Neuroscience1202 (Module 3) - Lectures 12-17 - weeks 6-10 - w/ kim hellemans PDF

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Addiction - Lecture 12Drug and Drug AddictionReward & Pleasure The term reward refers to stimuli that are in some way desirable or positive and can affect behaviour. - Examples: food, money, drugs. Humans, like other animals, naturally find certain activities to be rewarding. This is with good r...

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Addiction - Lecture 12 Drug and Drug Addiction Reward & Pleasure • The term reward refers to stimuli that are in some way desirable or positive and can affect behaviour. – Examples: food, money, drugs. • Humans, like other animals, naturally find certain activities to be rewarding. This is with good reason, as rewarding activities are usually critical to survival. – Examples: eating, sleeping, sex, exercise, etc., • Rewarding stimuli can be different depending on an individual’s personal experience. Therefore, we learn to value more than just what we’re born liking. – The ability to learn new rewards is also valuable, because it teaches us to repeat successful behaviours.

Discovery of the Reward System • Olds and Milner (1954) discovered the phenomenon of intracranial self-stimulation (ICSS) more or less by accident. • In the first ICSS experiment, a rat was fitted with an electrode located in a certain part of his brain. • This electrode was connected to a stimulator that was controlled by a lever in the rat’s cage. • The rat could therefore self-stimulate that part of his brain. • Rats would press the lever thousands of times an hour, ignoring everything else that the experimenters could offer. – Rats would ignore food, water, access to a sexually receptive female, and whatever other rat treats the experimenters could think of. • The rats would eventually collapse from exhaustion or else be forcibly removed from the experimental cage. • To researchers, this sort of behaviour closely resembled the behaviour of human drug addiction – They reasoned that the brain areas targeted by the electrodes must therefore be involved in drug addiction.

The Reward System • The discovery of ICSS ushered in a new era in the study of addiction, because it revealed a circuit in the brain that is responsible for rewarding behaviours and the accompanying sensations of pleasure.! • The official name for this circuit is the mesocorticolimbic dopamine system, but sometimes it is called the reward system for short. ! • The anatomy of this system is hinted at by its name. It begins with a structure in the midbrain called the ventral tegmental area (VTA). Neurons in the VTA project axons to regions in the limbic system and cortex.! • Dopamine is the main neurotransmitter used in this system."

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Ventral tegmental area (VTA)! –

Contains neurons that produce dopamine. Axons from these neurons project to the:

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Hippocampus (Hipp)!

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Nucleus Accumbens (NAc)!

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Prefrontal Cortex (PFC)

The mesocorticolimbic dopamine system •

Every addictive drug affects this system in some way. – Addictive drugs increase dopamine release in the Nucleus Accumbens (NAc).

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The purpose of dopamine release in the NAc seems to be a “teaching signal”. – This is related to the expectation and experience of a rewarding stimulus. – Unexpected rewards lead to especially large dopamine release.

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Together with the PFC and Hippocampus, this system allows for the experience of reward, as well as the learning needed to go after it again. – In this case of natural, healthy rewarding stimuli, this system is quite useful. ON DRUGS, In general, addictive drugs lead to supra-physiological dopamine. In other words, a dopamine release that is much larger than what would normally be seen with naturally occurring rewards."

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How Do We Diagnose “Addiction”? What Is Addiction? •

Addiction is a state of uncontrolled drug use that persists in spite of negative consequences associated with taking or procuring that drug – Negative consequences include: health effects, cost, family disruption, loss of (legal) employment, etc.

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Addiction develops over multiple exposures to addictive drugs. Users progress from least harmful (recreational) use to most harmful (daily/binge use) – Addiction is not an inevitable consequence of trying a drug, but repeated drug use does raise the risk of addiction.

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Individuals with addiction are not weak or foolish. Addiction is very powerful.

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The definition of addiction remains controversial. – Addiction is *not* a diagnostic term

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DSM-5 now uses term “Substance Use Disorder”, and also includes behavioural addictions, diagnosed under “Addictive Disorders”.

