Hello. Welcome back to drugs and the brain at Caltech and Coursera.

This is Henry Lester at Caltech and, just to prove it, here is my Cal-tech pocket protector. and I'll just stick it right back here in my pocket for the rest of today's session. And it will be there most times, most days. We're going to talk mostly about diseases in this brief introductory module. Reminder that there will be no assessments after this module, but from the next one on there will be assessments. The first topic is, that drugs act on transporters. In particular, neurotransmitter transporters. Two often used classes of drugs these days, are first of all drugs that act on the sodium coupled citoplasma membrane or cell membrane: serotonin transporters. Drugs that act on the serotonin transporters are both drugs of therapy and of abuse, the therapeutic drugs or the serotonin selective reuptake inhibitors or SSRI's. They are antidepressants, and they have trademarks that we are all, familiar with. And they block the uptake of serotonin, mostly into presynaptic nerve endings. Another class of neurotransmitter transporter blockers, also have uses both in therapy and in abuse. These are the Dopamine transporter blockers. Here is Dopamine. These transporters are also expressed on pre synaptic nerve terminals. They are also sodium coupled. They have trademarks that are familiar to us and there are other drugs that work on these Dopamine transporters that are drugs of abuse,such as Cocaine and Amphetamine. this will put us in a position to understand all of the major classes of recreational drugs. Now the recreational drugs are not necessarily drugs of abuse. a very familiar recreational drug is caffeine, and I may be partaking of this recreational drug from time to time during our course. I'll have a little sip now. in addition we'll be talking about LSD, morphine and heroin, tetrahydrocannabinol, THC, cocaine, PCP or phencyclidine and of course nicotine, the topic of my research. So this will be our constellation of recreational drugs and we'll spend a couple of modules talking about how they work on each of their target molecules : their receptors. We'll move to the topic of drug dependence or addiction, and we will use those terms more or less independently. We'll talk about the major components of addiction

and dependence. First tolerance and then dependence, and goal seeking behavior. Tolerance means that an organism becomes less sensi tive to the drug as time goes on, and dependence means that an organism cannot function normally without that drug, and goal seeking behavior means that the organism tries to get that drug. we'll discuss the metabolic and cellular mechanisms of tolerance. again using as an example nicotine addiction we will talk about the various components of an addiction. The fact for instance that nicotine gives a sense of well being but also some nicotine addicts believe that they think better when they smoke and that's called cognitive sensitization. Some people smoke for stress relief, some people smoke because they are fairly sure that if they stop smoking, they're going to gain ten to fifteen pounds in the first year. And some people smoke and get nicotine in order to self-medicate. So the question becomes in every case of drug abuse and dependence : what are the changes in the brain during chronic exposure to that drug? And we'll try to address some of those questions during this course. in order to address these questions we have to go all the way from genes, through gene expression RNA, through proteins, through the differences between the exogenous drugs (the ones that come from outside) versus the indigenous (the natural neurotransmitters), how the drugs bind to their receptors, the intercellular events that occur after drugs bind repeatedly, for days or weeks. Effects on neurons. Effects on the junction between neurons, the synapses. Effects on circuits of neurons and finally effects on behavior. so this is a complex topic. We'll t ry to touch upon all of these topics during the course. in particular we'll talk about how activation of a G Protein coupled pathway for prolonged periods of time, can lead to changes at the level of genes and how this can be hijacked by nicotine receptors and by other receptors, that can introduce intra-cellular messengers on their own. This is thought to be a major component of drug addiction. So here is a graph, schematic, of a pathway of the sort I just told you about. Nicotine receptors leading to intra-cellular transmitters, and leading to gene activation. Now the course is not going to emphasize nicotine addiction to the extent that this introduction does, but it's a convenient

way of tying the introduction together. So then, we will be in a position to talk about drugs for neural diseases and a classical drug in that respect in use for just about 40 years now is L-dopa or levodopa. And we'll discuss how levodopa gets converted by an enzyme. An enzyme is a protein that's a catalyst from the Greek, to leaven, as in, and the enzyme that levels bread from yeast. We'll talk about how this enzyme converts L-dopa to dopamine itself. L-dopa does enter the brain but dopamine does not. And so this will give us an opportunity to re-emphasize the important aspects of blood brain barrier, and drug entry into the brain. indeed parkinson's disease, which is treated with L-Dopa, will be an example for neuro-degeneration, and we'll talk about that more than we talk about Alzheimers, or ALS. Parkinson's disease involves degeneration of neurons that make dopamine in a particular region of the brain, the Substantia Nigra. We'll then move on to drugs for psychiatric diseases. We'll treat them as chemicals. We'll talk about their permeation through membranes and of course their targets. A major question for psychiatric drugs is what happens during the two to three weeks that it takes between the time a person starts taking a psychiatric drug and the time he feels completely better. This is a topic that is of great interest to me in my present research and to all psychiatric researchers as well. The answers are not known. An exception is the novel antidepressant ketamine, called on the street Special K. Ketamine exerts it's antidepressant effects within about two hours. However, when used at higher doses, Ketamine also causes hallucinations, and many other kinds of unpleasant behavior, so, this is an active field of research for drug companies. Another classical by now anti-depressant, is fluoxetine, also known as prozac. This one is one of the psychiatric drugs that takes two to three weeks to act. We'll also talk about the anti-psychotic drugs, those that are used primarily for schizophrenia as well as for bi-polar disease. We'll discuss the classical anti-psychotic drug chlorpromazine. And its benefits and its side effects and some newer classes of psychotic drugs. The so called atypical antipsychotics such as clozapine whose trademark is clozaril. And of course we'll be coming back to nicotine from time to time too which is used by

schizophrenics to self medicate. A good example of a patient with probable bipolar disease was the painter van Gogh who had a meteoric unfortunately short career and at the end of that career, he did kill himself. So, this will be our exemplar bipolar patient. And one of our exemplar schizophrenia cases will be David Helfgott, the subject of the movie "Shine", the great pianist, we'll talk about his life and about his psychotic episodes, all based on the book by his wife, and we'll discuss the medications that he now takes, again, according to the biography by his wife. We may also have the chance to talk about another famous psychiatric patient John Nash, who was the topic of the movie "A beautiful mind". Then, toward the end of the course we're going to come back to this mystery about what happens during the two to three weeks that constitute the therapeutic lag: the time that a patient takes before he feels completely better. We'll talk about the fact that contemporary ideas about psychiatric drugs emphasized binding to classical targets, but that an idea that I'm very fond of called 'inside-out drug action', emphasizes binding to the same targets but actually within the cell, in the endoplasmic reticulum, and the Golgi's system. Then we'll turn to this interesting topic of developing new drugs for the brain. And we'll talk about Eroom's law, note that Eroom is moore spelled backwards. Moore's law applies to semiconductors and to computers, and Moore's law basically says that it gets cheaper by a factor of two every eighteen months, a factor of ten every five years, to do data processing. Well just the opposite applies to drugs these days, and has applied to drugs for the last sixty years. You can develop fewer and fewer drugs per billion dollars spent on R&D spending. This is a particular problem with neural drugs. We'll talk about the prospects for changing this process, and perhaps one of you students, as a result of this course, will be motivated to. Get a new idea that changes the course of Eroom's Law. So, I'll just remind you to look at the disclosures on the course web page and the disclaimer about medical advice and, next time we'll talk about what is a drug. Thank you so much.