Exam 3 Review

1. Exam 3 Review Biology of Mental Disorders

2. Substance Abuse Disorders: Clinical Presentation • DSM-V Criteria • Take more or for longer than intended • Desire/effort to cut down/control use • Time spent using/recovering • Craving • Failure to fulfill obligations • Continued use despite recurrent problems when using • Reduce important activities in order to use • Recurrent use in physically hazardous situations • Tolerance • Withdrawal • Mild: 2-3 symptoms • Moderate: 4-5 symptoms • Severe: >5 symptoms

3. Substance Abuse Disorders: Risk Factors • Early exposures/genetic (Diathesis) • Sensitize reward and/or HPA stress response system • Negative role-models of stress management • Family history of mood/anxiety disorders • Developmental Crises (Early-life stress) • Adolescence disrupts hedonic homeostasis: • Stress of separation • Group identity • Hormonal changes + Onset of mood dysregulation • Events in adulthood that disrupt hedonic homeostasis: • Divorce • Death of loved one • Job loss • *Developmental events not necessarily a biomarker* • Anxiety usually precedes substance abuse; depression usually follows

4. Substance Abuse Disorders: Spiral of distress

5. Substance Abuse Disorders: Hedonic HomeostasisDysregulation

6. Substance Abuse Disorders: Cellular Circuitry • How drugs affect mesolimbic pathway • Drugs that bind to Gi protein coupled receptors • Morphine, exogenous heroin, THC • Drugs that bind to ionic channels • Nicotine binds to nAChR • Valium and sleep aids bind to Cl- receptors • Drugs that bind to serotonin reuptake transporters: • Cocaine, methamphetamine

7. Substance Abuse Disorders: Cellular Circuitry • Ways to make drugs active on reward system for longer: • Inhibit the inhibitor (GABA): prevents inhibition of DA receptors, allowing more dopamine to be released (ex: morphine) • Inhibit reuptake: allows serotonin to remain in synapse for longer (ex: cocaine) • Increase DA release onto NAc (ex: amphetamine)

8. Substance Abuse Disorders: Cellular Circuitry • Negative feedback mediated through dynorphin (dyn) • Dyn: • endogenous opioid that binds to kappa opioid receptor (κ) • inhibits DA neuron excitability • released from NAcneurons to outputs and feedback loop on VTA neurons • Normal conditions: • VTA releases DA • DA stimulates NAc to release GABA and dyn • GABA and dyn release leads to less DA release (negative feedback pathway) • Balance excitability

9. Substance Abuse Disorders: Cocaine sensitization • Cocaine conditions: • Acts on NAc • Downregulates dyn, allowing dopaminergic neurons in VTA to remain in hyperexcitable state • Requires transcription factor of delta fosB • Could contribute to cocaine sensitization

10. Substance Abuse Disorders: Opiates • How withdrawal mediates negative reinforcement affect • After chronic morphine exposure, cAMP & PKA levels reduced • Cells try to correct this by upregulating PKA levels • cAMP levels increase, need more morphine to keep them inhibited • “cold turkey”  have a lot of adenylyl cyclase, and have uncomfortable withdrawal symptoms

11. Substance Abuse Disorders: Binge/Intoxication Systems Circuitry • Subcortical (mesolimbic/basal ganglia) • NAc reinforcement pathway • DA also involved in habit formation • Striatum/globus pallidus: unconscious decision-making and valuation (ex: riding a bike). • Drug-taking and drug-seeking behaviors can become habitual • Modeled with lever press experiments (“Breakpoint” reward model)

12. Substance Abuse Disorders: Withdrawal/Negative Affect Systems Circuitry • Subcortical pathway in extended amygdala: amygdala, hypothalamus, BNST • Norepinephrine and corticotrophin releasing factor (CRF): mediate stress pathways (ex: HPA axis) • Anxious, uncomfortable feelings from abstinence: central brain regions + peripheral/adrenal hormones • Pathways create negative emotional state and lead to negative reinforcement of drug taking • Modeled with reinstatement paradigm (abstinence after chronic exposure)

