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Dopamine signaling

All the natural reinforcers that have been studied so far (such as food for a hungry animal, water for a thirsty one, or sexual contact) have one physi-ological effect in common – they cause the release of dopamine in the nucleus accumbens. The re-lease of dopamine appears to be a necessary condition for positive reinforcement to take place.

Addictive drugs – including amphetamine, co-caine, opiates, nicotine, alcohol, PCP, and canna-bis – trigger the VTA to release dopamine in the nucleus accumbens. Different drugs stimulate the release of dopamine in different ways. Before we get into the specifics of how different drugs stimu-late dopamine signaling, we need to mention one important feature of the dopamine synapse.

Once dopamine has been released, moved across the synaptic cleft and interacted with its receptors, the dopamine synapse clears dopamine from the synaptic cleft by pumping it back into the presynaptic terminal using specific transporters. This process is known as reuptake (Figure 3). This means that any drug inhibiting the reuptake of dopamine from the synaptic cleft will cause dopamine levels to stay high, and its effects to persist, because it can’t be taken back up by the presynaptic terminal. Keep this in mind as we discuss how specific drugs change dopamine signaling.

LESSON 5.2 WORKBOOKHow do drugs alter synaptic transmis-sion?

Now that we know which neural pathway is activated in response to rewarding stimuli, let’s take a closer look at the synapses in the pathway and see how different drugs of abuse change their synaptic signaling.

What do all natural reinforcers have in com-mon?_____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

How does the dopamine synapse clear dopa-mine from the synaptic cleft?___________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

DEFINITIONS OF TERMS

Reuptake – process that involves transport of neurotransmitter out of the synaptic cleft by the same cell that released the neurotransmitter.

For a complete list of defined terms, see the Glossary.

Figure 3: Dopamine synapse. The dopamine synaptic cleft does not contain an inactivating enzyme, therefore in order to turn off dopa-mine signaling, dopamine must be recaptured and transported back into the presynaptic terminal by transporters in a process known as reuptake.

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Stimulant drugs: Cocaine and Amphetamine

Cocaine and amphetamine have similar behavioral effects: both are stimulants and both act as potent do-pamine agonists. However, their sites of action are different. Cocaine binds with and inactivates the dopa-mine transporter proteins, thus blocking dopamine reuptake and keeping dopamine levels in the synaptic cleft high. Amphetamine has two effects: It also inhibits the reuptake of dopamine, but its most important effect is to directly stimulate the release of dopamine from axon terminals.

Cocaine

When people take cocaine (Figure 4), they become eu-phoric, active and talkative. They say that they feel power-ful and alert. Some of them become addicted to the drug, and obtaining it becomes an obsession to which they de-vote more and more time and money.

Laboratory animals, which quickly learn to self-administer cocaine, also act excited and show intense exploratory ac-tivity. If animals are given continuous access to self-inject cocaine, they often self-inject so much that they die from an overdose.

One of the alarming effects seen in people who abuse either cocaine or amphetamine is psychotic behavior: hallucinations, delusions of persecution, mood dis-turbances, and repetitive behaviors. These behaviors so closely resemble those of paranoid schizophrenia that even trained mental health professionals cannot distinguish between them unless he or she knows about the person’s history of drug abuse. These effects disappear once people stop taking the drug.

As mentioned previously, cocaine use increases alertness, energy, motor activity and feelings of well-be-ing. But feelings of anxiety, paranoia and restlessness are also common effects of cocaine. With excessive use, cocaine can cause tremors, convulsions, stroke and even death.

Cocaine effects dopamine synaptic transmission by altering the way in which dopamine is removed from the synaptic cleft. Under normal conditions, the VTA releases dopamine onto the nucleus accumbens. Dopamine binds to receptors within the nucleus accumbens and this initiates downstream signaling in the nucleus accumbens neurons. As we saw before, dopamine signaling is normally stopped when the dopa-mine transporters (also known as pumps) in the dopamine reuptake system pump dopamine back into the presynaptic neurons, thus decreasing the levels of dopamine in the synaptic cleft.

LESSON READING

DEFINITIONS OF TERMS

Agonist – drug that facilitates the effects of a neurotransmitter on the

postsynaptic cell .

Stimulants – class of drugs that increase the activity of the central

nervous system.

For a complete list of defined terms, see the Glossary.

