EoN M3 Topic 3

Inverse agonist

• Binds to same site as agonist

• Activates a pathway that has the opposite effect of the agonist on the cell

Antagonist

• Blocks or dampens receptor response to an agonist

• Have affinity but not efficacy

• Binding to orthosteric or allosteric site

• Competitive = binds to same site as endogenous agonist

• Uncompetitive = binds to allosteric site when agonist is bound and blocks response

Negative allosteric modulator

• Binds to allosteric site and decreases efficacy and or affinity of endogenous agonist

• Will not do anything to the receptor by itself

Agonist

• Binds to the orthosteric site to stimulate a receptor

• Induces a conformational change that activates a receptor

• Can be endogenous or exogenous

• May require a co-agonist e.g. NMDA receptor requires glutamate + glycine

Positive allosteric modulator

• Binds to allosteric site and increases efficacy and or affinity of endogenous agonist

• Efficacy = Magnitude of effect

• Affinity = How strongly an agonist will bind

• Will not do anything to the receptor by itself

Orthosteric

Site where endogenous agonist binds

Allosteric

A site where compound binding can regulate response to endogenous agonist

Stimulants

• increase activity of the CNS and PNS

• common effects include alertness, euphoria, motivation, heart rate

• Caffeine, nicotine, amphetamines (MDMA, meth, ADHD meds), cocaine

Hallucinogens

• alter perception, thought, mood, and consciousness

• minimal effect on intellect, ANS activation and craving

• Psychedelics, dissociatives, deliriants

Depressants

• decreases activity of the CNS and PNS

• decreased alertness, anxiety, muscle tension, pain

• Alcohol, anti-seizure medication, anaesthetics

3 key dopaminergic pathways

Nigrostriatal - voluntary movement production (substantia nigra)

Mesocortical - cognition, memory + learning, emotional regulation (ventral tegmental area)

Mesolimbic - emotion, perception, reward (ventral tegmental area)

Primary reward

• necessary for survival

• e.g., food

Secondary reward

• helps get a primary reward

• e.g. money

Prediction error

• the difference between what was received and what was expected

• Positive prediction error from unexpected reward

• Negative prediction error from omission of predicted reward

Negative prediction error neural correlate

• activity in the ventral tegmental area drops below baseline

• Activity corresponds with the amount of dopamine release

Wanting

• Desire for a reward or a goal triggered by dues or imagery

• Activity in the ventral tegmental area (VTA) and the mesolimbic pathway (VTA projects to nucleus accumbens)

Liking

• Positive emotions related to pleasure, such as joy and euphoria

• activity in a series of "hedonic hotspots"; parts of the brain where activity corresponds to liking something, ranging from food through to social interaction.

• prefrontal cortex, small part of nucleus accumbens

• Signalling through opioid and endocanabinoid receptors

Risk factors for addiction

• heritability

• polymorphisms in genes encoding pathway proteins

• dopamine inactivation

• personality traits and temperament

• SES

• Availability

• Social stressors

• Antisocial peers

Symptoms of addiction

• craving

• tolerance

• withdrawal

Consequences of chronic substance use (brain)

• downregulation of dopaminergic system: lower level of dopamine receptors

• dysregulation in orbitofrontal cortex (important for inhibiting compulsive behaviours)

• reduced response to natural rewards

• tolerance

• preoccupation with drug taking

• craving

Anxiety disorders symptoms

• Excessive and disproportionate worry about a broad spectrum of topics, events, and activities for more days than not

• The worry is often about mundane everyday things that displaces from one thing to another

• The worry must be: 
      1. Difficult to control
      2. Associated with physical symptoms e.g restlessness, fatigue, sleep difficulty

Depressive disorders symptoms

• At least one of:
  Depressed mood most of the day nearly every day
  or
  Anhedonia: Markedly diminished interest of pleasure in all or almost all activities mode of the day nearly every day

