1. Substance Use Disorders
Clinical Phenomenology
Biological Models
Risk Factors
Effects of Substances on Brain Structure and Function
Substance abuse – acquired, relapsing, remitting disorder of mood and behavioral regulation due to voluntary exposure to exogeneous neurotoxin
Known exogenous etiology and reliance on behavioral signs makes it one of the easier syndromes to model in animals, so we know a good bit about the underlying biological processes

2. Disability-Adjusted Life Years (DALYs) Lost due to Different Conditions

3. US Economic Costs (2016) Health Care Overall Tobacco $130 billion
Costs of Substance Abuse
Health Care
Overall
Tobacco
$130 billion
$295 billion
Alcohol
$25 billion
$224 billion
Illicit Drugs
$11 billion
$193 billion
Perhaps largest theoretically avoidable cost of any disorder or disease
Enduring level of cost attests to power of the reinforcing effects of these substances

4. DSM-V Criteria Substance Intoxication Substance Withdrawal
Development of reversible, substance-specific syndrome due to recent ingestion
Clinically-significant, problematic, behavioral or psychological changes
Symptoms not attributable to another medical or psychiatric disorder
Substance Withdrawal
Clinically-significant, problematic, behavioral, cognitive or physiologic changes with cessation/reduction of prolonged or heavy use
Causes significant distress or impairment in social/occupational function
2013 study of ~ 8000 in 8 Canadian colleges - nearly 60% of students consumed more than 5 alcoholic drinks in a single occasion during the past 15 days.

5. DSM-V Criteria Substance-Specific Use Disorder
Problematic pattern of use leading to 2 or more of the following:
Take more or for longer than intended
Desire/effort to cut down/control use
Much time spent using or recovering
Craving
Results in repeated failure to fulfill role obligations
Continued use despite recurrent problems d/t use
Reduce important activities d/t use
Recurrent use in physically hazardous situations
Tolerance (need more to achieve same effect)
Withdrawal (see previous)
DSM-IV separated Abuse and Dependence (required tolerance or withdrawal).
DSM-V combined in recognition of spectrum-nature of disorder
Accurate diagnosis of syndrome is complicated by 1) dependence on clinical judgments re: key criteria and 2) unreliable self-report d/t denial as a common psychological symptom
Mild 2-3 symptoms
Moderate 4-5 symptoms
Severe > 5 symptoms

6. Drug-seeking behavior accounted for by principles of operant conditioning
Early stages (Binge Intoxication) –conditioning via positive reinforcement (drug-seeking to increase pleasure/positive affect)
dominated by impulsive, reward-seeking behavior without regard for long-term consequences
Late stages (Withdrawal/Anticipation) –conditioning via negative reinforcement (drug-seeking to avoid pain/negative affect)
dominated by compulsive behavior in face of adverse consequences (‘hair of the dog’, ‘craving’)
Koob & LeMoal, 1997

7. Reward/Stress Circuitry Promotes Survival
nAcc/VTA system
activated during eating, social affiliation, threat-avoidance, pair-bonding, mating
associated pleasure positively reinforces behaviors that promote survival
Extended Amygdala
activated by stressors (food deprivation, threat, loss)
associated pain/negative affect negatively reinforces behaviors that avoid/manage stressors
Operant behaviors mediated by reward/stress circuitry
General concepts – different substances affect circuitry differently
nACC/VTA – central reward circuitry
self-administered electrical stimulation preferred over food, water, mating, leads to exhaustion and death
substances lower stimulus threshold required for self-administered stimulations (enhances pleasure derived from lower levels of stimulation
nAcc/VTA lesions and NT inhibition blocks effects of some substances
Extended Amygdala – upregulation of CRF/norepinephrin/dynorphin activity in these structures associated with pain/negative affect

8. Hedonic Homeostasis Dysregulation Protracted Abstinence
Initial Exposure
Repeated Exposure
Protracted Abstinence
Heavy Dependence
One dominant model that explains the relapsing-remitting, downward spiral of the disorder – based on opponent process theory
Survival promoted by maintaining hedonic homeostasis (the ‘just – right’ balance of pleasure and pain) by increasing pleasure-promoting behaviors and decreasing pain promoting behaviors in face of everyday stressors.
Hedonic set point (0) is the ‘just – right’ balance of pleasure and pain
Lines are net ‘pleasure/pain experience’ – drops below set point because can’t stay high all the time
Substance use involves rapid, NT-mediated, positive hedonic responses that decrease in amplitude with time. These are opposed by negative responses that are slower to build up and decay and increase in amplitude over time
A) Introducing addictive substance dysregulates homeostasis which can become chronic in vulnerable persons. Increasing nACC/VTA activity (a –Process) is followed by up-regulation of activity in HPA and other systems (b –process) (via opponent-process mechanisms) that increase discomfort when the drug wears off.
B) Sensitization (increased pleasure response with repeated exposure for some drugs) reinforces repeated administration, but tolerance eventually develops – varies depending on the substance
Over time, there is a lowering of pleasure-pain balance below the ‘hedonic set point’ through tolerance and chronic up-regulation of HPA axis activity (and other counter adaptations) when not using. This induces dysphoria, cravings and further use to restore homeostasis.
With protracted abstinence, there is a reversion to the sensitized state, but pleasure-pain balance stays below hedonic set point through chronic up-regulation of HPA axis activity. These two factors place person at high risk for relapse (persistent craving and sensitization).
Koob & LeMoal, 1997

