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What’s Up-The Neurobiology of Learning and Adolescent Substance Abuse

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1 What’s Up-The Neurobiology of Learning and Adolescent Substance Abuse
Merrill Norton Pharm.D.,D. Ph., NCAC II, CCS Clinical Associate Professor University of Georgia College of Pharmacy Athens,Georgia 30602

2 Neurobiology and Behavior
How are human behaviors and neurobiology related? Neurobiology and Behavior

3 Learning “...relatively permanent changes in behavior produced by experience” Learning involves changes in the nervous system produced by experiences Nervous system changes are physical Learning allows us to adapt our behaviors to the environment Learning involves interactions among the motor, sensory, and memory systems 14.3

4 Forms of Learning Perceptual learning functions to identify objects and situations Stimulus-Response learning involves making a response when a particular stimulus is present Classical conditioning Operant Conditioning Motor learning involves forming new circuits in motor system Relational learning involves identifying connections between stimuli 14.4

5 Overview of Learning 14.5 Dualism-mind is separate from the body
Descartes believed that the pineal body directed fluid from the ventricles into the holow fibers we call nerves-this induced muscle action. The pineal gland is where the soul controls the physical body Monism: the belief that the mind is the working of the body (no need for a separate soul. Determinism-the notion that mental states are produced by physical mechanisms. Reductionists-we break complex phenomena into less complicated sytems. 14.5

6 Relational Learning Relational learning involves connections between individual stimuli Examples of relational learning include Forming an association between the image of an object and the sounds of that object Knowing the content of a space and the relationship between the objects in that space (spatial learning) Remembering sequences of events (episodic learning) Viewing and recalling the actions of another person (observational learning) Dualism-mind is separate from the body Descartes believed that the pineal body directed fluid from the ventricles into the holow fibers we call nerves-this induced muscle action. The pineal gland is where the soul controls the physical body Monism: the belief that the mind is the working of the body (no need for a separate soul. Determinism-the notion that mental states are produced by physical mechanisms. Reductionists-we break complex phenomena into less complicated sytems. 14.6

7 The Hebb Rule Donald Hebb argued that synapses that are active at the same time that the postsynaptic neuron fires, are strengthened over time Implies that repeated neural activity will produce physical changes in the nervous system Rats exposed to enriched environments exhibit neural changes: Thicker cortex More glial cells More Acetylcholine(Long term Memory) 14.7

8 Thoughts, Feelings, and Behavior
Neurobiological Foundations of Mental Health and Illness (Modified from Andreasen and Black, 2001) Thoughts, Feelings, and Behavior Mind/Brain Systems (mental/cognitive systems such as emotion or language, chemical systems such as dopamine or serotonin). Circuits Cells Membranes Molecules Genes


10 Limbic Cortex and Hypothalamus

11 Forebrain Brain CEO: Frontal Cortex Planning Attention Judgment
Reflection Prioritizing Self control Strategizing Sequencing Anticipation Organization Impulse control Second thought Working memory Modulating mood Response flexibility Goal-directed behavior Foresee consequences Forebrain

12 anterior cingulate gyrus
The “Oops” Center– anterior cingulate gyrus The cingulate is responsible for helping focus attention Links cingulate and emotional hippocampus for integrating reason & emotion to guide decisions May involve ability to empathize Undergoes high myelination (doubles) during adolescence “Oops center” anticipates risk, detects and keeps us from making errors

13 Myelin Development

14 Developmental Model of Psychopathology
6 MOS Autism Schizoid Reactive Attachment Separation Anxiety ODD Conduct Disorder Tourettes PDD Mental Retardation Anxiety Eating Disorder Schizophrenia Depression Abuse/ Dependence Eating Disorder Identity Abuse/ Dependence ODD ADHD Separation Anxiety Overanxious Conduct Disorder Abuse/ Dependence


16 Mood Chart of the Human Brain
Homeostasis Mania Euphoria Normal Sadness Depression

17 How Drugs Work - Feel Good – Euphoria/reward
Interact with neurochemistry Results: - Feel Good – Euphoria/reward - Feel Better – Reduce negative feelings Slide Source: Steve Hanson, MSEd, Director, John L. Norris ATC, New York State Office of Alcoholism and Substance Abuse Services

18 Dopamine Spells REWARD
Release Recycle SLIDE ANIMATION NOTE: Slide initially loads without wording on the image. At approximately one-second intervals, the words “release,” “activate,” and “recycle” appear onscreen. You may wish to coordinate a brief introductory overview explanation with the animation and then expand on the explanation after the slide is complete. FACULTY NOTE: (from NIDA teaching instructions – you may use this narrative text as a guide, but it does not need to be repeated word for word) Explain that drugs concentrate in areas of the brain that are rich in dopamine synapses. Review dopamine transmission in the nucleus accumbens. Point to dopamine in the synapse and to dopamine bound to dopamine receptors and to uptake pumps on the terminal. When drugs (cocaine is the drug in this example) are present in the synapse, they (represented in turquoise) bind to the uptake pumps and prevent them from removing dopamine from the synapse. This results in more dopamine in the synapse, and more dopamine receptors are activated. This causes many changes inside the cell that lead to abnormal firing patterns. As a result, there are increased impulses leaving the nucleus accumbens to activate the reward system. With continued use of drugs (cocaine), the body relies on the drug to maintain rewarding feelings. The person is no longer able to feel the positive reinforcement or pleasurable feelings of natural rewards. Source: National Institute on Drug Abuse (NIDA) Teaching Packet No. 1: “The Brain & the Actions of Cocaine, Opiates, and Marijuana Activate