What are the psychological and behavioral effects of taking cocaine?__________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

Where does cocaine act within the reward pathway?______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

Figure 4: Cocaine. When people take cocaine they become euphoric, active and talkative. Once addicted to cocaine, obtaining it becomes an obsession.

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Cocaine blocks the activity of dopamine transporters. Since dopamine transport-ers are responsible for removing excess dopamine from the synaptic cleft, when they are blocked, dopamine cannot be removed from the synaptic cleft, and do-pamine levels increase which increases dopamine signaling at the nucleus ac-cumbens (Figure 5).

Compare the healthy brain at the top with the brain of a cocaine abuser at the bottom of Fig-ure 6. Didn’t we say cocaine is a stimulant? Why then does cocaine reduce brain activity if it increases the activity of dopamine neuro-transmission at the nucleus accumbens syn-apse? This is because the output neurons from the nucleus accumbens are actually inhibitory. That is to say when they are activated they shut down signaling in the regions they synapse with. When they are stimulated by cocaine the inhibition is even more intense.

You can watch an animation describing how cocaine affects the brain online — see this unit on the student website or click below:

■ Video: How Does Cocaine Affect the Brain?

LESSON READING

Figure 5: Mechanism of cocaine action. Cocaine increases synaptic dopamine by binding to the dopamine transporter and inhibiting dopamine reuptake.

Cocaine  

Figure 6: PET scans showing decreased activity in cocaine addict. Cocaine reduces brain activity because output from the nucleus accumbens is largely inhibitory.

What is the effect of cocaine on dopamine levels in the nucleus accumbens? ____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

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Amphetamine

Amphetamines include methamphetamine, crystal meth, and crack. Amphetamines are also central ner-vous system stimulants, increasing alertness and focus, while decreasing fatigue and appetite. They also produce hyperactivity and anxiety. With chronic use and/or high doses, amphetamines can also cause seizures, stroke, coma, and death.

Amphetamine (Figure 7) has two effects on the VTA-nucleus accumbens synapse: The first effect is similar to cocaine – it also prevents dopamine reuptake. The most important effect of amphetamine however is to stimulate release of dopamine into the synaptic cleft (Figure 8).

Under normal conditions, the VTA releases moderate amounts of dopamine onto the nucleus accumbens. Dopamine then binds to receptors within the nucleus accumbens and effects downstream signaling, as we have seen before. Then, to stop dopamine signaling, dopamine transporters (also called dopa-mine reuptake pumps) pump dopamine back into the presyn-aptic neurons, which decreases the levels of dopamine in the synaptic cleft.

Amphetamines can alter dopamine synaptic transmission by blocking dopamine transporters like cocaine does. When the dopamine transporters are blocked, dopamine cannot be removed from the synaptic cleft, and dopamine levels remain high, which increases dopamine signaling in the nucleus accumbens, just as we saw for cocaine.

The second way amphetamines can al-ter synaptic transmission is by entering the presynaptic terminals of the VTA’s neurons and causing dopamine to be re-leased even in the absence of action po-tentials. This release also increases the level of dopamine signaling to the nucle-us accumbens. Scientists are still trying to figure out exactly how amphetamines cause the release of dopamine in the ab-sence of action potentials, but somehow this mechanism gives amphetamines an-other way to alter dopamine signaling in the reward pathway.

LESSON READING

Figure 7: Amphetamines include meth-amphetamine, crystal meth and crank. Amphetamines are CNS stimulants.

Figure 8: Mechanism of amphetamine action. Amphet-amine (AMPH) increases synaptic dopamine in two ways. First, it binds to the dopamine transporter and inhibits dopamine reuptake. Second, it enters the presynaptic terminal and stimulates dopamine release. The combined effect is a massive increase in synaptic dopamine levels.

Amphetamine  

What are the psychological and behavioral effects of taking amphetamine? __________________________________________________________________________________________________________________________________________________________________________________________________________________

Where does amphetamine act within the re-ward pathway?__________________________________________________________________________________________________________________________________________________________________________________________________________________

How does amphetamine alter synaptic sig-naling of the reward pathway? What is the drug target?__________________________________________________________________________________________________________________________________________________________________________________________________________________

What is the effect of amphetamine on dopa-mine levels in the nucleus accumbens?_____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

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Opiates: Heroin and Morphine

Opium, derived from a sticky resin produced by the opium poppy, has been eaten and smoked for centu-ries, and in 1847 scientists figured out to make it themselves, producing heroin, the most commonly abused opiate. Addiction to opiates, like heroin, has several high personal and societal costs.