9. Most substances of abuse upregulate reward system by increasing DA release on nAcc
Linden, 2012

10. Up-regulation of cAMP Pathway Modulates Symptoms of Opiate Withdrawal
One mechanism whereby withdrawal engages systems mediating negative affect and negatively reinforce drug-seeking
Morphine suppresses cAMP activity
System upregulates adenylyl cyclase and protein kinase A activity in response in order to restore cAMP levels to normal
Higher concentrations of these enzymes mediate tolerance (with higher concentrations more drug is needed to produce the same effect on Nacc/VTA complex).
With blocking of morphine activity (by naloxone), there is an overshoot in cAMP levels, d/t higher concentrations adenylyl cyclase and protein kinase A.
Excess cAMP levels in locus coeruleus is associated with physical symptoms of withdrawal (shaking, sweating), in VTA with dysphoria
Nestler, 2004

11. Drug-seeking behavior accounted for by principles of operant conditioning
Early stages (Binge Intoxication) –conditioning via positive reinforcement (drug-seeking to increase pleasure/positive affect)
dominated by impulsive, reward-seeking behavior without regard for long-term consequences
Late stages (Withdrawal/Anticipation) –conditioning via negative reinforcement (drug-seeking to avoid pain/negative affect)
dominated by compulsive behavior in face of adverse consequences (‘hair of the dog’, ‘craving’)
Koob & LeMoal, 1997

12. Koob & LeMoal, 2010 Binge/intoxication stage.
Reward neurotransmitters (DA and opioid peptides) engaged in the nucleus accumbens shell and core
Engage stimulus–response habits that depend on the dorsal striatum.
Koob & LeMoal, 2010

13. Withdrawal/negative affect stage
Withdrawal/negative affect stage. Associated with activation of a set of nuclei referred to as the ‘extended amygdala’
BNST – bed nucleus of the stria terminalis
CeA – central nucleus of the amygdala – involved in anxiety/fear experience
AcB shell/core – transition zone in the medial portion (or shell) of the nucleus accumbens.
Major NTs - corticotropin-releasing factor, norepinephrine, dynorphin.
Major projections to the hypothalamus and brainstem.
Koob & LeMoal, 2010

14. Preoccupation/Craving stage involves representations of
conditioned reinforcement in BLA = Basolateral amygdala
contextual information by Hippo = hippocampus thehippocampus.
Executive control, contingencies, outcomes and subjectives states represented in OFC/mPFC/ACC with connections to amygdala
Maas 1998 showed increased BOLD response in the anterior cingulate and left dorsolateral prefrontal cortex in a cocaine-using group, compared to controls in response to drug-related cue.
Self-reported levels of craving and activation in these regions were correlated
Koob & LeMoal, 2010

15. From: Fowler, et al Sci Pract Perspect. 2007 Apr; 3(2): 4–16.
TABLE 1
Brain imaging techniques used in drug abuse research
IMAGING TECHNIQUE
Structural magnetic resonance imaging (MRI)
Functional magnetic resonance imaging (fMRI)
Magnetic resonance spectroscopy (MRS)
Positron emission tomography (PET)
Single photon emission computed tomography (SPECT)
PRINCIPAL APPLICATIONS
Map tissue morphology, composition
Visualize changes in oxygenation and blood flow associated with brain activities
Measure cerebral metabolism, physiological processes involving specific brain chemicals; detect drug metabolites
Quantify biochemical and pharmacological processes, including glucose metabolism; drug distribution and kinetics; receptorligand interaction; enzyme targeting
Measure receptorligand interaction, physiological function, biochemical and pharmacological processes
From: Fowler, et al Sci Pract Perspect Apr; 3(2): 4–16.

16. How “high” a person feels correlates well with how much cocaine is available in the striatum: A PET study
(Volkow et al., 1997).

17. Loss of grey matter density as determined by structural MRI in methamphetamine-addicted individual
(Kim et al., 2005). 

18. fMRI, cocaine associated cue viewing by addicted person, left, and healthy control, right
(Wexler et al., 2001).