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According to the DSM, patients must show 2 or more of 11 listed behavioural criteria (within the past year), including: 1. Using in spite of adverse consequences 2. Preoccupation with obtaining the drug 3. Great deal of time spent trying to get the drug 4. Craving 5. Use results in failure to fulfill major role obligations 6. Tolerance 7. Withdrawal

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Like other disorders, individuals are scored on a spectrum, from mild, moderate to severe substance use disorder

Drug Withdrawal • •

Acute and protracted drug use leads to drug withdrawal" Behavioural and physiological symptoms that occur upon cessation of drug use" – Opposite to drug effects; compensation for drug effects on body" – Severity may change with characteristics of the user, history of drug use" • E.g., a hangover" • Muscle aches and cramps, anxiety attacks, sweating, nausea, convulsions, death

Drug Tolerance •

Increased amount of a drug needed to achieve intoxication, or a diminished drug effect with continued drug use of the same amount of a drug – Can become tolerant to some aspects of a drug, but not to others • e.g., Alcohol: Tolerance to intoxicating effects achieved faster than tolerance to motor (cataleptic) effects – Can have very high blood levels of drug and not appear intoxicated

Addiction: A Definition • “A syndrome at the centre of which is loss of control over a reward-seeking behaviour” – Robert West, Theory of Addiction

The Mesocorticolimbic Dopamine System on Drugs • By over-stimulating the mesocorticolimbic dopamine system, addictive drugs hijack our brain’s reward system. " • Because of this, the brain begins to over-prioritize behaviours and stimuli it has associated with drugs." • In this way, the life of the drug addict quickly spins out of control, as the normal, healthy behaviours regulated by the reward system fall by the wayside."

Each drug also acts on various other neurotransmitter systems to produce the unique effects of that drug.

Cannabis Addiction - Lecture 13 Cannabis • • • •

Most commonly used illegal drug in the world Most controversial Comes from the cannabis sativa and cannabis indica plant Over 100 cannabinoids known – Most common is Δ-9- tetrahydrocannabinol (Δ9-THC) • Main psychoactive ingredient; responsible for the “high” associated with use – Also contains cannabidiol (CBD) • Also psychoactive, not intoxicant

Cannabis Administration • Inhalation (smoking)" – ~ 50% enters lungs, almost all of that enters body" – Reaches brain in about 30 sec., peaks ~ 30–60 min., lasts 3–4 hours; subjective state for 12 hours" – Vaping – peak concentrations occur 10 min after administration" • Distributed everywhere; likes to stay in fatty tissue" • Oral (eating), aka “edibles”% - Absorbed from gut slowly; absorption improved by adding oil (e.g., baking) - Onset is ~1h, peak 2-3 h - Larger oral dose needed to have same effect as inhaled"

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Cannabis: Psychological Effects •

Functional effects (may impair performance of driving, etc.)" – Cognitive: " • Decreased attention, concentration (easily distracted), learning" • Short-term memory impaired" – Temporal disintegration = loss of ability to retain and coordinate information for a purpose (related to distorted time sense)" – Behavioural: " • Decreased movement, increased talkativeness" – Perceptual" • Decreased visual perception, especially peripheral" • Decreased pain perception (analgesic)" • Decreased time perception (overestimate passage of time; i.e., 30 mins has passed and you feel like it’s been 3 h)"

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Subjective effects: – May have to learn to discriminate subjective effects – can be separated into four stages: the “buzz,” the “high,” the stage of being “stoned,” and the “come-down.” Sometimes mood swings to anxiety and/or panic, especially at higher doses – Can sometimes produce transient psychotic symptoms such as depersonalization, derealization, agitation, and paranoia More than any other known drug, effects are modulated by surroundings (i.e., self-recorded mood ratings correlated with mood of others)

Cannabinoids: Pharmacodynamics • There exists an endogenous cannabinoid (endocannabinoid; eCB) system • Endogenous ligands: anandamide (AEA) and 2arachidonoylglycerol (2-AG) • Two main receptors: CB1 (brain) and CB2 (immune system) • Anandamide and THC bind to CB1 • 2-AG and CBD bind to both CB1 and CB2"

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How THC works in the brain • • •

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CB1 receptors are located pre-synaptically on axon terminals AEA and 2-AG are retrograde messengers—carry information in the opposite direction from normal (i.e., postsynaptic to presynaptic) Synthesized and released in response to depolarization of the postsynaptic cell – Function: to inhibit/regulate the activity of several neurotransmitters THC mimics the shape of AEA and works by this mechanism Cumulative effect of pathways is euphoric feelings associated with cannabis use – Increases dopamine in the nucleus accumbens

