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Neurotransmitters, Psychoactive Drugs, and the Reward Pathway
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Unit 10: Neurobiology
Neurotransmitters, Psychoactive Drugs, and the Reward Pathway

Drugs that have effects on the central nervous system are known as psychoactive drugs. The mode of actions of both therapeutic drugs (e.g., Ritalin, Prozac, and Paxil) and recreational drugs (e.g., alcohol, cannabis, cocaine, and nicotine) affect the firing of certain neurons by changes in various neurotransmitters or receptors. Not all drugs have specific modes of action; alcohol, for example, has many and varied effects. We will focus, however, on a few examples of those drugs that have specific effects.

Humans and many other animals engage in many activities from which they derive pleasure. Researchers working with various animals have shown that there are regions of the brain, such as the ventral tegmental area, that are more active when animals engage in pleasurable acts. When researchers stimulate these areas experimentally, the animals will perform various tasks in order to receive further stimulation. Hence, the neural pathway comprising of those regions has been called the reward pathway.

Like many drugs, nicotine from tobacco products acts on the reward pathway. This drug, however, is unusual in that it directly affects the dopamine receptor in the reward pathway's neurons. Unlike the action of most drugs, no intermediary steps are involved: nicotine binds to the receptor and stimulates the postsynaptic neuron. The overstimulation of the postsynaptic cell, however, also has effects at the cellular level. Over time, it leads to a decrease in the number of dopamine receptors being expressed and inserted to the membrane, as well as a change in the shape of the cell. The reduction of receptors is referred to as desensitization. When the nicotine is removed, because there are fewer receptors on the postsynaptic cell, more dopamine than normal is required for proper stimulation of postsynaptic neuron. Addiction can result because nicotine becomes needed just to maintain the normal stimulation of the postsynaptic cells.

Allelic variation at the dopamine receptor gene appears to affect one's likelihood of becoming addicted to nicotine. Individuals who have the A1 allele have fewer dopamine receptors than those that do not have the allele. These individuals also have more difficulty in quitting smoking and are more likely to exhibit other addictive and compulsive behaviors. The genetic components of many types of addiction are the topic of intensive research - and often heated debate.

Figure 4. Dopamine transporter
Cocaine also works on dopamine and the reward pathway but does so in a different way. Recall that some neurotransmitters are normally taken up by the presynaptic neuron by reuptake receptors, or transporters, in the presynaptic membrane (Fig. 4). The molecular structure of cocaine is such that it can block the binding site for dopamine on its reuptake receptor. Because this cell is now impaired in the reuptake of dopamine, an excess of dopamine builds up in the synapse. This excess leads to overstimulation of the postsynaptic neuron. Because the action is occurring in the reward pathway, overstimulation leads to euphoria. The effects of overstimulation of the postsynaptic cell by cocaine are much the same as those of nicotine: the reduction of the number of receptors leads to desensitization and the possibility of addiction.

Figure 5. Chemical structures of dopamine-like drugs
There have been concerns that Ritalin (methylphenidate), used for treatment of attention deficit and hyperactivity disorder (ADHD), is chemically similar to cocaine. Indeed, Ritalin increases dopamine levels by interfering with reuptake. Moreover, Ritalin and cocaine compete for the same receptor site. One crucial difference between these two drugs is that Ritalin acts much more slowly than cocaine. While cocaine's effects on dopamine levels occur within seconds, the response from Ritalin (when administered in pill form) takes about an hour. Some studies suggest that, far from leading to addiction, Ritalin treatment in childhood may be associated with decreased risk of drug and alcohol use later on. Other studies, however, suggest that Ritalin may be a gateway drug: by using it, teens may be more willing to experiment with other drugs. As of 2003 the consequences of Ritalin treatment remain unresolved (Fig. 5).


Prozac and Serotonin Reuptake
Soon after it was released to the market in 1988, Prozac (fluoxetine hydrochloride) became the most prescribed drug to treat depression. It and several other antidepressants inhibit the reuptake of serotonin, a neurotransmitter that affects mood, sleep, and appetite. These drugs are called selective serotonin reuptake inhibitors (SSRIs) because, unlike older antidepressants, they have little effect outside of serotonin reuptake. By inhibiting the reuptake of serotonin, Prozac and SSRIs increase the level of serotonin in the synapses. The increased levels of this neurotransmitter generally result in an improved mood. Depressed patients often had lower than normal levels of serotontin.


Cannabis, the Cannabinoid Receptors, and Endocannabinoids
The active ingredient of marijuana, from the cannabis plant, is THC (delta-9-tetrahydrocannabinol). This chemical exerts its effects on the brain by binding to receptors called the cannabinoid receptors. Scientists have identified two cannabinoid receptors (CB1 and CB2), and evidence suggests that there may be others. Although CB1 is found in many regions of the brain, CB2 is present only in certain cells of the immune system. Because the receptor is present in several brain regions, THC can have manifold effects. For instance, THC may affect memory formation. CB1 is prevalent in the hippocampus, a region of the brain strongly associated with memory. By binding to and activating CB1, THC decreases activity of neurons in the hippocampus and interferes with the proper function of that region, which may translate to an interference with memory formation.

The human body does not produce THC, so why would there be receptors that can bind it? During the 1990s researchers discovered that the body makes chemicals, such as anandamide, that can bind to the cannabinoid receptors. The function of these chemicals, called endocannabinoids, and their receptors is still unknown. To investigate the role of the CB1 receptor, scientists have studied mutant mice that lack the receptor. Compared with normal mice, these mice have a decreased appetite, are less active, and have a reduced lifespan; however, the mice have an enhanced memory.

The CB receptors have recently been associated with some beneficial actions, such as pain relief and extinguishing some fear behaviors. THC has even been prescribed as medication in some states for pain relief for various diseases including glaucoma, AIDS, and cancer. 3

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