• First, because heroin (Figure 9) is an illegal drug is most countries, an addict becomes by definition, a criminal.

• Second, because of tolerance, a person must take increasing amount of the drug to achieve a “high”. The habit thus becomes more and more expen-sive, and the person often turns to crime to obtain enough money to support his or her habit.

• Third, addicts that inject opiates often don’t have access to sterile one-use needles, so a substantial percentage of people who inject illicit drugs have been exposed to hepatitis or HIV.

• Fourth, if the addict is a pregnant woman, her infant will also become dependent on the drug, which easily crosses the placenta barrier. The infant must be given opiates right after birth, and then weaned off the drug with gradually decreasing doses.

• Fifth, the uncertainty about the strength of a given batch of heroin means that a user could unwittingly take an overdose, with possibly fatal consequences.

Heroin and morphine are both opiates. They are analgesics, meaning they reduce pain without producing unconsciousness. Heroin and morphine produce a sense of relaxation and sleep, and at high doses can cause coma and death.

Heroin and morphine increase the activity at the nucleus accumbens in two ways, both are different from how cocaine and amphetamines act. Both heroin and morphine work on a group of inhibitory neurons that normally inhibit the VTA. Under normal circumstances these neurons decrease the activity of the VTA. However when heroin and morphine bind to their receptors, they can no longer decrease the activity of the VTA. When the inhibition to the VTA is blocked, the VTA’s activity is increased, which results in an increase in dopamine signaling to the nucleus accumbens. Thus when either heroin or morphine are present, more dopamine is released by the VTA to the nucleus accumbens because the VTA is no longer inhibited.

Heroin and morphine can also affect the nucleus accumbens directly by binding to receptors for opiates found on the nucleus accumbens itself. The body itself produces natural opiates, which play an important role in reducing pain sensations and many neurons have receptors for these natural opiates. The nucleus accumbens is no exception. Both heroin and morphine can bind to these receptors and in this way can directly affect the activity of the nucleus accumbens.

LESSON READING

DEFINITIONS OF TERMS

Opiates – class of drugs with pain reducing qualities.

For a complete list of defined terms, see the Glossary.

Figure 9: Heroin is the most commonly abused opiate.

What are the psychological and behavioral effects of taking heroin? _______________________________________________________________________________________________________________________________________________________________________________

Where does heroin act within the reward pathway?_____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

How does heroin alter synaptic signaling of the reward pathway? What is the drug target?__________________________________________________________________________________________________________________________________________________________________________________________________________________

What is the effect of heroin on dopamine lev-els in the nucleus accumbens?________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

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NicotineWhile nicotine (Figure 10) might seem rather tame in comparison to cocaine, amphetamine and opiates, it is still an addictive drug, and it accounts for more deaths than all the other so called “hard” drugs combined. The combination of nicotine and other substances in tobacco smoke is carcinogenic and leads to cancer in the lungs, mouth, throat and esophagus. The World Health Organization (WHO) estimates that 50% of people who begin to smoke as adolescents and continue to smoke will die from smoking-related diseases.

Nicotine is extremely addictive; many people continue to smoke even when their health is seriously af-fected. Although tobacco companies and others with vested interests have tried to argue that smoking is a “habit” rather than an “addiction”, it is clear that people who regularly use tobacco behave like compulsive drug users. Smokers tend to smoke regularly or not at all; few smoke just a little. Male smokers smoke an average of 17 cigarettes per day, while female smokers smoke an average of 14. Nineteen out of twenty

smokers smoke every day, and only 60 out of 3500 smokers sur-veyed smoke fewer than 5 cigarettes a day. Of those who attempt to quit smoking by enrolling in a special program, only 20% man-age to abstain for one year. The record is much poorer for those who try to quit on their own: one-third manage to stop for one day, one-fourth manage for one week, but only 4% manage to stop for six months.

Ours is not the only species that will willingly self-administers nicotine, laboratory animals will too. Nicotine binds to and stimulates nicotinic acetylcholine receptors in the VTA. Once nicotine binds to these receptors, the neurons in the VTA fire action potentials. These action potentials cause the VTA to release dopamine onto the nucleus accumbens, thus increasing dopamine levels in the synaptic cleft. Scientists have also learned that nicotine can increase the actual amount of dopamine that the VTA re-leases, although they do not understand how. They do know that when nicotine binds to its receptors, the VTA releases more dopamine than normal. Thus nicotine binding to its receptor not only causes dopamine to be released in response to an action potential, but also the amount of dopamine released is greater.

