How drugs affect neurotransmitters
Dopamine appeared very early in the course of evolution and is involved in many functions that are essential for survival of the organism, such as motricity, attentiveness, motivation, learning, and memorization. But most of all, dopamine is a key element in identifying natural rewards for the organism. These natural stimuli such as food and water cause individuals to engage in approach behaviours. Dopamine is also involved in unconscious memorization of signs associated with these rewards. It has now been established that all substances that trigger dependencies in human beings increase the release of a neuromediator, dopamine, in a specific area of the brain: the nucleus accumbens. Lien: Neurobiology of addiction and implications for treatment But not all drugs increase dopamine levels in the brain in the same way.Some substances imitate natural neuromediators and take their place on their receptors. Morphine, for example, binds to the receptors for endorphin (a natural "morphine" produced by the brain), while nicotine binds to the receptors for acetylcholine.Other substances increase the secretion of natural neuromediators. Cocaine, for example, mainly increases the amount of dopamine in the synapses, while ecstasy mainly increases the amount of serotonin.Still other substances block a natural neuromediator. Alcohol, for example, blocks the NMDA receptors.
Opiates (heroin, morphine, etc.)
The human body naturally produces its own opiate-like substances and uses them as neurotransmitters. These substances include endorphins, enkephalins, and dynorphin, often collectively known as endogenous opioids. Endogenous opioids modulate our reactions to painful stimuli. They also regulate vital functions such as hunger and thirst and are involved in mood control, immune response, and other processes.
The reason that opiates such as heroin and morphine affect us so powerfully is that these exogenous substances bind to the same receptors as our endogenous opioids. There are three kinds of receptors widely distributed throughout the brain: mu, delta, and kappa receptors.
These receptors, through second messengers, influence the likelihood that ion channels will open, which in certain cases reduces the excitability of neurons. This reduced excitability is the likely source of the euphoric effect of opiates and appears to be mediated by the mu and delta receptors.
This euphoric effect also appears to involve another mechanism in which the GABA-inhibitory interneurons of the ventral tegmental area come into play. By attaching to their mu receptors, exogenous opioids reduce the amount of GABA released (see animation). Normally, GABA reduces the amount of dopamine released in the nucleus accumbens. By inhibiting this inhibitor, the opiates ultimately increase the amount of dopamine produced and the amount of pleasure felt.
Chronic consumption of opiates inhibits the production of cAMP, but this inhibition is offset in the long run by other cAMP production mechanisms. When no opiates are available, this increased cAMP production capacity comes to the fore and results in neural hyperactivity and the sensation of craving the drug.
Alcohol
Alcohol passes directly from the digestive tract into the blood vessels. In minutes, the blood transports the alcohol to all parts of the body, including the brain.Alcohol affects the brain’s neurons in several ways. It alters their membranes as well as their ion channels, enzymes, and receptors. Alcohol also binds directly to the receptors for acetylcholine, serotonin, GABA, and the NMDA receptors for glutamate.
Click on the labels in the diagram to the right to see an animation about how alcohol affects a GABA synapse. GABA’s effect is to reduce neural activity by allowing chloride ions to enter the post-synaptic neuron. These ions have a negative electrical charge, which helps to make the neuron less excitable. This physiological effect is amplified when alcohol binds to the GABA receptor, probably because it enables the ion channel to stay open longer and thus let more Cl- ions into the cell.
The neuron’s activity would thus be further diminished, thus explaining the sedative effect of alcohol. This effect is accentuated because alcohol also reduces glutamate’s excitatory effect on NMDA receptors.
However, chronic consumption of alcohol gradually makes the NMDA receptors hypersensitive to glutamate while desensitizing the GABAergic receptors. It is this sort of adaptation that would cause the state of excitation characteristic of alcohol withdrawal.
Alcohol also helps to increase the release of dopamine, by a process that is still poorly understood but that appears to involve curtailing the activity of the enzyme that breaks dopamine down.
Cocaine
Cocaine acts by blocking the reuptake of certain neurotransmitters such as dopamine, norepinephrine, and serotonin. By binding to the transporters that normally remove the excess of these neurotransmitters from the synaptic gap, cocaine prevents them from being reabsorbed by the neurons that released them and thus increases their concentration in the synapses (see animation). As a result, the natural effect of dopamine on the post-synaptic neurons is amplified. The group of neurons thus modified produces much more dependency (from dopamine), feelings of confidence (from serotonin), and energy (from norepinephrine) typically experienced by people who take cocaine.In addition, because the norepinephrine neurons in the locus coeruleus project their axons into all the main structures of the forebrain, the powerful overall effect of cocaine can be readily understood.