19. Cocaine user (right) has lower activity in the orbitofrontal cortex compared to control (2-deoxyglucose uptake, PET study)

20. Reduced D2 dopamine receptor availability in the striatum in cocaine users (right)

21. Reduced levels of monoamine oxidase in the organs of a smoker: another PET study
(Fowler et al., 2003b).

22. Substance Abuse is a Neurodevelopmental Stress Disorder
Early exposures/genetic factors (Diathesis)
sensitize reward and/or HPA stress response system
provide negative role models for managing stressors
increased risk for mood/anxiety disorders (low hedonic set point)
Developmental Crises (Stress)
Adolescence
normally disrupts hedonic homeostasis via
stress of separation/individuation, social group identification
mood dysregulation d/t hormonal changes
- increased exploratory behavior, risk-seeking via
incomplete frontal lobe development
decreased parental supervision
Adults
divorce, death, job loss
Diathesis-Stress Model – common theme in psychiatric disorders
For majority, substance misuse becomes a passing phase (college drinking)
May become a persistent problem for those predisposed due to genetic factors or early stressors
Suggests preventative treatments (focused early education, surveillance, behavioral treatment)
Not exclusive to adolescence – other developmental crises (divorce, death, job loss) may provoke increased use

23. Population-Based Twin Studies Concordance Rates for Abuse/Dependence
Monozygotic
Dizygotic
Males
Females
Alcohol
.68
.58
.20
.29
Marijuana
.77
.31
Cocaine -
.37
Opiates
.67
Tobacco
.61
.47
.30
Stimulants
.53
.24
Sedatives
.44
.25
Psychedelics
.32
No specific risk genes identified.
ETOH + Alcohol DH (ADH) = Acetaldehyde
Acetaldehyde + Acetaldehyde DH (ALDH) = Acetate
Acetaldehyde assoc with flushing & palpitations
Asians have higher prevalence of active form of ADH and inactive form of ALDH gene
Net effect is higher levels of Acetaldehyde & less frequent ETOH use among Asians in general
Antabuse – inhibits ALDH, slows acetaldehyde metabolism in response to ETOH ingestion – produces same reaction

24. Prevalence of Substance Abuse in Adolescence
Large, US nationally representative sample
Kilpatrick, 2000

25. Independent Risk Factors for Abuse/Dependence
Odds Ratios
HARD
DRUG
ETOH
THC
Early in life risk-taking (males) , disruption of hedonic homeostasis via trauma exposure, poor modeling of stress management
PTSD was independent risk factor, suggesting that it is not just exposure to threatening situations (not everyone gets PTSD), but the emotional response that predisposes to SA
Lower AA rates may reflect lack of access due to lower SES in AA (not controlled in analysis) or positive cultural factors (controlling for other exposures associated with low SES)
Kilpatrick, 2000

26. Anxiety Usually Precedes SA Depression Usually Follows
Percent of Cases where Anxiety Onset Before Substance Issues
Percent of Cases where Depression Onset Before Substance Issues
Likelihood of SU problems increases with number of diagnosed mood/anxiety disorders
Merikangas, 1998

27. Is this your Brain on Drugs?
Q: Observed associations between drug use and cognitive/psychiatric problems support which statement?
drugs cause brain damage
people who have poor judgment/emotional problems are more likely to use drugs
some other factor (e.g., poverty) causes both problems independently
problems with judgment/emotions develop around the same time that people get access to drugs

28. Is this your Brain on Drugs?
Q: Observed associations between drug use and cognitive/psychiatric problems support which statement?
drugs cause brain damage
people who have poor judgment/emotional problems are more likely to use drugs
some other factor (e.g., poverty) causes both problems independently
problems with judgment/emotions develop around the same time that people get access to drugs
A: All of the above
A causes B
B casues A
C causes A and B
B is coincident with A

29. Controls for nutritional, environmental and comorbidity factors
Kroenke, 2012

30. Cannabis Use and Decision Making under Risk
Performance on Iowa Gambling Task
Moderate = 8-35/week
Heavy = 53-85
Is risky decision-making a cause or an effect of marijuana use?

31. Reduction in Cortical Gray Matter Volumes In Chronic Marijuana Users
Matochik, 2005

32. Dose-Response Effect of Cannabis Use on IQ over Time
Dunedin Study, a prospective study of a New Zealand birth cohort of 1,037 individuals followed from birth (1972/1973) to age 38 y.
Cannabis use was ascertained in interviews at ages 18, 21, 26, 32, and 38 y. Neuropsychological testing was conducted at age 13 y, before initiation of cannabis use, and again at age 38 y
Increasing effect size demonstrates dose response -
Effects persist when controlling for other substance use, other psychiatric diagnoses and level of education
Meier, 2012

33. Most of this effect carried by those who started using in adolescence
Equivalent to dropping from 70th percentile to
65th (1 dx)
57th (2 dx)
50th (3 dx)
Meier, 2012

34. Neuroimaging findings of amphetamine use
Overall reductions in temporal and hippocampal volumes, anterior cingulate and prefrontal grey matter, relative to controls
Correlate with cognitive performance
Differences in Regional Neocortical Volumes
Differences in
Regional
Hippocampal
Volumes
Thompson, 2004

35. MDMA (Ecstasy) 10 weeks post MDMA use, rats show dose-dependent
diffuse reduction in serotonin transporter levels
increased anxiety response
Control
Low
MDMA works in the brain by increasing the activity levels of at least three neurotransmitters: serotonin, dopamine, and norepinephrine.
Leads to chronic depletion, death of serotonin-producing neurons
Low-Dose
(~1-2 pills)
SERT
Levels
High
High-Dose
(~ weekend of
heavy use)
McGregor, 2003