Sex, Drugs, and the Brain

1. Sex, Drugs, and the Brain A chemical journey through pain and pleasure

2. Evolution of the Limbic System Africanus had a brain about 1/3 the size of our modern brain Africanus was primarily instinctive in behavior Africanus was not capable of language Africanus had practically no prefrontal cortex and was probably not capable of weighing options Yet, deep inside our brain is the brain of Africanus. Our limbic system has not changed greatly in 2 million years. Australophithecus Africanus

3. The Limbic System Ventricle

4. The Neuron

5. Photographs of Real Neurons dendrite axon

6. The Synapse terminal button of neuron 1 presynaptic neuron 0.2 mm dendrite of neuron 2 postsynaptic neuron

7. Neurons Communicate through Chemical Messengers neurotransmitter neurotransmitter receptor

8. Monoamine Neurotransmitters • Common Features • phenol or catachol ring • 2-carbon aliphatic amine chain • Destroyed by MAO dopamine norepinephrine serotonin adrenaline

9. Biosynthesis of Dopamine and Norepinephrine tyrosine L-DOPA norepinephrine dopamine

10. Neurotransmitters are Carefully Regulated * Simultaneous formation and destruction affords careful regulation of neurotransmitter levels in brain biosynthesis * * MAO 3,4-dihydroxyphenylacetic acid

11. Dopamine Pathways The mesolimbic pathway aka the “pleasure center” The mesolimbic pathway is your reward system for behavior that needs to be reinforced (eating, seeking warmth or shelter, sex, winning a fight, etc.) septum

12. Methamphetamine Action

13. Cocaine Action

14. Heroin Action

15. Septum is Focal Point for Pleasure Dr. Robert Heath Dr. James Olds Stimulation of the septum produces intense pleasure

16. Molecular Design by Analogues azobenzene

17. Natural Neurotransmitter Analogues Psilocybe Mexacana cacao nutmeg Peyote cactus Yopo tree Ergot fungus

18. Naturally Occurring Dopamine Analogues mescaline (from Peyote cactus) dopamine (from brain) cathanone (from Kat) phenylethylamine (from chocolate) ephedrine (from Ephedra)

19. Synthetic Dopamine Analogues amphetamine (goofballs) methamphetamine (speed, crystal meth, crank) methylenedioxoamphetamine (MDA) methylenedioxomethamphetamine (MDMA, XTC, love drug, E)

20. Natural Serotonin Analogues Yopo from a Peruvian tree psilocybin from Psilocybe Mexicana (Magic Mushroom) serotonin from brain lysergic acid psilocin from Ergot fungus from Magic Mushroom

21. Synthetic Serotonin Analogues diethyltryptamine(DET) lysergic acid diethylamide(LSD, acid) dimethyltryptamine(DMT)

22. Pioneers of Neurotransmitter Analogues Dr. Albert Hoffman Dr. Alexander Shulgin

23. Harvard University Psilocybin Research Project Dr. Timothy Leary Aldous Huxley Prof. Richard Alpert Two year study of the effects of psilocybin analogs on the scholarly creativity of students

24. Molecular Design of Dopamine Antagonist by QSAR Used with permission from Wyeth-Ayerst Laboratories, 2005

25. Practical Uses of Neurotransmitter Analogues L-DOPA (Parkinson’s) Tigan (antischizophrenic) Clozapine (antipsychotic) Haloperidol (antipsychotic)

26. The Remote-Controlled Cockroach This cockroach has an electrode array implanted in its brain, and can be steered by radio control From Northwestern University, Chicago, IL

27. Sex and Love are Different nucleus accumbens Think about sex Think about love prefrontal cortex

28. Addicted to Love (quite literally!) Dr. Helen Fisher Rutgers University Dr. Sue Carter University of Illinois Dr. Karen Bales University of California These researchers study the role of neuropeptides in pair-bonding (romantic love)

29. What We Learned from the Prairie Vole Prairie vole is a monogamous species. That is, it finds a mate and stays together for life Its close cousin, the Montane vole, is non-monogamous. It never mates with the same partner twice Yet, the Prairie vole and Montane vole have essentially the same brain. So, what causes this dramatic behavioral difference?

30. Two Important Neuropeptides different by only two amino acid residues

31. Effects of Oxytocin on Behavior Injecting oxytocin into a Montane vole will cause it to temporarily act like a Prairie vole Injecting a Prairie vole with an oxytocin blocker will cause it to temporarily act like a Montane vole In humans, oxytocin levels increase when we are in love, increase when we simply touch our pets, and, in women, increase dramatically just after childbirth Hypothesis: Could oxytocin be the molecule of love?

