Drug Addiction

Definition of Drugs

Chemical substances which interact with the biochemistry of the body

Function of drugs

• Inhibit or reinforce enzyme activity

• Block or activate receptors

• Interact with neurotransmitters or hormones in other ways

• Attack “invaders” (e.g. antibiotics)

Definition of psycho-active drugs

Any chemicals that influence the way we feel or act.

Interactions of psycho-active drugs

• Nervous system and/or the endocrine system

• Act at synapses (among other places)

Agonists - Effect on post synaptic cell

Mimics/increases action of the neurotransmitter

Antagonists - Effect on post synaptic cell

Blocks action of the neurotransmitter

Agonists - Effect on receptor

Mimics action of the neurotransmitter

Antagonists - Effect on receptor

Blocks action of neurotransmitter

Autoreceptor

• Some NTs bind to these receptors

• Function as a negative feedback loop

• Reduce release of more neurotransmitters

• Mechanism to not waste NTs

Agonist at presynaptic level

• If a drug binds to the presynaptic receptor, it views it as an agonist

• Stops the release of more neurotransmitters

• If it is specific only to the presynaptic terminal, it is an antagonist at the synapse level.

Antagonist at presynaptic level

• If a drug is an antagonist in the presynaptic receptor, it binds to it.

• Stops/prevents feedback of autoreceptor

• Is therefore an antagonist at a synapse level because more NTs continue to be released into the synapse.

Pharmacokinetics: Intake

How a drug

·      Get into your body

·      Distribute

·      Get into the brain

·      Leave the body

Fastest route of intake

Intravenous injection

Slowest route of intake

Digestive tract

Intake of cocaine

Fastest → intravenous

→ Smokes

→ Intranasal

Slowest → Oral

Concentration and strength of drug

The quicker the concentration of the drug goes up in your blood, the stronger the effect.

Pharmacokinetics: distribution

Intravenous → distributed in blood across the body

Water-soluble molecules

Can be directly dissolved in the blood, but do not pass through cell membranes

Lipid-soluble molecules

Need carriers to transport them through the blood, but can pass directly through cell membranes

Penetration through skin

Cell membranes are made of fats

• Lipid soluble molecules can

• Water-soluble molecules can’t

Blood-brain barrier - capillaries around the body

• Gaps between endothelial cells

• Allows blood to flow in and out

Blood brain barrier - Capillaries in the brain

• No gaps between endothelial cells

• Stops molecules in blood stream from getting to brain unless they are needed (e.g. glucose)

• Special transport molecules that get molecules to the brain

Blood brain barrier - lipid soluble drugs

• Endothelial cell’s membrane has a lipid bilayer

• Therefore, lipid soluble drugs can easily cross blood-brain barrier.

Blood brain barrier - Non-lipid soluble drugs

• Cannot break the blood-brain barrier

• E.g. Alcohol is both water and libid-soluble, so can pass blood-brain barrier.

Ways drugs are eliminated from the body

• By chemical breakdown (by enzymes)

• By excretion (filtered by kidneys and released in urine)

Elimination of lipid-soluble drugs

• Can only be eliminated from the body if they are in the bloodstream

• Therefore, they remain in fat cells

• Take longer to be cleared - longer half-life

Biological Half-Life

Rate it takes for drug to be eliminated

Dose response curve

Intolerant subjects - minimum amount of drug → strong effect

Tolerant subjects - require more drug to get the same effect

Homeostasis

Mechanisms to maintain the state in the body

Metabolic tolerance

Better elimination of the drug

Functional tolerance

•       change in receptor numbers

•       change in receptor sensitivity

•       change in intracellular cascades

Negative feedback systems

• Counter the feedback of the drug

• Mechanisms are slow, gradual physiological responses.

Effect of negative feedback systems

·      Better elimination of the drug (metabolic)

·      Increase or decrease the number of receptors that react to the drug

·      May change receptors to be less sensitive to the drug. (functional)

Defintion of tolerance

• An active response of your body to a drug.

• It takes time to respond.

Withdrawal

Physical dependence on drug

• The body builds up a tolerance response.

Withdrawal effect

Tolerance mechanisms are present, even in the absence of the drug.

• Still changes in receptors.

• The tolerance mechanism pushes in the opposite direction to what the drug did.

Withdrawal and homeostasis

Pushes your body away from homeostasis

• Results in the opposite effect to the drug.

  • E.g. take away painkillers = more pain

• TAKES TIME TO GET RID OF WITHDRAWAL SYMPTOMS.