19 What memories do you associate with this image?
visual colour shape smell language taste emotions auditory

20 Basal Ganglia- “The Secretary”

21 Limbic System- “The Driver”

22 Brain Development/Aging
Recent research(imaging studies) have given scientists an estimate of brain chemistry development: Age % complete (pre-puberty) Age % complete(post puberty) Age % complete Age % Age %

23 Addiction Risk Factors
Genetics Young Age of Onset Childhood Trauma (violent, sexual) Learning Disorders (ADD/ADHD) Mental Illness Depression Bipolar Disorder Psychosis Slide Source: “Alcohol and Other Drugs and the Courts” curriculum, Judge Peggy Fulton Hora, Alameda County Superior Court, Hayward, CA and Peter Banys, M.D., Assoc. Clinical Prof. of Psychiatry, University of California at San Francisco, VA Medical Center, San Francisco.




27 Personality & Perception
NORMAL BRAIN “Rational Animals Thinking Brain 1 Cortex Planning Inhibitions Sensorium Midbrain Personality & Perception 2 Diagam_Brain Normal C. Diagam_Brain Normal C. Diagam_Brain Normal C. 3 HICC Hypothalamic Instinctual Control Centers 6 F’S Food Intake Feelings Fluid Intake Fight Flirtations Flight NORMAL BRAIN FUNCTIONS Diagam_Brain Normal C.

28 “The Necessary Nine” Norepinephrine/Epinephrine-stimulant,anger,fear,anxiety,fight,flight Serotonin-depressant,sleep,calm,pleasure GABA-relaxant,stress reduction,seizure threshold Endorphins-pain relief,pleasure Acetylcholine-involutary actions,memory,motivation Anandamide-memory,new learning,calmness Glutamate-organization of brain signaling,memory,pain Dopamine-perception,movement,pleasure PIP- loving of one’s self,others,GOD


30 norepinephrine GABA serotonin cannabinoid opiate NMDA acetylcholine
Alcohol Benzodiazepines Valium Xanax Ativan Non benzodiazepine Ambien Sonata Barbiturates Fiorinal Soma Cocaine Amphetamine Methamphetamine Ephedrine Ritalin LSD Psilocibin DMT Ibogaine Marijuana opiate NMDA acetylcholine Ecstasy Mescaline DOM Opioids Opiates Heroin Buprenex Oxycontin PCP Ketamine Nicotine GHB

31 “It makes me feel goooood”
“I want a beer” Thinking Brain Judgment Brain Instinctual Brain “It makes me feel goooood” Pleasure Brain “Miller Lite”

32 Neurotransmitters of Dependence
Recovery PIP Dopamine Glutamate Acetylcholine Anandamide Endorphins / Enkelphins GABA Serotonin Epinephrine / Norepinephrine Depletion may take less than 12 months Replenishment may take 5 to 7 years

33 Alcohol and the Adolescent Brain

34 SPECT SCANS Cocaine 2 yrs Alcohol 25 yrs Normal Marijuana 12 yrs


36 The Hijacking of the Brain and the HPA Axis
Cortisol Exercise,Food,Psychoactive Chemicals Endorphins

37 Psychoactive Chemicals
Alcohol Ecstasy/Methamphetamine Marijuana

38 Alcohol as a Reinforcer: Neural Systems
The Secretary The Driver Alcohol and a reinforcer: Neural Systems There has been considerable research into understanding the neural circuits involved in reinforcement. This is the dopamine (DA) system. The DA system originates in the ventral tegmental area (VTA) and connects to the nucleus accumbens, prefrontal cortex as well as hippocampus. This is the mesocorticolimbic system. Activation of the VTA results in the release of DA in the nucleus accumbens and limbic system and the prefrontal cortex. This is associated with rewarding/reinforcing effects, not only for alcohol but for almost all abused drugs. Activation of mesocorticolimbic system

39 Methamphetamine

40 Methamphetamine


42 Before and After


44 Slide 10: Serotonin Transporters
Serotonin (in pink) is present in the synaptic space only for a limited amount of time. If it is not bound to the serotonin receptor, serotonin is removed from the synaptic space via special proteins called transporters (in green). The serotonin transporters are proteins located on the serotonin neuron terminals and they are in a unique position to transport serotonin from the synaptic space back into the neuron where it can be metabolized by enzymes. Explain to your students that the serotonin transporters are the primary targets for Ecstasy.