In chronic cocaine consumers, the brain comes to rely on this exogenous drug to maintain the high degree of pleasure associated with the artificially elevated levels of some neurotransmitters in its reward circuits. The postsynaptic membrane can even adapt so much to these high dopamine levels that it actually manufactures new receptors. The resulting increased sensitivity produces depression and cravings if cocaine consumption ceases and dopamine levels return to normal.
Dependency on cocaine is thus closely related to its effect on the neurons of the reward circuit
Nicotine in Tobacco
Whether it is acetylcholine or nicotine that binds to this receptor, it responds in the same way: it changes its conformation, which causes its associated ion channel to open for a few milliseconds. This channel then allows sodium ions to enter the neuron, depolarizing the membrane and exciting the cell. Then the channel closes again, and the nicotinic receptor becomes temporarily unresponsive to any neurotransmitters. It is this state of desensitization that is artificially prolonged by continual exposure to nicotine.
Tobacco dependency, which then develops very quickly, arises because nicotinic receptors are present on the neurons of the ventral tegmental area which project their terminations into the nucleus accumbens. In smokers, repeated nicotine stimulation thus increases the amount of dopamine released in the nucleus accumbens. Between cigarettes, however, chronic smokers maintain a high enough concentration of nicotine to deactivate the receptors and slow down their recovery. This is why smokers develop a tolerance to nicotine and experience reduced pleasure from it.
After a brief period without smoking (a night’s sleep, for example), the baseline concentration of nicotine drops again, and some of the receptors regain their sensitivity. When all these receptors become functional again, cholinergic neurotransmission is raised to an abnormally high level that affects all the cholinergic pathways in the brain. Smokers then experience the agitation and discomfort that leads them to smoke another cigarette.
Another substance in tobacco smoke, not yet clearly identified, inhibits monoamine oxydase B (MAO B), an enzyme that breaks down dopamine after its reuptake. The result is a higher concentration of dopamine in the reward circuit, which also contributes to the smoker’s dependency.
Caffeine
The stimulant effect of coffee comes largely from the way it acts on the adenosine receptors in the neural membrane. Adenosine is a central nervous system neuromodulator that has specific receptors. When adenosine binds to its receptors, neural activity slows down, and you feel sleepy. Adenosine thus facilitates sleep and dilates the blood vessels, probably to ensure good oxygenation during sleep.Caffeine acts as an adenosine-receptor antagonist. This means that it binds to these same receptors, but without reducing neural activity. Fewer receptors are thus available to the natural “braking” action of adenosine, and neural activity therefore speeds up (see animation).
The activation of numerous neural circuits by caffeine also causes the pituitary gland to secrete hormones that in turn cause the adrenal glands to produce more adrenalin. Adrenalin is the “fight or flight” hormone, so it increases your attention level and gives your entire system an extra burst of energy. This is exactly the effect that many coffee drinkers are looking for.
In general, you get some stimulating effect from every cup of coffee you drink, and any tolerance you build up is minimal. On the other hand, caffeine can create a physical dependency. The symptoms of withdrawal from caffeine begin within one or two days after you stop consuming it. They consist mainly of headaches, nausea and sleepiness and affect about one out of every two individuals.
Lastly, like most drugs, caffeine increases the production of dopamine in the brain’s pleasure circuits, thus helping to maintain the dependency on this drug, which is consumed daily by 90% of all adults in the U.S.
Amphetamines
Amphetamines are drugs used to combat fatigue. Like cocaine, amphetamines increase the concentration of dopamine in the synaptic gap, but by a different mechanism. Amphetamines are similar in structure to dopamine, and so can enter the terminal button of the presynaptic neuron via its dopamine transporters as well as by diffusing through the neural membrane directly. As the animation to the right shows, once inside the presynaptic neuron, amphetamines force the dopamine molecules out of their storage vesicles and expel them into the synaptic gap by making the dopamine transporters work in reverse.Amphetamines also seem to act by several other mechanisms. For example, they seem to reduce the reuptake of dopamine and, in high concentrations, to inhibit monoamine oxydase A (MAO-A).
Amphetamines may also excite dopaminergic neurons via glutamate neurons. Amphetamines would thus remove an inhibiting effect due to metabotropic glutamate receptors. By thus releasing this natural brake, amphetamines would make the dopaminergic neurons more readily excitable.