Classical conditioning and Tolerance – Siegal (1978)

Tolerance response triggered by context at which you took it

• Context triggers a compensatory response that raises tolerance

  • More likely to overdose in novel surroundings e.g. on holiday

• Triggers withdrawal symptoms

  • Even people who have been clean, context triggers withdrawal leading to relapse

Psychological Drug Dependence - Operant conditioning

1.     Stimulus →

2.     Perceptual - Neural circuit detects stimulus →

3.     Motor - Neural circuit controls particular behaviour →

4.     Behaviour →

5.     Reinforcing stimulus (reward) →

6.     Reinforcing system

• Strengthens connection between the Perceptual and Motor system

Intra-Cranial Self-Stimulation - Rats

·      Experiment – wanted to control rats

·      Stimulated the rats’ brains when they were in a certain place

·      If it hurt the rat, it would avoid that area

·      ACTUALLY found the rat went to that area more and more

Intra-Cranial Self-Stimulation - Operant Chamber

·      Stimulated same part of brain when pressing the lever

·      Rat repeatedly pressed the lever

·      Indicates REWARD SYSTEM was stimulated

Telencephalon

• Forebrain

• Cerebral cortex and basal ganglia

Diencephalon

• Forebrain

• Thalamus and Hypothalamus

Mesencephalon

Midbrain (stays the midbrain)

Tectum and Tegmentum

Metacephalon

• Hindbrain

• Cerebellum and Pons

Mylencephalon

• Hindbrain/spinal cord

• Medulla and Spinal cord

Mesotelencephalic Dopamine System

Connects midbrain to end brain

·      Dopamine functions as a neurotransmitter

·      Cell bodies in the mesencephalon

·      Makes lots of synapses in the telencephalon

Ventral tegmental area

-       Lots of dopaminergic neurons

Nucleus accumbens

-       Where dopaminergic neurons make synapses

Medial forebrain bundle

• A bundle of axons running from mesencephalon and telencephalon

Stimulation of medial forebrain bundle

• Easier to target than VTA

• Triggers the release of dopamine

Process of intracranial self-stimulation

Plant an electrode into the bundle of axons

• The animal presses the lever during intracranial self-stimulation of the MTP dopamine system

• The dopamine levels go up.

HOWEVER, this is correlational, NOT causal

How to test whether dopamine release is causally involved in the rewarding effect of intracranial stimulation?

Block the action of dopamine while stimulating

Stellar, Kelley & Corbett (1983)

1.     Stimulated Medial Forebrain bundle

• Releasing dopamine, get rats to self-stimulate

2.     Infuse dopamine antagonist (receptor blocker) in nucleus acumens

• Rats did NOT learn to press the lever

3.     Shows that dopamine released by stimulation is responsible for learning.

Role of VTA and nucleus accumens in reinforcement system

• Release of dopamine is part of reinforcement system in the Neural Model of Instrumental Conditioning

• Areas are part of reward sensation in brain

Why reward and pleasure are NOT the same

• Dopamine is released with punishing stimuli as well

• Overtrained rats do not release dopamine upon reward

  • Even if they enjoy the food

• Dopamine blockers make rats work less hard for food, but they still enjoy it

  • Antagonists – won’t learn but still enjoy food

Seeking/wanting hypothesis

Dopamine is not associated with pleasure

It is to do with:

1.     Gathering information

2.     Compulsion to do something again and again

E.g. Drug addicts have a compulsion to take the drug even if they do not enjoy it anymore

Evidence for seeking

Dopamine levels in male rat NA

1.     New environment (sex chamber) – increase dopamine levels

• No reward, info gathering

2.     Female gets introduced

• Next to male (cant reach)

3.     Introduced in the same compartment

4.     Female is taken away again

Dopamine increases where you wouldn’t expect “pleasure”

Associations of dopamine

1.     Novelty seeking, exploration

2.     Compulsion to repeat behaviour (even if pleasure has worn off)

Effect of cocaine and amphetamine on dopamine

Increases levels

Evidence supporting effect of cocaine and amphetamine on dopamine

Rat Study

1.     Self-injections into NA when lever pressed

• Dopamine increases

2.     Repeatedly press lever

• Learning to repeat behaviour that led to dopamine release

Psychological Drug Dependence in Humans

• Bypass systems in brain that assess whether something is good or bad

• Straight to releasing dopamine from VTA into NA

• Compulsion to take drugs in the future (behaviour that led to release in dopamine)

Brain areas associated with drug addiction

Mesotelencephallic dopamine pathway

• Mesencephalon:

  • Ventral Tegmental Area (VTA)

• Telencephalon:

  • Nucleus Accumbens (NA)

• Diencephalon (lateral hypothalamus):

  • Medial forebrain bundle