Biology 202

2006 First Web Paper

On Serendip

Neurobiology and behavior
Prof. Grobstein

The prevalence of addiction within our society ranges from movie stars dealing with a cocaine habit in the tabloids to the backyards of our home towns where adolescents get high off of prescription drugs. Although there is already much knowledge one the physical manifestations of addiction, there is also a hint of unfamiliarity when it comes to looking at the workings of the brain. Addiction, so far, has revealed to be a complicated change of the brain that can easily overwhelm a person's life. Current research has revealed that several intertwined pathways focusing on rewards and learning are the key players of this lifestyle.

These major pathways in the brain are quite different from the intial model of addiction, the opiate model. This model was developed by Abraham Wikler on the belief that it is drug withdrawal symptoms that drive the cycle of addiction. Withdrawal symptoms are physical side effects, such as shaking and nausea, and cravings addicts experience when their bodies are depleted of their usual intoxicants. Follow the mind set of the opiate model, it is the want to diminish the withdrawal symptoms that keeps addicts within their vicious cycle (2). According to Wikler, then, so long as the withdrawal symptoms, especially the drug craving, are under control it should be relatively easy to detoxify an addict. The millions of addicts and thousands of drug rehabilitation clinics, however, easily prove that this is not the case.

Wikler soon realized that his simple theory had two major holes: "One was that the model cannot explain why an addict would [take drugs] so regularly and in such a quantity to become physically dependent in the first place . . . [and how this theory can] account for relapse after subsidence of the withdrawal syndrome." (2).

The first hole in Wikler's theory is on the foundation of addiction itself. What is it that makes a person want to take a substance to the point of addiction? The key to this answer is reinforcement. Reinforcements are positive consequences that encourage a behavior to continue. In the case of drug dependence, that positive outcome is the high. The role of reinforcement and rewards in drug addiction was studied by Bozarth and Wise using rats. They "demonstrated that a single injection of heroin is reinforcing in drug-naïve rats, inducing a clear preference for the environment in which the effects of that drug were experienced." (2). The rats tested in this experiment easily become accustomed to the feelings of a drug after simply one dose and are even encouraged to seek more of it. It is possible that the first dose of heroine is all a person needs to feel the positive effects that encourage them to continue taking that drug. The bottom line of this idea is that reinforcement plays a big role in addiction. If drugs were unpleasant, people would not be encouraged to seek them and take them again and again.

The pathway in the brain that is responsible for these reinforcing effects is the mesolimbic dopaminergic pathway. Rewards, both natural (food, sex) and substance based (alcohol, opiates), are founded in this pathway. The pathway runs on dopamine, a common neurotransmitter that is known for its role in the pleasure pathway and drug addiction. Researchers are not exactly sure what mechanism dopamine plays in the mesolimbic dopaminergic pathway, but they have two hypotheses. The first believes that drug use heightens dopamine concentrations in the brain, which results in pleasure. This model gives the idea that drug usage creates a rush of dopamine in the brain. This rush produces a long lasting feeling of pleasure. The second theory is that drugs make the dopamine system more sensitive to dopamine. Drugs, then, increase the brain's responsiveness to dopamine and drug taking is basically keeping the brain's receptors sensitive to get that desired high. (1). But this still is not the end of the story. Dopamine makes one happy, but how does one remember it makes them happy? This is where the pathways of memory and learning come into play.

"The imbedding of the experience of substance use in tandem with the attendant conditioned environmental stimuli produces an "addiction memory" or "neural ghost". This neural ghost remains imbedded in the mesolimbic circuitry, particularly the amygdala – often outside of conscious awareness. Upon stimulation of the mesolimbic pathway, either by conditioned drug cues or by drug priming, the circuit is activated, inducing a desire, or wanting, for additional drug. The formation of the associations between salient stimuli and internally rewarding events is facilitated by stimulation of dopaminergic neurons." (1). A physical change takes place in the brain every time an addict gets high. A neural ghost becomes engraved in the mesolimbic pathway, particularly the part the runs through a region of the brain associated with memory, the amygdala. The activation of the mesolimbic pathway along with the memory creation of the amygdala create an effect called priming. Priming is a way of creating simple associations. These associations create an even stronger attachment to the drug than just the ordinary high. All of the people, places, and tools become wrapped in the brain as one entity that corresponds to getting high.

The way priming takes place between the drug-induced high and the environment where that high takes place is through a process known as Pavlovian classical conditioning. Classical conditioning is a theory of learning that says when two stimuli presented one after the other together the later stimulus will be able to induce a response without the earlier stimulus. For example a dog can be conditioned to salivate at the sound of a bell if it believes the bell signals food. Food on its own will cause the dog to salivate, but when the food is paired with the bell an association is made. The dog believes that the bell is a signal for it. In the end, it will salivate if only the bell is presented.

