Drugs of abuse or acute stress elicit long-term potentiation LTP at excitatory synapses on dopamine cells in the ventral tegmental area VTA.
Morphine prevents a novel form of LTP at inhibitory synapses on the same dopamine cells. Both changes are likely to increase dopamine cell firing. The actions of orexin in the VTA might be important for several of the behavioural adaptations caused by cocaine and, perhaps, other drugs of abuse. At excitatory synapses on medium spiny neurons in the nucleus accumbens, cocaine causes a form of long-term depression LTD that is due to the removal of synaptic AMPA receptors.
It also impairs endocannabinoid-mediated LTD. In contrast, during withdrawal from chronic cocaine administration, there appears to be an increase in excitatory synaptic transmission.
Further work is necessary to determine whether other drugs of abuse have the same effects. Other key brain areas in which drugs of abuse affect synaptic function and plasticity include the bed nucleus of the stria terminalis and the amygdala.
There may be important differences in the effects of drugs of abuse on synaptic function and plasticity depending on whether the drug is self-administered or not. It will be important in future work to use animal models that more closely mimic the behaviour of human substance abusers.
Addiction is caused, in part, by powerful and long-lasting memories of the drug experience. Relapse caused by exposure to cues associated with the drug experience is a major clinical problem that contributes to the persistence of addiction.
Here we present the accumulated evidence that drugs of abuse can hijack synaptic plasticity mechanisms in key brain circuits, most importantly in the mesolimbic dopamine system, which is central to reward processing in the brain.
Reversing or preventing these drug-induced synaptic modifications may prove beneficial in the treatment of one of society's most intractable health problems. La fine structure des centres nerveux.
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These alterations underlie drug tolerance where higher doses of the drug are needed to produce the same effect , withdrawal, addiction, and other persistent consequences. Some longer-term changes begin as adjustments to compensate for drug-induced increases in neurotransmitter signaling intensity. For example, the brain responds to repeated drug-induced massive dopamine surges in part by reducing its complement of dopamine receptors. Similarly, methadone and some other opioids induce neurons to retract a portion of their mu opioid receptors, making them unavailable for further stimulation.
The retraction is short-lived, after which the receptors return to the neuron surface, restoring normal responsiveness to subsequent stimulation.
This dynamic of reducing and then restoring receptor availability may thwart the development of tolerance to these drugs. Morphine, in contrast, does not cause receptors to retract, and the resulting opioid overstimulation triggers intracellular adjustments that appear to promote opioid tolerance. The drug-related mechanisms producing cumulative changes in neurotransmission sometimes are epigenetic in nature.
For example, in mice, cocaine alters important genetic transcription factors and the expression of hundreds of genes. Other changes, such as proliferation of new dendrites branchlike structures on neurons that feature neurotransmitter receptors on their surface may be compensatory.
Some epigenetic changes can be passed down to the next generation, and one study found that the offspring of rats exposed to THC—the main psychotropic component of marijuana—have alterations in glutamate and cannabinoid receptor formation that affects their responses to heroin. Some drugs are toxic to neurons, and the effect accumulates with repeated exposures. Similarly, methamphetamine damage to dopamine-releasing neurons can cause significant defects in thinking and motor skills; with abstinence, dopamine function can partially recover , but the extent to which cognitive and motor capabilities can recover remains unclear.
To determine whether a drug affects a particular neurotransmitter system, or how, researchers typically will compare animals or people who have a history of drug exposure with others who do not. In experiments with animals, drug exposure often takes place under laboratory conditions designed to mimic human drug consumption. Studies can be divided into those in which measurements are made in living animals or people and those in which animal brain tissue is removed and examined.
Scientists may perform chemical assays on brain tissue to quantify the presence of a neurotransmitter, receptor, or other structure of interest. In a recent experiment, scientists assayed brain tissue from day-old rat pups and found that pups that had been exposed to nicotine in utero had fewer nicotinic acetylcholine receptors in the reward system than unexposed rats.
Scientists place the tissue in a laboratory solution of nutrients cell culture that enables neurons to survive outside of the body. The researchers may then, for example, add the drug being investigated to the solution and observe whether or not the neurons respond by increasing their release of neurotransmitters.
In both living animals and extracted tissue, the techniques for measuring neurotransmitter quantities and fluctuations include microdialysis and fast-scan cyclic voltammetry FSCV.
Microdialysis involves taking a series of samples of the intercellular fluid containing the neurotransmitter through a microscopic tube inserted into the tissue or living brain. FSCV, which was developed by NIDA-funded scientists, monitors neurotransmitter fluctuations at tenth-of-a-second intervals by measuring electrical changes related to neurotransmitter concentrations.
A common design for experiments with either animals or people is to give study subjects a chemical that has a known effect on a particular neurotransmitter, and then observe the impact on behavior. Typically, the chemical is either an agonist promoter or antagonist blocker of signaling by the neurotransmitter. Another team using a similar strategy showed that nicotine-induced disruption of glutamate signaling contributed to aspects of nicotine withdrawal.
Both findings point to manipulation of the glutamate system as a potential strategy for treating some addictions. Researchers are now attempting to parlay this discovery into a novel treatment for cocaine addiction.
