Addiction

Last post for PHAR3303! This was probably my favourite lecture from this guy. It covers three main theories of drug addiction: negative reinforcement, positive reinforcement and incentive sensitisation.

Withdrawal-Based Negative Reinforcement

Negative reinforcement is when a behaviour is done in order to avoid a negative response. For example, you might hurry up and hand in an assignment in order to avoid a late penalty. In the case of drugs, people take drugs to avoid withdrawal effects.

What are withdrawal effects? Well, when we take drugs, there are usually compensatory effects that cause us to develop tolerance to the drugs. When we stop taking drugs, the compensatory effects continue even though the drug effects have stopped, causing withdrawal effects. Withdrawal effects are usually opposite to those produced by the drug, so if the drug caused analgesia (pain relief), you might get hyperalgesia (excessive pain) instead. No wonder withdrawal effects can be quite aversive!

There are, however, some limitations to this theory. Firstly, animals will give themselves drugs, even if they have never had the drug before (and therefore don't have any withdrawal symptoms to avoid). Secondly, some drugs (such as cocaine and amphetamine) only have minor withdrawal effects, which are not bad enough to fully explain addiction. Furthermore, locking up people until the withdrawal effects have subsided doesn't seem to cure them of addiction.

Positive Reinforcement: "Wise's Psychomotor Stimulant Theory of Addiction"

Positive reinforcement is when a behaviour is done in order to get a positive response. For example, you might work hard on an assignment because you want good marks. In the case of drugs, people take drugs because they stimulate pleasure centres in the brain. In fact, drugs may stimulate pleasure centres better than natural rewards (like food). This is known as Wise's Psychomotor Stimulant Theory of Addiction.

The "reward system" is made up of neurons in the mesolimbic dopamine system. Cell bodies of these neurons sit in the ventral tegmental area (a.k.a. A10) and project to the nucleus accumbens. Dopamine terminals can be selectively lesioned by first pretreating with desimipramine (in order to prevent lesioning of noradrenaline terminals) and then infusing 6-OHDA into the nucleus. When dopamine terminals are lesioned, or when high doses of dopamine blockers are administered, animals stop seeking cocaine and amphetamine. They would, however, keep seeking amphetamine if it was infused straight into the nucleus accumbens, which to me suggests that receptors on cell bodies in the nucleus accumbens may be responsible (though I could be wrong, I don't know much about neuroscience). Interestingly enough, lesioning dopamine terminals didn't prevent heroin-seeking, but destruction of the cell bodies of the nucleus accumbens did.

Incentive Sensitisation Theory of Craving

The Incentive Sensitisation Theory of Craving was developed after findings that dopamine levels increase before a reward (like sex, food or drugs).

How did we discover this? you might ask. Well, there are several different ways of measuring dopamine levels in vivo. These include in vivo microdialysis and in vivo chronoamperometry. In in vivo microdialysis, a very small dialysis membrane is inserted into a brain region. Artificial CSF is passed through, and chemicals diffuse into this liquid. This method has very good chemical resolution (i.e. it's very accurate at saying which chemical is what) but poor temporal resolution (i.e. you only get results a little while after the action- in this case, it takes minutes). In vivo chronoamperometry involves insertion of an electrode into the brain, and an electrical signal is measured when current is passed through at the same oxidation potential of a specific chemical. Chemical resolution for this method is poor, but temporal resolution is only seconds.

In vivo microdialysis came earlier, and since its temporal resolution is so poor, it made it seem like dopamine levels went up with drug administration, supporting the positive reinforcement theory. Chronoamperometry, however, found that dopamine went up before drug administration, and down right after they get the drug. Therefore, we have to distinguish between wanting something and liking something once you have it.

It turns out that dopamine is important for wanting, but not for liking. MOR receptors (mu opioid receptors) are important for liking whereas KOR receptors are aversive. Interestingly enough, MOR receptors also increased dopamine release, whereas KOR receptors decrease it. It is also important to note that while wanting can be sensitised (i.e. the more you get, the more you want), liking is desensitised (i.e. you get sick of things over time). Also, just as an aside, you're probably wondering how they measure "liking." The answer, for now, is mainly body language: animals make different faces depending on whether they like or dislike something. Also, rats make 50 000Hz vocalisations when they like something. Fun facts!

And that concludes my last post for PHAR3303! Good luck everyone!