13. Substance Abuse Disorders: Craving/Anticipation Systems Circuitry • Interplay of subcortical regions (hippocampus, BLA) and higher-order structures (mPFC, OFC) • Hippocampus-triggered memories of where you used drugs can stimulate preoccupation + conditioned reinforcement in BLA • mPFC /OFCmediate thoughts of acquiring/using drug • Persistent cravings after prolonged abstinence are very powerful • Cut burden of addiction if we could get people to stop using drugs and stay abstinent • Modeled with conditioned placement experiments

14. Substance Abuse Disorders: Experimental methods fMRI MRI • Imaging techniques • Structural Magnetic Resonance Imaging (MRI) • Volume changes (hippocampus, cortical gray matter, etc…) • Functional magnetic resonance imaging (fMRI) • BloodOxygenLevelDependentactivity in response to stimulus (or resting state) • Positron emission tomography (PET) • Radiolabeled glucose, dopamine, etc…injected and see levels of breakdown/activity in brain • Magnetic resonance spectroscopy (MRS) • Single photon emission computed tomography (SPECT) PET

15. Substance Abuse Lecture 1: Questions?

16. Substance Abuse Disorders: Positive and Negative Reinforcement • Positive reinforcement: • Taking the drug feels “rewarding” • Experiment to test this: rodent lever press: Rodent learns to press lever, receives drug, finds it rewarding. Positively reinforcement = keep pressing lever for reward, even with increasing delay between lever pressing • Negative reinforcement: • Take drug to alleviate negative symptoms whendrug wears off • Take drug to avoid withdrawal symptoms (vomiting, headache, shakes, low mood state, etc…) • Take drug to alleviate anticipated negative symptoms (ex: drink alcohol before going to parties to alleviate social anxiety)

17. Substance Abuse Disorders: Neuroanatomy of dopamine model of addiction • NAc: DA activity resulting from reward salience • vmPFC: enhances reward salience calculations • OFC: predicts alternative options/outcomes (shifting between NOW and LATER rewards) • ACC: monitors uncertainty of predicted vs actual outcome conflicts; conveys “decision” to inhibitory, dlPFC/dorsal striatal circuits • Amygdala, hippocampus, &lateral habenula: provide information about emotional salience, past experience, and reward-omission events (respectively); all contribute to lower drug dependence rates and ability to shift from NOW to LATER rewards • Can train delayed gratification

18. Substance Abuse Disorders: Stress and Addiction • Stressful situations can lead to relapse • Early-life stress can increase drug addiction susceptibility • Increased drug intake in maternally deprived Infant rats in adulthood • Isolated rats respond to very small doses of cocaine vs control • D2 receptors: • Subordinate monkeys with fewer D2R’s had higher addiction rates vs dominant monkeys with more D2R’s • CRH: • Causes drug seeking in previously “addicted” rats • Adrenal gland removal  less self-administration • CRFR1 antagonist decreases cocaine ingestion

19. Substance Abuse Disorders: Opiate mechanisms • Opioidsreinforce mesolimbic system • in normal state endogenous opioids (ex: endorphins) modulate pain signals • Act on opioid receptors • Opiate addiction differs from dopamine hypothesis of addiction • Opiate mechanism on DA system: Inhibits GABAergic input into DA neurons  increased DA release in NAc and direct inhibition of NAc (because they are Gi coupled) • Ablate NAc & Opiates still rewarding • Opiate addicted animals show withdrawal after given CB1 receptor antagonist • Cannabinoid receptor type 1 (CB1) antagonist abolishes reinforcing nature of cannabis, morphine, and heroin

20. Substance Abuse Disorders: Cocaine/Amphetamine mechanisms • Potent dopamine agonists • Cause hallucinations, paranoia, repetitive motor behaviors, mood disturbances • Cocaine: • Deactivates dopamine transporter proteins • Blocks dopamine reuptake • Amphetamine: • Blocks dopamine transporter • Forces unregulated release of DA out of cytoplasm • Free access to cocaine or heroin: • Heroin intake more moderate than cocaine • Cocaine is sensitizing; heroin induces tolerance

21. Substance Abuse Disorders: Nicotine mechanisms • Most commonly abused drug worldwide • Stimulates ACh receptors • Increases DA neuron activity in mesolimbic system • Stimulates DA release from NAc • Blocking nicotinic receptors in VTA inhibits DArelease in NAc; prevents reinforcement • Withdrawal & Cravings: • Nicotine desensitizes ACh receptors increased number of receptors • Abstinence: receptors return to baseline, but cravings persist • Glutamate LTP onto DA synapses in VTA