Cannabis
The sensations of slight euphoria, relaxation, and amplified auditory and visual perceptions produced by marijuana are due almost entirely to its effect on the cannabinoid receptors in the brain. These receptors are present almost everywhere in the brain, and an endogenous molecule that binds to them naturally has been identified: anandamide. We are thus dealing with the same kind of mechanism as in the case of opiates that bind directly to the receptors for endorphins, the body’s natural morphines.Anandamide is involved in regulating mood, memory, appetite, pain, cognition, and emotions. When cannabis is introduced into the body, its active ingredient, Delta-9-tetrahydrocannabinol (THC), can therefore interfere with all of these functions.
THC begins this process by binding to the CB1 receptors for anandamide. These receptors then modify the activity of several intracellular enzymes, including cAMP, whose activity they reduce. Less cAMP means less protein kinase A. The reduced activity of this enzyme affects the potassium and calcium channels so as to reduce the amount of neurotransmitters released. The general excitability of the brain’s neural networks is thus reduced as well.
However, in the reward circuit, just as in the case of other drugs, more dopamine is released. As with opiates, this paradoxical increase is explained by the fact that the dopaminergic neurons in this circuit do not have CB1 receptors, but are normally inhibited by GABAergic neurons that do have them. The cannabis removes this inhibition by the GABA neurons and hence activates the dopamine neurons.
In chronic consumers of cannabis, the loss of CB1 receptors in the brain’s arteries reduces the flow of blood, and hence of glucose and oxygen, to the brain. The main results are attention deficits, memory loss, and impaired learning ability.
Ecstasy
Ecstasy (MDMA) is a synthetic drug. It acts simultaneously as a stimulant and a hallucinogen because of its molecular structure, which is similar to that of both amphetamines and LSD. Like amphetamines and cocaine, ecstasy blocks the reuptake pumps for certain neurotransmitters, thus increasing their levels in the synaptic gap and their effect on the post-synaptic neurons’ receptors.While ecstasy also potentiates the effects of norepinephrine and dopamine, it is distinguished from other psychostimulants by its strong affinity for serotonin transporters. The initial effect of ecstasy is thus an increased release of serotonin by the serotonergic neurons. The individual may then experience increased energy, euphoria, and the suppression of certain inhibitions in relating to other people.
A few hours later, there is a decrease in serotonin levels, amplified by the reduced activity of tryptophane hydroxylase, the enzyme responsible for synthesizing serotonin. This decrease can last much longer than the initial increase. Once again, an artificial increase in the level of a neurotransmitter exercises negative feedback on the enzyme that manufactures it. As a result, when intake of the drug ceases, the excess turns into a shortage.
Like all psychoactive drugs that produce a sensation of pleasure, ecstasy also increases the release of dopamine into the reward circuit. In addition, the extra serotonin produced by ecstasy leads indirectly to excitement of the dopaminergic neurons by the serotonergic neurons that connect to them.
The toxicity of ecstasy for humans has not been clearly established, but animal studies have shown that chronic high doses of MDMA lead to selective destruction of the terminal buttons of the serotonergic neurons.
Benzodiazepines
Benzodiazepines, such as diazepam (Valium) and clonazepam (Rivotril) are anxiolytics that can also have hypnotic or amnesia-inducing effects. Like alcohol, these drugs increase the efficiency of synaptic transmission of the neurotransmitter GABA by acting on its receptors.A GABA receptor is actually a macromolecular complex that, in addition to containing sites for binding GABA, also contains sites for binding other molecules such as benzodiazepines that modulate GABA’s activity.
When benzodiazepines bind to a specific site on a GABA receptor, they do not stimulate it directly. Instead, they make it more efficient by increasing the frequency with which the chlorine channel opens when GABA binds to its own site on this receptor (see animation). The resulting increase in the concentration of Cl- ions in the post-synaptic neuron immediately hyperpolarizes this neuron, thus making it less excitable.
Barbiturates bind to another site on the GABA receptor, with similar effects. But the advantage of benzodiazepines is that, unlike barbiturates, they do not open the Cl- channels directly, but instead act more subtly by potentiating the effect of GABA. Mixing benzodiazepines with alcohol is still very dangerous, however, because their respective effects on the Cl- channels can be additive.
We now know that benzodiazepines can cause a drug dependency even in what are considered therapeutic doses, and even in a short course of treatment.
ANIMATIONS:
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