Red Flags for Use • Family history of psychiatric illness (particularly depression/anxiety) • Current psychiatric illness • Lifetime history of trauma • Using alone, or to relieve anxiety/stress/depression/ poor mood

Schizophrenia - Lecture 14 + 15 Schizophrenia Introduction

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• Classified as a psychotic disorder. • Psychosis (from G. “psyche” – mind/soul and “-osis” – abnormal condition) means a loss of contact with reality. • Schizophrenia affects approximately 1/100 people in North America. " • The annual cost of schizophrenia in the US is estimated at around $60 billion, due largely to the cost of treatment and lost wages. • Schizophrenia is a highly debilitating common disease with severe consequences for patients and their loved ones, and for this reason, it is an area that has received a lot of attention from researchers. "

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History • The condition historically known simply as “madness” or “lunacy” likely corresponds to what we now call schizophrenia." • Emil Kraeplin (1856-1926) was the first to thoroughly define the symptoms of schizophrenia, combining several elements of insanity into one disorder." • Catatonia, hebephrenia (silly and immature emotionality), and paranoia had previously been as separate disorders. • He also distinguished schizophrenia from manic-depression (which we now call bipolar disorder) • Kraeplin called schizophrenia dementia praecox – “premature dementia (L.)” because the disorder usually appears in late adolescence." • Eugen Bleuler (1857-1939) introduced the term schizophrenia, replacing Kraeplin’s “dementia praecox”.! • This name change is important, because it shows that Bleuler believed that the core problem was not premature aging of the brain.! • The word schizophrenia means “split mind (G.)”, and this comes from Bleuler’s belief in the “breaking of associative threads” – the destruction of forces that connect one function to the next.! • In other words, the various elements of the individual’s mind become disconnected from each other. Thoughts no longer have any logical connection to each other, or to reality in general.! • Unfortunately, the concept of “split mind” has lead to the popular but incorrect use of schizophrenia to refer to split/multiple personalities."

Myths about Schizophrenia • MYTH: People who have schizophrenia are violent and dangerous." • FACT: Individuals who are being treated for schizophrenia are not more violent than anyone else. For those living with untreated schizophrenia, they are the greatest danger to themselves - the greatest risk is self-harm or suicide. • MYTH: People who have schizophrenia have multiple personalities." • FACT: Schizophrenia is not the same as multiple personality disorder (aka dissociative identity disorder.)" • MYTH: People who have schizophrenia see things that aren’t there." • FACT: Schizophrenia is characterized mostly by auditory hallucinations (voices, etc.,.) Visual hallucinations are possible, but much less common."

Characteristics of Schizophrenia

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• The symptoms experienced by people with schizophrenia can be divided into three basic groups. • Positive symptoms are symptoms that go beyond normally occurring experiences. • E.g. hallucinations, delusions, paranoia. • Negative symptoms are characterized by a deficit or absence in a normal behaviour, loss of function • E.g. apathy, limited thought/speech, emotional and social withdrawal.! • Cognitive symptoms (also called disorganized symptoms) are symptoms that are characterized by erratic changes in speech, motor behaviour, and emotions. • E.g. disorganized speech, inappropriate emotional reactions"

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Positive Symptoms • Delusions: irrational beliefs or paranoia that misrepresents reality.! - Delusions of grandeur: i.e., belief that one is famous (such as Napoleon or Jesus Christ), or important in some special way (capable of ending world hunger, for example).! - Delusions of persecution: i.e. when an individual believes that others are “out to get him/her”.! - Erotomanic delusions: i.e. when an individual believes that another person (often a celebrity) is in love with him/her. ! • Delusions can be classified as bizarre if they are clearly implausible.! - i.e. Belief that an outside force has removed the individual’s internal organs and replaced them with those from someone else! • Delusions can instead be non-bizarre, if they are somewhat plausible.! - i.e. Believing that the government is listening to the individual’s phone calls! • Delusions expressing a loss of control over mind and body are common.! - i.e. Belief that outside forces are inserting thoughts into one’s mind, or that one’s body is being manipulated by some outside force." • Hallucinations: the experience of sensory events without any input from the surrounding environment. " • Hallucinations can involve any of the senses, but auditory hallucinations such as voices are the most common in schizophrenia." - Many hallucinations are simply a running commentary of what’s going on. - Others can be more sinister. “Command hallucinations” involve voices giving orders."