22. Substance Abuse Disorders: Alcohol mechanisms • Indirect agonist at GABAAR’s • Indirect antagonist at NMDAR’s • Increases DA neuron activity in mesolimbic system; increase DA release from NAc • GABAAR and NMDAR stimulation leads to apoptosis • Interferes with synaptic plasticity • Block euphoric effects by administering a D2DR antagonist

23. Substance Abuse Disorders: Drug Addiction and Epigenetics • Changes in gene expression after acute and chronic cocaine use • (delta fos regulates dyn expression) • Methylation/deacetylation of histones • Acute cocaine exposure: • Histone 3 doesn’t change; histone 4 changes • Chronic cocaine exposure: • Histone 3 changes; histone 4 doesn’t change

24. Substance Abuse Lecture 2: Questions?

25. Major Depression Disorder (MDD): Symptoms • 5 or more of the following nearly every day for  2 weeks • Depressed mood* • Loss of interest or pleasure* • Sleep disturbance (hyper- or insomnia) • Feeling worthless, guilt, self-depreciation • Diminished energy • Trouble concentrating or indecisiveness • Appetite disturbance (weight gain or loss) • Psychomotor agitation or retardation • Recurrent suicidal thoughts, plans or attempts • Clinically significant distress or impairment • Not attributable to direct physiologic effects of drug or medical condition

26. Major Depression Disorder (MDD): Symptoms • >50% of depressed patients remain untreated • Of treated, only 1 in 2 responsive to treatment • 1 in 10 workers took time off for depression • Large, associated costs

27. Major Depression Disorder (MDD): Causes • Environmental: • Early life adversity (ex: parental loss) • Chronic stressful events • Assault • Genetic: • No autosomal syndromes identified; variable inheritance • Linkage found; failure to replicate findings • Seems to run in families (odds ratio) • Monozygotic twin studies show genetic component

28. Major Depression Disorder (MDD): Relapsing/Remitting disorder • Groups: mild early life adversity vs. severe early life adversity • Exposure to mild or severe stress after depressive episode • Mild early/adult stress: low rate of recurrence • Mild early/adult stress: secondary stress is severe, recurrence more likely • Severe early/adult stress: responsive range blunted by effects of severe early life adversity

29. Major Depression Disorder (MDD): Environmental Stress and level of functioning

30. Major Depression Disorder (MDD): 5HT transporter • Serotonin-transporter-linked polymorphic region (5-HTTLPR) • Short (s) form: • produces modest amount of transporter mRNA/protein • More susceptible to depression • Long (l) form: • regulatory sequence for enhanced production of 5HT transporter • Less susceptible to depression

31. Major Depression Disorder (MDD): S and L forms • S and L effects appear with major stressor • Sex differences: SS Women and men have increased risk of developing depression, but risk highest in women • Social stress test • SS women had higher/longer increases in cortisol • *Not a diagnostic biomarker*

32. Major Depression Disorder (MDD): S and L forms • S carriers: • Reduced activity in cingulate and amygdala • Weaker amygdala-cingulate feedback loop • Cingulate less able to blunt amygdala fear response • LL genotype: • Amygdala activates cingulate • Stronger feedback loop

33. Major Depression Disorder (MDD): BDNF • Enhances synaptic transmission, plasticity, spine growth, CREB activation (opposite effects of cortisol) • Val allele: • Most common • Better memory (MWM) • Met allele: • Evolutionarily new • Protective against s allele • But decreases efficacy of BDNF • Higher rates of MDD diagnosis

34. Major Depression Disorder (MDD): SIRT1 • SIRT1: • Codes for a histone deacetylase (HDAC) • Candidate gene for depression • Promotes dendritic branching in HPC neurons

35. Neurobiology of Depression: Biomarkers • Neuroanatomical volume loss: • Dorsolateral prefrontal cortex (dlPFC) • Orbitofrontal cortex (OFC) • Cingulate gyrus • Hippocampus • Decreased 5-HT density in PFC and hippocampus • Neurotransmitters: • Monitor monoamine levels • Depleted tryptophan • Antidepressants increase DA, NE, 5-HT availability • Low 5-HT metabolites