Through binding to nicotinic receptors, nicotine stimulates the central nervous system, causing increased alertness, and decreased appetite. Like other drugs nicotine also has unpleasant effects such as nausea, vomiting, diarrhea, and confusion. When people stop smoking, they often start overeating and gain weight. One lab discovered why: As you will see in the Metabolic Diseases module, eating and changes in metabolism are regulated by the activity of two different types of neurons whose cell bodies are located in the hypothalamus. One of these sets of neurons secretes the peptide called melanocyte-stimulating hormone (MSH). MSH affects neurons that normally increase appetite. When nicotine is present, it inhibits these neurons, suppressing appetite. How-ever when nicotine is removed, such as when people try to stop smoking, this inhibition is removed and the MSH neurons can stimulate eating again — so people overeat and gain weight.

You can watch a video about nicotine’s effect on the brain online — see the student website or click below: ■ Video: Visualization award winner in Science - Nicotine addiction and molecule diffusion

LESSON READING

Figure 10: Nicotine is the active ingredient in cigarettes and chew-ing tobacco.

What are the psychological and behavioral effects of taking nicotine? _______________________________________________________________________________________________________________________________________________________________________________

Where does nicotine act within the reward pathway?_____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

How does nicotine alter synaptic signaling of the reward pathway? What is the drug target?__________________________________________________________________________________________________________________________________________________________________________________________________________________

What is the effect of nicotine on dopamine levels in the nucleus accumbens?________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

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LESSON READING

DEFINITIONS OF TERMS

Apoptosis – type of cell death in which the cell uses specialized cellular machinery to kill itself.

Depressant – class of drugs that decrease the activity of the central

nervous system.

For a complete list of defined terms, see the Glossary.

Alcohol

Alcohol (Figure 11) also has enormous costs to society. A large percentage of deaths and injuries caused by car acci-dents are related to alcohol use. Addition-ally, alcohol contributes to violence and aggression. Chronic alcoholics often lose their jobs, homes, and families; and many die of cirrhosis of the liver, exposure, or diseases caused by poor living conditions and abuse of their bodies. Alcohol consumption by pregnant women leads to fetal alcohol syndrome, one of the leading causes of mental retardation in the Western world today. Therefore, understanding the physi-ological and behavioral effects of alcohol is an imporant issue.

Alcohol’s serious effects on fetal development occur during the brain growth spurt period, which occurs during the last trimester of pregnancy and for several years after birth. One study found that exposure of an immature rat brain to alcohol triggered widespread death of neurons called apoptosis. This resulted in the death of various areas of the immature brain, and abnormal brain development.

Alcohol acts as a depressant in the central nervous system. Alcohol consumption produces a decrease in anxiety, disinhibition, intoxication, memory impairment and sleep. At high doses, alcohol can cause vomit-ing, unconsciousness and even death due to the inhibition of the brain’s breathing center. Alcohol is considered a sedative because it reduces the excitability of neurons. Alcohol has this effect by increasing the activity of the brain’s main inhibitory neurotransmitter, GABA. Alcohol can bind to the GABA receptor and increasing its activity. When alcohol is present, GABA signaling is increased, thus increasing inhibition.

Alcohol can also affects the brain’s reward system. It does this by inhibiting the same inhibitory neurons that project to the VTA that opiates work on. Recall that when they are active these inhibitory neurons decrease the activity of the VTA, which decreases the levels of dopamine the VTA releases onto the nucleus accum-bens. However, when alcohol is present, the activity of these inhibitory neurons is blocked which removes their inhibition of the VTA. This removal of inhibition increases the activity of the VTA. The VTA is then able to increase dopamine signaling to the nucleus accumbens. Thus when alcohol is present, more dopamine is released by the VTA onto the nucleus accumbens because inhibition is removed.

Figure 11: Alcohol is the most commonly used drug in the United States.