45 Slide 11: Ecstasy and Serotonin Transporters
When Ecstasy binds to the serotonin transporters, more serotonin ends up in the synaptic space. This occurs for two reasons. First, Ecstasy can prevent the transporters from carrying serotonin back into the terminal. Second, Ecstasy can cause the transporters to work in reverse mode-- they actually bring serotonin from the terminal into the synaptic space. So, more serotonin is present in the synaptic space and more serotonin receptors become activated. This is the major short-term effect of Ecstasy that alters brain chemistry. While the serotonin system is the primary target for Ecstasy, Ecstasy has similar effects on the dopamine (another neurotranmsitter) system as well. Ecstasy can inhibit dopamine transporters and cause an increase in dopamine levels in the synaptic space (not shown here). To help students understand how the alteration in brain chemistry results in psychological changes, go to the next slide.

46 Slide 18: Long-term Effects in Monkeys
The loss of serotonin transporters, along with a decrease in serotonin, suggest that the serotonin neurons are damaged. While it is not possible to detect this directly in the brains of living humans, animal studies have revealed that this is the case. A very important experiment was performed in monkeys to determine if Ecstasy can actually damage neurons. Monkeys were given Ecstasy twice a day for 4 days (control monkeys were given saline). One group of monkeys’ brains were removed 2 weeks later for analysis and another group of monkeys lived for an additional 7 years before their brains were removed. Scientists examined the brains for the presence of serotonin. This slide shows the presence of serotonin in neurons of the neocortex from 3 typical monkeys. On the left, the monkey who did not receive any Ecstasy had a lot of serotonin (in pink) in the neocortex. Two weeks after a monkey received Ecstasy, most of the serotonin was gone (point to the middle panel), suggesting that the serotonin neuron terminals were destroyed (there was no destruction of the serotonin cell bodies arising back in the brainstem). Point to the right hand panel and show students that this damage appeared to be long-term because 7 years later there was some recovery, but it was not complete (in fact, the pattern of regrowth of serotonin terminals was abnormal - point out one of the areas where the pink lines are running sideways). Scientists found similar changes in limbic areas of the brain such as the hippocampus and amygdala. The monkey experiments are an important reminder that humans may suffer the same fate, although this still remains to be demonstrated. Tell the students how difficult it is to do this same kind of experiment in humans because it requires removing pieces of the brain to look for the loss of the serotonin neurons. Image courtesy of Dr. GA Ricaurte, Johns Hopkins University School of Medicine.

47 Slide 19: Ecstasy Causes Destruction of Serotonin Nerve Terminals
This slide illustrates the degeneration of serotonin nerve terminals after long-term or repeated use of Ecstasy (you can refer back to slide 9 to compare this degenerating terminal to a healthy terminal). Remind students that we have several pieces of evidence that support this effect of Ecstasy. Ecstasy users have lost serotonin, serotonin metabolites and serotonin transporters on serotonin neuron terminals. In contrast, the serotonin cell bodies are still intact but the genetic instructions from the nucleus for any regrowth of terminals may be abnormal Scientists have made a great deal of progress in understanding how Ecstasy might actually damage the serotonin terminals. The damage involves the production of oxygen radicals (unstable forms of oxygen), which are very destructive to proteins, lipids and DNA. The rich supply of mitochondria (which are a major source of oxygen radical formation) found in the terminals may cause the terminals to be especially sensitive to drugs like Ecstasy






53 Is Marijuana Addicting?


55 The Brain’s Marijuana Receptor Sites
                                                   The “Secretary” “Fight or Flight” Coordination

56 Brain Cannabinoid Receptors
Basal Ganglia Unconscious muscle movements Limbic System Hippocampus Short term memory processed into long term memory Amygdala Controls rage, lust, fear and other strong emotions Cerebellum Balance and planning of movement

57 Anandamide Sanskrit ananda means “bliss”
Chemical messenger involved in mood, memory, pain perception and appetite Natural molecular key THC fits same receptor Anandamide is fragile and breaks down quickly No intense high like THC Chocolate

58 MJ use Lowers Glucose Metabolism in Frontal and Temporal Lobes
Temporal Gyri P. hipp. Medial OFC Superior Middle Inferior

59 Marijuana Makes People Stupid…
and they stay stupid..

60 Multiple Neurotransmitter Receptor Sites For Marijuana
Anandamide Dopamine GABA Glutamate

61 The Blood-Brain Barrier
THC Binds To Glial Cells of BBB

62 The learned helplessness that results from exposure to the absence of control generalizes to other situations. Marijuana creates the state of learned helplessness.

Drug Addiction: A Complex Illness Drug addiction is a complex illness. The path to drug addiction begins with the act of taking drugs. Over time, a person’s ability to choose not to take drugs is compromised. This in large part is a result of the effects of prolonged drug use on brain functioning, and thus on behavior. Addiction, therefore, is characterized by compulsive, drug craving, seeking, and use that persists even in the face of negative consequences.

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