Neurobiology of Addiction Final Exam

DSM-V Clusters

Impaired control

Social impairment

Risky use

Pharmacological

Risk Factors for Addiction

Age of first use

Genetics

Environment

Comorbidity of mental illness

Addiction Cycle

Acute reinforcement → escalating/compulsive use → dependence → withdrawal → recovery or relapse

Drug Names

Chemical name

Non-proprietary (generic)

Proprietary (trade)

Common (street)

DEA Scheduling

I. no medical use, high abuse

II. recognized medical use, high abuse risk

III. recognized medical use, lower abuse than I and II

IV. recognized medical use, lower abuse than III

V. recognized medical use, lower abuse than IV

Partition Coefficient

P_m/b = C_oil/C_water

Higher P_m/b, higher rate of transportation

Basic drugs

Intestine: high pH → non-protonated → uncharged → high P_m/b

Stomach: low pH → protonated → charged → low P_m/b

Acidic drugs

Intestine: high pH → protonated → uncharged → high P_m/b

Stomach: low pH → non-protonated → charged → low P_m/b

IV Administration

Rapid onset, short duration, high concentration to brain

Inhalation Administration

Rapid onset, short duration, high surface area and vascularization of lungs

Subcutaneous/Intramuscular Administration

Gradual onset, long duration, implantation below skin/into muscle releases drug slowly

Oral Administration

Slow absorption, long duration, first-pass effect

Pharmacokinetics

Absorption, distribution, metabolism, elimination

Pharmacodynamics

Intensities and time courses of effects of drug

Zero-Order Kinetics

High concentration of drug → all enzymes saturated

Constant amount removed

First-Order Kinetics

Low concentration of drug → time between metabolism of molecules

Constant fraction removed

Potency

Measured by ED₅₀ (low = high)

Efficacy

Maximal effect a drug can produce

E = beta/alpha

Therapeutic Index

TI = TD₅₀/ED₅₀

Higher TI = safer

Binding Affinity

Kd = k_-1/k₊₁ where Kd is free drug concentration where half of sites are bound

Low Kd high binding

Competitive Antagonist

Reversible binding of agonist and antagonist at the same site

Same maximal effect, higher ED₅₀

Non-Competitive Antagonist

Reversible binding of agonist and antagonist at different binding sites

Lower maximal effect, same ED₅₀

Allosteric Modulator

Different binding site and only exhibits effect in presence of agonist

Same maximal effect, higher or lower ED₅₀

Desensitization

Decreased response to agonist

Ion channels: change conformation

GPCR: internalization to cytoplasm → down regulation by lysosomes

Measure validity of animal models

Face, construct, content, and predictive validity

Advantages of Animal Models

Control environment and genetics

Assess behavior before and after drug administration

Manipulate brain regions

Gather information from brain regions, circuits, cells, NTs, etc

Study stages of abuse cycle

Disadvantages of Animal Models

Risk of anthropomorphizing

Cannot reproduce social and personal factors

Difficult to measure perceived effect

Two Bottle Choice Experiment

Animals given choice between bottle with water vs. ethanol (controlled for flavor and calories) → choose ethanol → rewarding effects

Genetic variation: breed mice that have high ethanol preference → generations continue to show higher ethanol preference than control

Progressive Ratio

Used to quantify reinforcing properties through the amount of work (eg. lever pressing) the animal is willing to put in to receive the drug

Higher break point (greatest amount of work before unwilling), higher reinforcement

Extended Access Experiment

Rats given long-term access (LgA) to drug (6hrs/session) take more drug overall and within the first hour than those with short-term access (ShA) to drug (1hr/session)

LgA rats gradually took more and more drug throughout sessions showing escalation

Adversity Experiment

Animals receive drug paired with adverse stimulus

Measures persistence of drug use despite punishment → compulsivity

Relapse Experiment

Train animals to self-administer drug → extinguish response → test reinstatement by cues associated with drug use, stress, or priming dose

Intra-Cranial Self-Stimulation (ICSS)

Implant electrode into specific brain region → train animal to lever press for activation

