L04 The Dopaminergic System

• DA once of the most misunderstood NTs

• 5HT + DA connected and perhaps explains enjoyment state → incorrect oversimplification → it plays a much more complex role

• this view leads to idea that it is good thing to raise DA through several ways (thru good foods) → and then leads to idea that some ways are better than others (TV, alcohol, junk food = bad)

• leads to view that bad DA increases are associated with TV/substances and ultimately leads to addiction

Dopamine (DA)

• Monoamine (w/5-HT, NA + ADR) and catecholamine (w/NA + ADR)

• Catecholamines have a similar structure as well as shared synthesis + metabolism pathways

  • Shared drug sensitivity

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• DA fits into 2 categories

• this means that something like monoamine oxidase could affect DA because DA is a monoamine; or the enzyme called catechol-methyl transferase could also affect DA because DA is a catecholamine

• structural designations matter because compounds structured in the same way tend to be involved in the same synthesis + metabolism pathways as well

A dopaminergic neuron

• Synthesis

• Vesicular storage

• Transport

• Dopamine release

• Receptors (including autoreceptors)

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Synthesis + Metabolism (precursor → dopamine)

• Precursor is tyrosine

• Rate-limiting step is tyrosine hydroxylase (TH)

• Metabolized by Dopamine-β-hydroxylase (DBH) to NA

• In turn, NA is used for ADR (L05)

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Metabolism (breakdown + metabolite)

• Breakdown by catechol-O-methyl-transferase (COMT) and monoamine oxidase (MAO)

  • Regional variation (e.g. more COMT in PFC)

  • Potential therapeutic targets

• HVA (homovanillic acid) is a metabolite

  • Sometimes used as a surrogate measure of DA levels

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Other measures

• Spontaneous eye-blink rate (EBR) was once favored

• EBR was correlated with cognitive processes and was thought to be correlated with DA levels

• More recent studies question this idea (found reverse)

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Individual differences

• DA signaling may vary between healthy individuals

• Reasons unclear but many possibilities (e.g. Genetic variations in COMT, DA synthesis and more)

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Vesicular storage

• DA is transported into vesicles by VMAT2

• Reserpine inhibits VMAT2

• With reserpine: transmitter levels drop, sedation and depression-like behavior observed

• Effects of VMAT2 inhibition are reversed by L-DOPA

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Transport

• The dopamine transporter (DAT) brings extracellular DA back into the cell

• Many clinical drugs (e.g. for ADHD) and drugs of abuse (e.g. cocaine) affect DAT

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DA receptors

• We mostly cover D1 + D2 receptors.

• Gs-coupled and excitatory

• Gi-coupled and inhibitory

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D2 autoreceptors

• Inhibitory feedback following DA release

• Affect K+ channels and voltage-gated Ca2+ channels to limit future DA release

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Dopamine in the body

• Peripheral dopamine (outside the brain) has specific functions

  • Vascular tone, Immune function and more

• Neural dopamine (our interest, inside the brain) has different functions

• The two compartments are separate

  • Peripheral DA doesn’t enter the brain (BBB)

  • Complicates inference of neural DA through peripheral fluids

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DA Pathways

Four pathways, implicated in different functions and different disorders.

• Mesostriatal/Nigrostriatal = midbrain (SN) to striatum

  • Role in movement

  • 80% of your brain’s DA is in this pathway

• Mesocortical = midbrain (VTA) to cortex (PFC) (boxed)

  • Role in cognition and other functions

• Mesolimbic = midbrain (VTA) to limbic system (BG) (boxed)

  • Role in motivation and other functions

• Tuberoinfundibular = hypothalamus to pituitary

  • Hormones (prolactin release)

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The Nervous System + Movement

Basal Ganglia (BG)

• Group of structures involved in movement

  • Suppression, facilitation, etc.

• Diverse inputs

  • including the frontal cortex

• Includes the caudate, putamen (= dorsal striatum), globus pallidus, subthalamic nucleus and substantia nigra

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SM in Movement

• SN neurons use DA to signal to other structures

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Altered DA, altered movement!

• DATKO mice show more movement

• D1RKO mice show more movement and altered responses to cocaine

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Parkinson’s Disease (PD)

• Progressive disorder affecting movement*

• Associated with loss of SN neurons (~60% post-mortem)*

• Age is a major factor; genetics might contribute also (α-synuclein) as might certain environmental factors

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PD symptoms (motor + non-motor)

• Increased risk of impulse control disorders has been observed but may be associated with medication.

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If the problem is ‘too little’ DA, would pharmacologically increasing DA levels be a treatment?

