuptake of adrenalin by cells in the cortex of the brain, thus intensifying the effects of adrenalin and producing a sense of euphoria and (sometimes) hallucinations. Cocaine use leads to psychological dependency and can cause convulsions, respiratory failure, and death.

Amphetamines are drugs that mimic the effects of epinephrine, or adrenalin. Because effects such as mental illness and brain damage can result from overuse of amphetamines, they currently have limited medical use. Metamphetamines are similar to amphetamines in structure and action but have fewer undesirable side effects. Ritalin (methylphenidate), commonly used to treat attention deficit disorder, has essentially the same mode of action as amphetamines. Ritalin abuse by school and college students has become a common concern.

Because of their adverse effects, the Food and Drug Administration (FDA) has taken action to remove two over-the-counter products that have amphetamine-like action: ephedrine, an agent with actions similar to those of epinephrine and the main active ingredient in the herb ephedra, used for weight loss and in energy-enhancement cold medicines; and weight loss products that contain phenylpropanolamine, which can raise blood pressure and increase the risk of stroke.

Opiates such as morphine and codeine are thought to enhance the release by neurons of the neurotransmitter dopamine; the release of dopamine leads to a sense of euphoria. These drugs are addictive and are often abused. In general, all antipsychotic medications work by blocking dopamine receptors in the forebrain. Nicotine mimics the action of the neurotransmitter acetylcholine at receptors having to do with the transmission of signals between autonomic nerve cells and skeletal muscle. 

Acetylcholine is the neurotransmitter produced by neurons referred to as cholinergic neurons. In the peripheral nervous system acetylcholine plays a role in skeletal muscle movement, as well as in the regulation of smooth muscle and cardiac muscle. In the central nervous system acetylcholine is believed to be involved in learning, memory, and mood. Acetylcholine is synthesized from choline and acetyl coenzyme A through the action of the enzyme choline acetyltransferase and becomes packaged into membrane-bound vesicles. After the arrival of a nerve signal at the termination of an axon, the vesicles fuse with the cell membrane, causing the release of acetylcholine into the synaptic cleft. For the nerve signal to continue, acetylcholine must diffuse to another nearby neuron or muscle cell, where it will bind and activate a receptor protein.

There are two main types of cholinergic receptors, nicotinic and muscarinic. Nicotinic receptors are located at synapses between two neurons and at synapses between neurons and skeletal muscle cells. Upon activation a nicotinic receptor acts as a channel for the movement of ions into and out of the neuron, directly resulting in depolarization of the neuron. Muscarinic receptors, located at the synapses of nerves with smooth or cardiac muscle, trigger a chain of chemical events referred to as signal transduction.

For a cholinergic neuron to receive another impulse, acetylcholine must be released from the receptor to which it has bound. This will only happen if the concentration of acetylcholine in the synaptic cleft is very low. Low synaptic concentrations of acetylcholine can be maintained via a hydrolysis reaction catalyzed by the enzyme acetylcholinesterase. This enzyme hydrolyzes acetylcholine into acetic acid and choline. If acetylcholinesterase activity is inhibited, the synaptic concentration of acetylcholine will remain higher than normal. If this inhibition is irreversible, as happens in the case of exposure to many nerve gases and some pesticides, sweating, bronchial constriction, convulsions, paralysis, and possibly death can occur. Although irreversible inhibition is dangerous, beneficial effects may be derived from transient (reversible) inhibition. Drugs that inhibit acetylcholinesterase in a reversible manner have been shown to improve memory in some people with Alzheimer’s disease. 

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