36. Neurobiology of Depression: protective factors/Treatments • Environmental: • Strong social support networks • Exercise • Stimulates Gαs receptors, increases cAMP & BDNF • Antidepressants • D1 agonist (SKF83959) increases cAMP levels • SSRI’s (ex: Prozac, etc…)

37. Major Depression Disorder Lecture 1: Questions?

38. Neurobiology of Depression: Symptoms in animal models • Behavioral despair • Forced swim test • Tail suspension test • “Learned Helplessness”; controlled vs. uncontrolled shock exposure • Decreased food and water intake • Weight loss • Sleep disturbance • Weak response to rewarding stimulation • Failure to avoid shock given the choice/warning • Symptoms last a day or two after induction;not all animals demonstrate phenotype

39. Neurobiology of Depression: Symptoms in animal models • Anhedonia • Decreased self stimulation, sucrose preference, sexual interest • Lever-press

40. Neurobiology of Depression: Symptoms in animal models • Disturbed sleep • Increased REM density, loss of circadian rhythm • Activity changes • Decreased baseline activity, decreased novel exploratory behavior • Appetite • Either hyperphagia or anorexia, increased fat, carbohydrate preference • Impaired cognition • Impaired hippocampal dependent learning tasks

41. Neurobiology of Depression: Symptoms in animal models • Chronic mild stress exposure • Ex: conical tube paradigm • Longer lasting effects (depressive phenotypes) • Responsive only to chronic anti-depressant treatment • May be strain dependent/genetic factors • Stress from dominant conspecifics or predators • Ex: brief, chronic exposure to predator scent • Influenced by early life events • Good symptom manifestation

42. Neurobiology of Depression: Neonatal Environment • Cross fostering experiments: • BALB/c (poor MWM learners) raised by C57 mothers (good learners); C57 pups raised by BALB/c mothers • BALB/c pups raised by C57 mothers became good learners • C57 pups raised by BALB/c mothers still good learners • Embryo transplant experiments: • Found C57 embryos transplanted into BALB/c mother learned poorly • *Epigenetic significance & importance of in uteroenvironment*

43. Neurobiology of Depression: HPA Axis • Stress upregulates mineralocorticoid receptors (MR) & glucocorticoid receptors (GR) in hippocampus • Stress causes corticotropin-releasing hormone (CRH) to be released by hypothalamus • CRHcauses pituitary to secrete ACTH • ACTHstimulates adrenal gland to release cortisol • Cortisol increases glucose levels & decreases inflammatory/immune response

44. Neurobiology of Depression: Dendritic Spines • Stress alters dendritic morphology • Lack of branching • Decreased BDNF • Decreased neurogenesis • Neuronal atrophy Unpredictable stress Repeated Restraint Social isolation

45. Neurobiology of Depression: Mineralcorticoid • Different course of action and affinities than cortisol • Chronic stress decreases mineralcorticoid (MC) expression and resiliency • MR polymorphisms may predict depression susceptibility • MR agonist can be used as a therapeutic (issues with specificity though)

46. Neurobiology of Depression: Increasing cAMP No treatment Acute Chronic treatment treatment • MDD associated with increased Gαi levels • Antidepressants increase Gαs coupling to AC • However, DA and 5-HT interact with both Gs and Gi receptors. • cAMP homeostasis in depression

47. Neurobiology of Depression: Neurogenesis • Neurogenesis throughout life in hipp and SVZ • V-TK: virally expressed thymidine kinases, prevents neurogenesis;interacts with stress • Inhibited neurogenesis correlates with increased stress (alters HPA axis) • Antidepressants require neurogenesis to function: • Irradiated monkey brain with antidepressants look like monkeys that never received antidepressants

48. Major Depression Disorder Lecture 2: Questions?

49. Anxiety Clinical: Fear vs. Anxiety

50. Anxiety Clinical: Anxiety disorders • Excessive fear/anxiety response to stimuli that do not normally evoke such a response • Physiologic (autonomic arousal) • Emotional (fear, marked distress) • Cognitive (anticipation, rumination, distractibility) • Behavioral (avoidance/endured with distress) • Classified by evoking object/situation • Frequent and persistent • Interferes with normal functioning • High prevalence: 350 million people worldwide; up to 30% suffer at some point