What are the psychological and behavioral effects of taking alcohol? __________________________________________________________________________________________________________________________________________________________________________________________________________________

Where does alcohol act within the reward pathway?_____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

How does alcohol alter synaptic signaling of the reward pathway? What is the drug target?_____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

What is the effect of alcohol on dopamine levels in the nucleus accumbens?_____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

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Marijuana

Another drug that people regularly self-administer is THC, the active ingredient in marijuana (Figure 12). THC comes from the flowering hemp plant, Cannabis sativa, and is a class of chemical called canna-binoids. THC is found in several different forms such as marijuana and hashish, both of which may be smoked or eaten. The consumption of cannabis for its intoxicating effects is thought to date back thousands of years to Eastern cultures. The practice of marijuana smoking was introduced in the United States in the early 1900s by Mexican and West Indian immigrants.

Marijuana is the most heavily used illicit drug in the United States. Marijuana use causes euphoria, disinhibition, relaxation, altered sensations and increased appetite. Long-term use of marijuana has been associated with deficits in cognitive function, respiratory problems and impaired immune function.

Studies with laboratory animals show that in rodents THC produces changes in motor activity, catalepsy (inability to move), hypothermia, and analgesia. Cannabinoids disrupt memory in several kinds of learning tasks, an effect that is thought to be related to activation of the hippocampus.

When marijuana is smoked, THC rapidly passes from the lungs into the bloodstream which carries THC into the brain. Once in the brain, THC binds to receptors, called cannabinoid receptors. These receptors are particularly concentrated on the VTA. The binding of THC to canna-binoid receptors on the VTA stimulates them to fire an action potential. These action potentials cause the VTA to release dopamine, thus increasing dopamine signaling at the nucleus accumbens.

There are many concerns about the adverse effects of chronic cannabis use. In young people the amount of cannabis use directly correlates with poor educational performance, although whether this is a causal effect is not clear. Long-term use has been associated with at least temporary decrements in cognitive function, although whether these effects persist has been disputed. Likewise, it has been suggested that heavy cannabis use produces persistent cognitive deficits and/or apathy, loss of achievement motivation and decreased productivity, but the evidence supporting these suggestions is not strong. Because of this, researchers currently favor the hypothesis that early cannabis use is linked to lifestyles that devalue edu-cational achievement.

On the other hand, there are real health risks associated with marijuana smoking that involve respiratory problems.

Figure 12: Marijuana. The active ingredient in marijuana, THC is regularly self-administered, resulting in euphoria, disinhibition, relaxation, altered sensa-tions and increased appetite.

What are the psychological and behavioral effects of taking marijuana?________________________________________________________________________________________________________________________________________________________________________________

Where does marijuana act within the reward pathway?_____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

How does marijuana alter synaptic signaling of the reward pathway? What is the drug tar-get?__________________________________________________________________________________________________________________________________________________________________________________________________________________

What is the effect of marijuana on dopamine levels in the nucleus accumbens?_____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________

LESSON READING

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Drugs of abuse have similar effects

All drugs of abuse increase dopamine activity at the synapse between the VTA and the NAc, but they do it in slightly different ways:

• Cocaine and amphetamine both inhibit dopamine reuptake transporters, thus increasing the amount of dopamine remaining in the synaptic cleft.

• Heroin and other synthetic opiates, like morphine, effect dopamine signaling in two ways. First, they inhibit inhibitory neurons projecting to the VTA. By removing this inhibition, the drugs increase VTA activity and the release of dopamine. Second, the drugs can also directly affect the nucleus accumbens by binding to opiate receptors.

• Alcohol, like the opiates, inhibits inhibitory projections to the VTA, thereby increasing VTA activity and its release of dopamine.

• Nicotine stimulates the VTA, where the dopamine neurons originate, directly, increasing dopa-mine release.

• THC the active ingredient in marijuana binds to cannabinoid receptors on the VTA which stimu-lates it to release dopamine.

Drugs of abuse can increase the amount of dopamine in the synaptic cleft between 2 - 10 fold more than normal. In some cases, this occurs almost immediately (as when drugs are smoked or injected), and the effects can last much longer than those produced by natural rewards.

LESSON READING

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STUDENT RESPONSES

On the diagram of the reward circuit below, draw in where each drug of abuse affects the pathway. Make sure to include: cocaine, amphetamine, heroin & morphine, nicotine, alcohol, and marijuana.

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What do all drugs of abuse have in common? In terms of their activity on the reward pathway? In terms of their abuse potential?

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VTA  

NAc  

Prefrontal  Cortex  

Inhibitory    Neuron