Brain imaging techniques enable neuroscientists to directly assess neurotransmission in people and living animals. With positron emission tomography PET , researchers can compare people with and without a drug addiction, quantifying differences in their levels of a particular neurotransmitter e.
The findings indicated that the need to saturate these receptors is the primary driver of smoking behavior, but that sensory aspects of smoking, such as handling and tasting cigarettes, also play a role. Or, they can elicit a drug-related behavior or symptom e. Researchers use several imaging techniques, including PET, functional magnetic resonance imaging fMRI , and computerized tomography to monitor metabolic activity in selected regions of the brain.
Because each neurotransmitter has a unique distribution among the regions of the brain, information on locations of heightened or decreased activity provides clues as to which neurotransmitter is affected under the conditions of the study. Another technique, diffusion tensor imaging, provides information about the white matter neuron fiber pathways through which sending neurons extend to receiving neurons, often over long distances.
Studies that link genetic variants to contrasting responses to drugs and drug-related behaviors provide another avenue of insight into drugs and neurotransmission.
Such studies have shown, for example, that one rare variant of the gene for the mu opioid receptor is twice as common in the general population of European Americans as it is among European Americans who are addicted to cocaine or opioids.
The finding suggests that receptors that are built based on the DNA sequence of the variant gene confer resistance to those addictions. Another study linked a different variant of the same mu opioid receptor gene to reduced incidence and severity of neonatal abstinence syndrome among infants born to mothers who used opioids while pregnant.
In another type of study, researchers knock down or knock out specific genes in laboratory animals and observe whether drug-related behavior—for example, pacing restlessly after being given a stimulant—increases or decreases. Researchers have used this technique to explore how different subtypes of nicotinic acetylcholine receptor influence smoking behaviors, including how much a person smokes and susceptibility to symptoms of nicotine withdrawal.
Finally, researchers may implant modified genes into animals. In one such project, researchers, starting from clues provided by a South American caterpillar that eats coca leaves, modified the dopamine transporter gene to produce a transporter that is insensitive to cocaine. Mice who were implanted with this gene showed no preference for the drug over a saline solution. This result could point researchers toward medications capable of preventing or treating cocaine use disorders.
Research on cocaine illustrates how a drug can disrupt neurotransmission in multiple ways to promote intensified drug use, dependence, and addiction. Like all drugs that cause dependence and addiction, cocaine alters dopamine signaling.
Studies, mostly with animals, indicate that the interactions of cocaine with the dopamine and other neurotransmitter systems influence the risk of drug use, progression to addiction, and relapse after abstinence through a variety of pathways. By altering neurotransmission, drugs can produce effects that make people want to use them repeatedly and induce health problems that can be long lasting and profound.
Some important effects are shared by all drugs that cause dependence and addiction, most prominently disruption of the dopamine neurotransmitter system that results in initial pleasurable feelings and, with repeated use, potential functional and structural changes to neurons.
There are also drug-specific effects: Each drug disrupts particular neurotransmitters in particular ways, and some have toxic effects on specific types of neurons. Scientists use a wide variety of experimental tools and techniques to study drugs' effects on neurotransmission, and their consequences, in both animals and people. Their findings enhance our understanding of the experiences of drug users and the plight of people who are addicted, point the way to new behavioral and medication treatments, and provide potential bases for prevention strategies and monitoring progress in treatment.
PDF documents require the free Adobe Reader. Skip to main content. Search form. Archive Home. Networks of neurons send signals back and forth to each other and among different parts of the brain, the spinal cord, and nerves in the rest of the body the peripheral nervous system. To send a message, a neuron releases a neurotransmitter into the gap or synapse between it and the next cell. The neurotransmitter crosses the synapse and attaches to receptors on the receiving neuron, like a key into a lock.
This causes changes in the receiving cell. Other molecules called transporters recycle neurotransmitters that is, bring them back into the neuron that released them , thereby limiting or shutting off the signal between neurons.
Drugs interfere with the way neurons send, receive, and process signals via neurotransmitters. Some drugs, such as marijuana and heroin, can activate neurons because their chemical structure mimics that of a natural neurotransmitter in the body. This allows the drugs to attach onto and activate the neurons. Other drugs, such as amphetamine or cocaine, can cause the neurons to release abnormally large amounts of natural neurotransmitters or prevent the normal recycling of these brain chemicals by interfering with transporters.
This too amplifies or disrupts the normal communication between neurons. Drugs can alter important brain areas that are necessary for life-sustaining functions and can drive the compulsive drug use that marks addiction. Brain areas affected by drug use include:. Some drugs like opioids also disrupt other parts of the brain, such as the brain stem, which controls basic functions critical to life, including heart rate, breathing, and sleeping.
This interference explains why overdoses can cause depressed breathing and death. When some drugs are taken, they can cause surges of these neurotransmitters much greater than the smaller bursts naturally produced in association with healthy rewards like eating, hearing or playing music, creative pursuits, or social interaction. It was once thought that surges of the neurotransmitter dopamine produced by drugs directly caused the euphoria, but scientists now think dopamine has more to do with getting us to repeat pleasurable activities reinforcement than with producing pleasure directly.
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