Measures threshold current needed to maintain self-stimulation

Conditioned Place Preference

Two unconditioned stimuli paired with two distinct environments

Drug Discrimination

Determine is the subjective effects of two drugs are perceived to be similar

Pharmacokinetic Tolerance

Enhanced drug metabolism due to an upregulation of enzymes

Lower area under curve (time vs [drug]), higher metabolism

Effects ethanol, barbiturates, and nicotine (possibly some opioids)

Pharmacodynamic Tolerance

Decreased drug effect in the CNS

Environment associated with drug use → increased tolerance — form of learning

Effects most if not all drugs

Acute Functional Tolerance

Develops during one drug exposure

eg. Mellanby effect in ethanol: impairment is great at given BAC while rising than the same BAC while falling

Functional Cross Tolerance

Occurs when two drugs act via similar mechanisms

eg. cocaine and amphetamines

Dependence

Demonstrated by eliciting drug withdrawal

Sedative-Hypnotics

Alcohol, barbiturates, benzodiazepines, non-benzodiazepines

Barbiturates

Clinical uses: anticonvulsant (phenobarbital), induce anesthetics (thiopental)

Side effects: rapid tolerance, severe withdrawal, respiratory depression

Mechanism: positive allosteric modulator at GABA_A receptors, increase duration of open state

Benzodiazepines

Clinical uses: anxiolytic, treat alcohol withdrawal, sedation, pre-surgery, anesthetic induction (propofol)

Side effects: motor incoordination, intoxication, amnesia, sedation, coma, respiratory depression

Mechanism: positive allosteric modulator at GABA_A receptors, increase frequency of open state

GABA_A Receptor Structure

Cys-loop ligand-gated ion channel

Five subunits with various isoforms

Each subunit has four transmembrane segments (TM1-4)

TM2 forms ion channel

BZ binding between α and γ subunits

GABA_A Receptor Function

GABA binds → increased Cl^- conductance → hyper-polarize cell → inhibition

GABA_A Receptor Function Experiment

Remove portion of ovary from Xenopus laevis → isolate mature oocytes → inject RNA or DNA coding for GABA_A receptor subunits → measure GABA induced Cl^- current using voltage clamps

Channel Bursting

Pattern of repeated openings and closings of a single GABA_A channel during activation

Duration and frequency affected by barbiturates and benzodiazepines

Inverse Agonists

Drugs with the opposite effects of the agonist

Must be some level of receptor activity in order to have an effect

Right shifts LDR curve (increased ED₅₀)

Orthosteric Site

Primary binding site for endogenous ligand that directly activates receptor

Allosteric Site

Separate modulatory site that indirectly influences activation of the receptor

How GABA_A receptors determined to be responsible for BZ behavioral effects

Electrophysiology: BZ increases GABA-induced Cl^- conductance

Antagonism: antagonist selective for BZ binding sites on GABA_ARs blocks behavioral and physiological effects

GABA_AR Subunit Knock In Mice

α₁ → lost sedation, amnesia, anticonvulsant

α_2/3 → lost anxiolytic and muscle relaxant effects

α₅ → lost cognitive impairment and memory effects

Dual Orexin Receptor Antagonists (DORAs)

New sleep aid

Competitive OX₁ and OX₂ antagonist

Decrease sleep latency and maintain sleep

No amnesia, lower euphoria and hallucination

Alcohol Metabolism

Ethanol → Acetaldehyde via ADH and NAD⁺ → NADH (chronic users recruit cyt. P450)

Acetaldehyde → Acetate via ALDH and NAD⁺ → NADH

Genetic Variation in Alcohol Metabolism

Mutated ADH → faster metabolism of alcohol → more acetaldehyde

Mutated ALDH → slower metabolism of acetate → more acetaldehyde

Build up of acetaldehyde → aversive → less likely to develop AUD

Assessment of Physical Dependence on Alcohol

Withdrawal (handling induced seizures) after:

1 ethanol exposure - single withdrawal

Continuous exposure - single withdrawal

3 ethanol exposures - 3 withdrawals

Higher alcohol exposure + multiple withdrawal → high severity of withdrawal → development of physical dependence

Acute Functional Tolerance to Alcohol

Occurs in one session of drinking

Higher level of impairment at certain BAC during rising stage than same BAC during falling stage