The conditioning hypothesis was tested by O'Brien, Ehrman, and Ternes. They did an "experiment in which withdrawal-inducing injections of the opiate antagonist naloxone were repeatedly given to methadone patients in the presence of distinctive cues. When a saline injection was subsequently given in the presence of the same cues, conditioned withdrawal symptoms were evoked." (2).This study looked at how distinctive cues can be paired with withdrawal syndromes. The methadone patients learned to associate the naloxone induced withdrawal syndromes with distinctive cues, such as a specific room for example. When they were given a placebo in that same room, the same withdrawal syndromes returned. The patients had come to associate that room with withdrawal. O'Brien et al. came to the conclusion that if certain stimuli can be associated with drug withdrawal then others can be associated with intoxication. This, in fact, is true; "in real-life situations experienced by opiate addicts, drug-related stimuli are repeatedly paired with both intoxication and withdrawal, leaving the possibility that drug-like responses could be conditioned to such stimuli in addition to, or instead of, withdrawal-like responses." (2). Drug addicts, therefore, have been trained to make associations between places, people, things and their drug of choice. They do not even need the physical drug infront of them for cravings to set in; even just seeing a familiar area where they enjoy get high can spark wanting for their drug. They cannot fully be freed from their habit if so many associations exist around them that enforce it. In order for these associations to take place, there is a learning process involved.

Just as dopamine is the main neurotransmitter in reward and reinforcement, glutamate is the primary neurotransmitter when it comes to learning and memory. "[As] the chief agent of fast neuron stimulation, glutamate is at the core of nearly all brain physiology and biochemistry and is central to the most sophisticated cortical processes. Glutamate receptors in the hippocampus appear to trigger the complex cascade of biochemical reactions that convert short-term memories into permanent ones, a process called long term potentiation." (3). Glutamate is the main player when it comes to memory. It is used in changing short-term memories to long term ones. When looking at an addict, one can see how glutamate would play a role in the addiction process. The associations that they make through conditioning, which was previously discussed, become more and more natural habit as certain areas, people, methods as hard wired into their brain with the help of glutamate. They learn, they remember, they know all the key players in their drug habit. Once this habit is built in, just like with any other process that humans learn, it is very hard to un-learn or un-remember it.

In addition, " [neuroscientists] of all sorts have paid intense attention to a crucial link in this chain, an intracellular signaling chemical called cyclic adenosine monophosphate (cAMP), because it turns genes on and orders them to make some very consequential proteins. These proteins help form new synaptic connections between neurons – the basis for long-term potentiation." (3). Glutamate is an extracellular signaling chemical. It is an external switch to the cascade of events that occur within a neuron. The second half of the story lies inside nerves cells, neurons, with cyclic adenosine monophosphate (cAMP). cAMP controls the activation of genes found in all cells. When cAMP is activated it instructs the formation of proteins which creates new connections between neurons and leads to long-term potentiation, or the transfer of information from short-term to long-term memory.

To put everything all together, dopamine controls the high a person feels every time they take their drug whether it is caffeine, methamphetamine, or ecstasy. Dopamine makes that person feel good through the various interactions that drug has with the dopamine pathway, the mesolimbic dopaminergic pathway. The connections made between the drug and other important environmental cues are learned and then put into memory through the help of glutamate. Lastly, it is cAMP that solidifies the long-term memory connections between neurons that turn drug use into full blown addiction.

Addiction is not simply the struggle between withdrawal symptoms as was previously believed. Addiction is a change in the brain, a physical change in the brain, as a result of a behavior. It is interesting to look at addiction in this new light and to understand that all of the intertwined pathways discussed in this paper may only be the surface. There is so much more to addiction, and other behaviors in general, and their affect on the brain. One of the main debates currently taking place in the field of neurobiology is whether the brain is behavior. This is to say that all behaviors, in essence, start in the brain. This equation can also be seen in reverse when it comes to addiction, that behaviors, in essence, can and do change the brain.

Works Cited

1) Adinoff, Bryon. (2004). "Neurobiological Process in Drug Reward and Addiction." Harvard review of psychiatry. 12 (6). 305 – 320.

2) Lyvers, Michael. (1998). "Drug Addiction as a Physical Disease: The Role of Physical Dependence and Other Chronic Drug-Induced Neurophysiological Changes in Compulsive Drug Self-Administration." Experimental and Clinical Psychopharmacology. 6 (1). 107 – 125.

3) Powledge, Tabitha M. (1999). "Addiction and the Brain". BioScience. 49 (7). 513 – 519.


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