Increasing DA in PD

• We cannot administer DA directly as it does not cross the blood-brain barrier

• L-DOPA, however, crosses and can be made into DA

• Drugs for PD can include L-DOPA (levodopa)

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Increasing DA through other targets

• Limit metabolism of DA with monoamine oxidase B inhibitors + catechol-O-methyl transferase inhibitors

Concerns about drug approaches

• L-DOPA non-selectively increases DA levels non-selectively

  • Other systems are affected (e.g. mesocortical)

• DA modulations by drugs do not restore normal signaling

  • Imprecise (timing and intensity)

• Side effects (e.g. nausea, dyskinesia, psychosis and delusion)

• Other treatment strategies being explored (e.g. DBS)

DA, motivation and substance use disorder

Key concepts

• Cost: Effort (time and energy) to obtain

  • High ~ many bar presses, Low ~ few bar presses

• Motivation: Drive to obtain (~ wanting, incentive salience)

  • More motivated, more willing to tolerate high cost

• Pleasure: Emotional response to acquisition (~ liking)

• All are inter-related and regulated by striatal DA.

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Reward System

• Many structures are in the mesolimbic pathway (DA)

• One key synapse is well-studied: Ventral Tegmental Area (VTA) → Nucleus Accumbens (NAc)

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DA neurons in the VTA

• Phasic DA: Brief, strong bursts (situational; ~ DA hits)

• Tonic DA: Weaker, baseline level over time

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DA ramping

• DA concentration increasing leading up to an action performed for reward

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Nucleus accumbens

• Thought to play a role in liking; contains so-called hedonic hotspots

• Circuit for liking may be small, circuit for wanting could be larger and involve dopaminergic transmission

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DA in wanting rather than liking

• Changes in the reward system and/or cognitive control?

• VTA function?

• More linked to DA

• Tolerance to pleasant effects?

• NAc function?

• Less linked to DA

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Feedback model

• Adjustments possible with experience (pleasure deafness theory)

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Substance use disorder (formerly addiction) - definition

“complex brain disease in which there is a compulsive engagement in behavior despite knowledge of harmful consequences”

• Issues with this approach

  • “Brain disease” suggests focusing on the brain is productive, even required

  • “Behavior” can refer to many things (e.g. drug use and gambling, but what else)

  • “Harmful” is hard to define (e.g. to the user or others)

• The term is being phased out as it is seen as vague and stigmatizing

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Risk factors

• Stability of home environment

• Early use + peer groups

• Education

• Employment

• Genetics

• Gender

• Mental health status

• Co-morbidities frequent

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Potential neural basis

SUD could be associated with systems for…

…mood, affect and personality (PFC and amygdala)

• Mental health comorbidities are common

• Drug use sometimes is related to personality

…motivation/reward (PFC and striatum/DA neurons key)

• Behaviors may be more “appealing”

• The evaluation of benefits and costs may be different

…cognitive control (PFC, in particular the OFC)

• Difficulty regulating behavior is part of the disorder

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The DA hypothesis

“Reward signal”

• DA signal ~ “better than expected” outcome (prediction error models

• DA signals might be associated with drugs* and many other rewards

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Craving

• Drug cravings in SUD are linked to DA release in the dorsal striatum

• Greater cravings ~ lower DAR availability for the radioligand

DA neurons in the VTA

• Self-stimulation of VTA neurons using implanted electrodes (via bar pressing) is reinforcing

• Reinforcing properties of self-stimulation are absent if dopaminergic projections are lesioned

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DA antagonists in animal models

• Self-administration tests for reinforcing properties (top)

  • # of bar presses

• Conditioned place preference tests assess preference (bottom)

  • Time spent in drug-paired chamber vs. another chamber

• Self-administration and CPP for some drugs in animals can be blocked by dopamine antagonists

DA signaling in addiction

• In many* addictions, there is reduced striatal DA release and reduced D2 receptor availability

• May suggest pervasive changes in reward value

DA signaling in addiction

DA hypothesis – Evidence

• Rewards and cravings are accompanied by DA release

• Stimulation of DA neurons is reinforcing

• Antagonism of DA receptors can prevent self-administration of substances

• Abnormalities in DA transmission occur in SUD

  • Striatal DA release + D2/3 receptor availability is reduced

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DA hypothesis – Problems

• Studies in humans are fewer and correlational

  • DA changes could come before (risk factor) or after (a result

• Best evidence comes from dopaminergic drugs (e.g. amphetamines)

  • Effects small/non-existent for non-DA drugs (nicotine, opioids and cannabis)

• DA release linked to a drug doesn’t predict its pleasurable properties

  • DA firing can be linked to other things, like the probability of reward delivery (e.g. cost, overall motivational state)

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Potential neural basis

From earlier slide:

SUD could be associated with systems for…

…mood, affect and personality (PFC and amygdala)

• Mental health comorbidities are common

• Drug use sometimes is related to personality

…motivation/reward (PFC and striatum/DA neurons key)

• Behaviors may be more “appealing”