Fetal Alcohol Syndrome

Alcohol readily crosses placenta

Neurobehavioral problems: hyperactivity, learning disability, depression, psychosis

Brain development: decreased brain weight

Facial features: flat mid face, short nose, indistinct philtrum, thin upper lip

Microdialysis

Direct measurement of neurotransmitter concentrations in specific brain regions

Probe → brain region → fluid dialysis → measure NT concentration in fluid

Dopamine Antagonists → NAc Effect on Alcohol

Fluphenazine → decreased alcohol delf administration

GABA_A Receptor Antagonists Effect on Alcohol

Picotoxin and IPPO → decreased self-administration and anti-punishment

Opioid Receptor Antagonism Effect on Alcohol

charged methylnaloxonium (local) → amygdala and NAc → decreased ethanol responding

Molecular Sites of Alcohol Actions

PAM at GABA_A receptors → anxiolysis, motor impairment, sedation, reinforcement

Inhibits NMDA receptors → memory impairment, cognitive deficits, withdrawal

Other: potentiate glycine, varied at nACh, enhances 5-HT3, and inhibits P2X receptors

How were sites of alcohol effect identified?

Electrophysiology

Structure of alcohol-binding proteins: LUSH cavity and GLIC resistant to ethanol until M2 mutationtential

Treatment of AUD

Approved:

Naltrexone: opioid receptor antagonist

Acamprosate: glutamate/GABA modulator → stabilize hyper-excitability during abstinence

Disulfram: ALDH inhibitor → drinking aversive

Potential:

Baclofen: suppress craving

Neuropeptide Y

Delirium Tremens

Severe alcohol withdrawal after chronic consumption for months

Treatment: BZs (reduce mortality), vitamins

Neuroadaptation for Alcoholics

fMRI on chronic and social drinkers shown image of alcohol:

alcoholics showed increased brain activity in prefrontal cortex and anterior thalamus

Health Consequences of Alcohol

Cardiomyopathy, ischemic heart disease, small increase in esophogeal and breast cancer risk, loss of grey and white brain matter, Wernicke-Korsakoff disease, liver disease

Wernicke Encephalopathy

Caused by vitamin B1 deficiency

Largely reversible

Effects: confusion, gait ataxia, weird eye movement

Treatment: I.V. thiamine

If untreated, 85% get Korsakoff psychosis

Korsakoff Psychosis

Damaged dorsal thalamus and mammillary bodies

Effects: apathy, detachment, antero- and retrograde amnesia

Steatosis

Common, treatable, few symptoms, hepatomegaly, elevated liver enzymes

Steatohepatitis

Fat, inflamed, injured liver

Occurs when 10+ drinks/day for decades

Cirrhosis precursor

Effects: jaundice, ascites, hepatic encephalopathy (toxin build up → brain damage

Can cause multi-organ failure (lethal)

Cirrhosis

Late stage liver disease

High morbidity

Effects: inflammation, fibrosis, necrosis

Without transplant → death in 10 years

Advantages of Inhalants

Cheap, legal, available, rapid high, painless, removal via exhalation (controlled magnitude and duration)

Classes of Inhalants

Volatile alkyl nitrites: vasodilation, smooth muscle relaxant

Gases: nitrous oxide, euphoria, spectrum of effects similar to stimulants, depressants, and hallucinogens

Volatile solvents: toluene, TCE, chloroform, ketones, acetone, butane, propane, sevoflurane

Toxicities of Inhalants

Irreversible cognitive deficits (especially toluene)

Sudden sniffing death syndrome: myocardium sensitized to adrenaline (butane, propane, aerosol chemicals)

Asphyxiation and damage to pulmonary tissues

Hepatitis

Malignancies

Teratogenic

Meyer-Overton Correlation

Potency positively correlated to lipophilicity (P_m/b)

Lead to the lipid theory of action

Issues with Lipid Theory of Inhalants

Anesthetics at clinical dose have minor effects on membrane order and fluidity

Isomers (same P_m/b) have different potencies

Alcohol cut-off effect

Some highly lipophilic compounds contradict the Meyer-Overton correlation

Mechanisms of Action of Inhalants

NMDAR inhibition

GABA_A and glycine-mediated current enhancement

Two-pore K⁺ channels