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Negative Symptoms (Five A’s)

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• Apathy: the inability to “get started”, to perform basic day-to-day functions. - This can lead to problems with hygiene, keeping a job, and keeping a place to live. • Autism: refers to the tendency to keep to oneself and lose interest in other people or the surroundings. - Note: ‘autism’ here refers to a set of behaviours, not comorbidity with autism the disorder. • Ambivalence: emotional and social withdrawal. • Anhedonia – “without pleasure (G.)”: indifference to activities that are typically considered to be pleasurable. • Affective flattening: the absence of visible emotions, facial expressions, and emotional inflections in speech. - Approximately 25% of people with schizophrenia exhibit a flat affect – it is as though they are wearing an expressionless mask all the time."

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* Pathognomonic: not unique to a specific disorder *

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Cognitive Symptoms

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• Disorganized speech: people with schizophrenia have a confusing way of talking. • They often jump about randomly from topic to topic, or go off on illogical tangents. • Inappropriate affect: occasionally, people with schizophrenia display emotions that are inappropriate for the current situation. • They may laugh or cry in situations that call for neither. • Disorganized behaviour: people with schizophrenia can show motor symptoms ranging from wild agitation to catatonic immobility. • Catatonic patients seem frozen in place, but may display waxy flexibility."

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DSM-5 Diagnostic Criteria

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• Key points: - Individual must have at least one of: delusions, hallucinations, or disorganized speech. - Diminished level of function. - Long-lasting symptoms. - Not due to drugs or some other medical condition."

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Development • Schizophrenia is usually diagnosed in late adolescence or early adulthood." • It strikes right as people enter the world and begin to gain independence, it is a cruel surprise that deprives people of the chance of a normal life. • There is usually a lag of 1-2 years between the first onset of symptoms and diagnosis. • In 85% of people, full-blown schizophrenia is preceded by a prodromal stage – a 1-2 year period where subdued symptoms begin to appear. • Magical thinking, minor illusions (feeling of a presence when one is alone, etc.,), and ideas of reference are common prodromal symptoms."

Prognosis • Complete remission is rare: most people (~78%) being treated for schizophrenia go through a pattern of relapse and recovery. • The prognosis for schizophrenia is poorer than for most other disorders, but recovery/remission is more likely given the following factors: • Good social adjustment prior to onset of schizophrenia. • A low proportion of negative symptoms. • A good social support system for patients. • The symptoms of schizophrenia may decrease with age, or at least “level out”."

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Etiology - Genetics

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• There is clear evidence for a genetic link to schizophrenia. • This can be shown by looking at how the relative risk of developing the illness changes depending on whether other people in one’s family have schizophrenia. • Monozygotic (identical) twins share 100% of their genes. • Therefore, if schizophrenia was 100% caused by genetics, both twins would always have schizophrenia. • In reality, the risk is only 48%. • Dizygotic (fraternal) twins only share 50% of their genes. Etiology - Stress • If schizophrenia was 100% genetic, then you’d • Stress seems to be a contributing epigenetic expect 50% of fraternal twins to have schizophrenia factor in the development of schizophrenia in if the other does" individuals who are susceptible. "

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Etiology - Perinatal Factors • There is evidence that problems before and shortly after birth (the perinatal period) can increase the risk of developing schizophrenia. " • Fetal exposure to influenza and other virus-like diseases may subtly damage the fetal brain in a way that causes the symptoms of schizophrenia later in life." • Toxoplasmosis gondii (t.gondii) (cat litter)" • Pregnancy and delivery complications are also correlated with the development of schizophrenia. (starvation)"

• Numerous studies have shown that diagnoses of schizophrenia are often preceded by a stressful life event." • Anecdotal evidence seems in favour of this as well. Schizophrenia often appears in the midst of the stressful transition to independent living that young adults undergo. • Stress and genetics interact. Having a risky genetic background may be a “loaded gun”, but stress may pull the trigger.

Anatomical Basis of Schizophrenia Structural changes

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• Anatomical studies of brains from people with schizophrenia show enlarged lateral ventricles. • Ventricle size on its own is not a problem, but since ventricles are empty space, it suggests that nearby parts of the brain either did not develop properly, or hav...