32. Might as Well Face it, You’re Addicted to Love … Robert Palmer, 1995 Love high endorphin levels High serotonin levels Low dopamine Low testosterone Heartbreak Low endorphin levels Sudden drop in serotonin Low dopamine Low testosterone Drug addiction High endorphin levels High serotonin levels Low dopamine Low testosterone Drug withdrawal Low endorphin levels Sudden drop in serotonin Low dopamine Low testosterone

33. The Chemistry of “Chemistry” A play in three acts

34. Meet the Players norepinephrine aka Mr. Excitement oxytocinaka Cuddles dopamine aka Mr. Desire vasopressinaka Mother Superior serotonin aka Mr. Happy testosteroneaka Sarge

35. Act 1: Strangers in the Night Scene 1: Testosterone elevates in the blood, signals the body to physically respond, and influences the decision making areas of the brain to “go for it” Scene 2: Sensory information enters the brainstem triggering the release of dopamine in the ventral tegmentum Scene 3: The ventral tegmentum fires a series of signals into the limbic system via the mesolimbic dopamine pathway Scene 4: Norepinephrine elevates in the limbic system signaling the onset of pleasure. The hypothalamus and pituitary convert norepinephrine into adrenaline triggering a “fight or flight” response, resulting in emotional excitement

36. The Mesolimbic Dopamine Pathway Scene 5: dopamine signals enter the septum, the main focal point of the “pleasure center” Scene 6: dopamine signals reach the nucleus accumbens, reinforcing this behavior Scene 7: dopamine signals make it to the prefrontal cortex, the decision making headquarters Scene 8: the prefrontal cortex now makes a series of decisions, weighing options and consequences, and simultaneously stimulates the septum, nucleus accumbens, and amygdala

37. Act 2: Now it gets Complicated Enter stage left: Oxytocin and Vasopressin As our lovers become increasingly enchanted with each others charms, the hypothalamus perks up and manufactures two neuropeptides, oxytocin (aka cuddles) and vasopressin (aka mother superior), and releases both of them into the cerebrospinal fluid. There they have full access to all the organs of the limbic system Scene 9: Oxytocin binds to hippocampus, allowing the lovers to remember each other Scene 10: Vasopressin binds to septum, dulling reward, and binds to amygdala causing warning signals, fear, and inhibition of attachment Scene 11: Oxytocin binds to nucleus accumbens, causing memory of “pleasure” to associate with this particular person

38. Pair-bond? Yes or no? Scene 12: The prefrontal cortex takes all sensory inputs, inputs from hippocampus, and inputs from memory, and goes into high gear to make decisions. These decisions are conveyed back to the limbic system as signals to the cingulate (“happy” vs. “unhappy”), amygdala (fear or threat of impending loss), septum (pleasure), and nucleus accumbens (habituation). Scene 13: In the meantime, “cuddles” and “mother superior” are battling it out. If cuddles wins, you’re in love. If mother superior wins, you’re just having fun. Scene 14: Oxytocin (cuddles) wins – you’re in love! and all this happens in just 4 minutes

39. The Script The scene takes place in the limbic system of a young man sitting with his date at the Underground Pub at York University on a Saturday night. There is no shortage of young women dancing a few feet away. Testosterone: Look at that one. No, look at that one. No, look at that one. Dopamine: Boy o boy o boy, is this gonna be fun or what? Vasopressin: Don’t look at other girls, you’ll die Testosterone: What’s a matter with you, yella? Reach over and hold her hand Vasopressin: Don’t touch her hand, you’ll die Oxytocin: Oh let’s hold hands all night and stare in her eyes, and hug Testosterone: Hug, shmug! What a waste of time. Go for the gusto soldier! Vasopressin: Stop! Do that and you’ll die Testosterone: Oh, don’t listen to that you’ll do nothing. Go for the gusto soldier! Oxytocin: I need a hug Dopamine: Boy o boy, is this gonna be fun or what? Vasopressin: If you listen to Sarge, you’ll die

40. Intermission All seems good with our lovers, BUT ….. Something nasty is happening in our lovers’ brains!! All this limbic activity is dropping serotonin level fast and hard Exit Stage Right

41. New Love is a Psychosis Within days, serotonin drops to levels mimicking that found in patients with obsessive-compulsive disorder When our lovers are separated they literally obsess over each other.

42. Act 3: Oxytocin to the Rescue Oxytocin acts as a serotonin reuptake inhibitor (naturally occurring Prozac). In about 6 months, serotonin is back to normal Enter stage left - Serotonin

43. THE END DISCLAIMER: As serotonin levels build, physical attraction between our lovers wanes. High oxytocin levels also inhibit the action of vasopressin and testosterone, further diminishing excitement in the relationship. This begins at about 17 months. There is about a 50% chance the relationship will end in roughly 4 years.

44. Acknowledgements York University Department of Chemistry Dr. Gillian Wu, Dean of Science and Engineering Science Speakers Bureau You

45. Proximity of amygdala and nucleus accumbens Nucleus accumbens amygdala

46. The Bonobo Chimpanzee Dr. Susan Block The Bonobo is a hominid and is our closest genetic relative sharing 99.7% of our genes

48. Pheromones DEET (alarm pheromone for ticks, fleas, mosquitoes) Hamsters (sex attractant) Cockroach (sex attractant) Gypsy moth (male sex attractant)

49. Truffles and Sex • Truffles have historically been used to “impress” a female date • Truffles are very expensive and are a sign of power and wealth • Consequently it had been assumed that the “power of the truffle” was due to it’s symbolism for wealth • HOWEVER …. It may be more complicated!

50. Truffles and Pigs Truffles are mushrooms that grow underground Female pigs can smell truffles over 1 meter underground. Sometimes they dig so ferociously that they have to be physically restrained.