• The evaluation of benefits and costs may be different

…cognitive control (PFC, in particular the OFC) → highlighted

• Difficulty regulating behavior is part of the disorder

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Role of the frontal cortex

• Reduced activity (particularly in the orbitofrontal cortex) may be associated with reduced ability to assess value and control behavior

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Treating SUD

• Many barriers (stigma, legal implications); many do not seek treatment

• Idea of addiction is a “choice” or “a disease” has implications

  • Societal level: support for treatment programs, laws and policies

  • Clinician level: treatments offered and how they are administered

  • Individual level: well-being and recovery

• Prognosis good; majority seeking treatment recover

  • Treatment takes many forms; including some pharmacological methods

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Pharmacological treatments

• Drug vaccines (controversial, efficacy uncertain)

• Switching to a less active/longer half-life form of drug

  • Methadone for opioid use disorder, varenicline and nicotine patches for smokers

• Counteract “pleasurable” effects of drug

  • Naltrexone for opioid use disorder and alcoholism (L02)

• Mitigate withdrawal effects of the drug

  • Acamprosate for alcoholism

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Symptoms of SZ

• Positive symptoms

  • Hallucinations (seeing/hearing things not there)

  • Delusions (beliefs not based in fact)

  • Disorganized speech

• Negative symptoms

  • Lack of emotion (pleasure, motivation)

  • Impaired social interaction

• Cognitive deficits

  • Impaired attention, memory and executive function

• Each symptom cluster may have its own mechanism

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Features of SZ

• ~1% of the population (similar worldwide)

• Onset and severity differs by sex (males affected earlier, worse outcomes)

• Multiple risk factors (e.g. cannabis, L08)

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Neural features of SZ

• Cortical atrophy (temporal cortex, HPC and PFC)

• Abnormal cell organization (HPC)

• Hypofrontality

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DA hypothesis of SZ

• Higher levels of DA metabolites (HVA)

• More D2 receptors

• Positive symptoms are similar to the effects of drugs that increase DA signaling (e.g. amphetamine, L-DOPA)

• Positive symptoms reduced by drugs that block DA signaling (DA antagonists; antipsychotic drugs such as haloperidol)

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Dopamine Hypothesis of SZ

• Higher DA activity in mesolimbic

• Lower DA activity in mesocortical

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How can we get two different effects on DA pathways?

Things might start in the PFC

• PFC differentially regulates both pathways

• PFC neurons are less active in SZ (hypofrontality)

• Downstream effects:

  • increased mesolimbic (higher DA)

  • decreased mesocortical (lower DA)

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Antipsychotic drugs

• Most antipsychotics block D2Rs

• Typical antipsychotics are relatively selective for D2

• Atypical antipsychotics (e.g. clozapine, risperidone) block other targets (e.g. 5-HT2 receptors)

• For conventional antipsychotics, extrapyramidal motor symptoms (esp. tardive dyskinesia) are common

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DA, memory and cognition

• In monkeys:

  • DA depletion in the PFC impairs working memory

  • Effects reversed by DA agonists

• In healthy humans, DA agonists (e.g. bromocriptine):

  • Improve outcomes for people with poor “undrugged” performance

  • No benefit in people with strong “undrugged” performance

• …we’ve seen this pattern before…

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The inverted U relationship

ADHD

• In the case of inattention, many examples:

  • Lack of attention to details or careless mistakes

  • Does not seem to listen when spoken to directly

• In the case of hyperactivity/impulsivity:

  • Excessive fidgeting

  • Running, climbing, restlessness in inappropriate situations

• Three forms (2 predominant forms + combined form)

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Why are ADHD rates rising?

Neural features of ADHD

• Reduced PFC volume/maturation (+ other effects)

  • Brain scans not part of diagnosis

• Complex alterations in the DA system

  • Transport and synthesis

• Treated with psychostimulants and non-stimulants

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Psychostimulants

• Most work by increasing DA or NA transmission

• Amphetamine (Adderall) and methylphenidate (Ritalin) both inhibit DAT and NA transporters

  • Long-term effects could include changes in DAT levels

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Why do these drugs work?

Non-stimulant use for ADHD

• 30% of people may not respond to stimulants

• Other people might be at risk for interactions

• Non-stimulants for ADHD are also available: atomoxetine (targets noradrenaline re-uptake), guanfacine and clonidine (which target α2 receptors, activated by noradrenaline)

• Different side effects for these particular drugs

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If they help with ADHD…

• 4 – 8% of University students report non-medical use for performance

  • Not limited to “bad students”, diligent students use it too

• Cognitive benefits in neurotypical people are modest

  • Benefits may go beyond cognition (e.g. reducing fatigue)

  • Increase motivation, but may decrease quality

• An important factor may be initial DA levels

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Other effects of DA drugs

• Altered time perception with dopaminergic drugs (faster with agonists, slower with inhibitors)

• May contribute to altered temporal perception in ADHD

• Temporal perception is fascinating – more next week (again, L05)

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