• At least three of the following: 
      1. Change in weight or appetite, whether increase or decrease
      2. Change in amount of sleep, either increase on decrease
      3. Change in movement, restless or feeling slowed down
      4. Fatigue
      5. Feelings of worthlessness or guilt
      6. Difficulty with concentration and indecisiveness
      7. Suicidality

Schizophrenia spectrum and other psychotic disorders symptoms

• At least one positive symptom, described as the addition of something to normal experience:
  Delusions: A false, fixed belief held despite evidence to the contrary e.g. belief in being conspired against or watched
  or
  Hallucinations: A false sensory experience in the absence of a stimulus being present e.g. hearing something that is not there
  or
  Disorganised speech

• At least one of: 
       1. Another positive symptom
       2. Grossly disorganised behaviour or catatonia, the abrupt absence of responding 
       3. Negative symptoms: the lack of something that is normally experienced 
       e.g. depressive symptoms, such as diminished emotional expression or anhedonia

• Disturbance in functioning on one or more areas is markedly below that achieved prior to onset

• difficulties with working memory

Aetiology

a set of factors that are associated with developing a mental heath condition

Pathophysiologoy

A change in brain function, caused by pathogenesis

Pathogenesis

the process by which a set of risk factors begin to change how the brain functions before the onset of a mental health disorder

GAD risk factors

Genetics:

• child of a parent with GAD more likely to develop

• Polymorphisms associated with serotonin signalling

Environment:

• parental modelling

• Childhood trauma

• Gene x environment interactions

Pathophysiology of GAD

• activation of sympathetic division of ANS

• Overactivity of amygdala activates the HPA axis

• release of cortisol from HPA axis (Hypothalamis-pituitary-adrenal)

• Excessive cortisol leads to degeneration of hippocampus

Pharmacological treatment of GAD

• Increasing activity of the GABAa receptor

• Benzodiazepines: act as a positive allosteric modulators of GABAa

• SSRI’s targeting 5-HT system: may work by increasing corticolimbic activity

MDD risk factors

Genetics::

• first-degree relatives of a person diagnosed are 2-3 times more likely to develop in their life time

• Likely arising from multiple genes having small effects

Environment:

• childhood trauma

Gene x environment interactions: serotonin gene transporter x early life stress

Treatment of MDD

• MAOIs, Tricyclics, SSRIS

• Ketamine

Monoamines

• serotonin

• dopamine

• epinephrine

• norepinephrine

Pathophysiology of MDD

• monoamine hypothesis: low levels of monoamines underlie symptoms of depression

Ketamine as treatment for MDD

• Ketamine acts as an NMDA receptor antagonist. This means that it will block entry of Na+ into a neuron

• This causes an increase in activity at the other ionotropic glutamate receptor, called the AMPA receptor

• Levels of a BDNF increase, which drives synaptogenesis

Pharmacological treatment of schizophrenia

Typical first generation antipsychotics

• D2 receptor antagonist

• debilitating extrapyramidal side effects

Atypical second generation anti pscyhotics

• clozapine

• Target D2 but also 5-HT receptors

• same efficacy as typical drugs but less motor side effects

Targeting Acetylcholine system

• Interacts with muscarinic acetylcholine receptors

• Downstream effect on regulating dopamine

Pathophysiology of schizophrenia

• Global decrease in GM and WM volume

• Decrease in cortical thickness, particularly PFC

• Increased ventricular volume

• Increased activity in auditory and speech processing areas with auditory hallucination

• Altered connectivity between L and R DLPFC. and PFC to HPC during WM tasks

• Dopamine hypothesis: increased dopamine signalling in mesolimbic pathway, decreased dopamine signalling in mesocortical pathway

• glutamate hypothesis: hypofunction of NMDA receptors, change in dopamine is a consequence of that glutamate

Schizophrenia risk factors

Genetics

• 50% chance for identical twins

• 10% chance if first-degree relative

• 108 genes implicated. DA, 5-HT, glutamate, GABA

Environment

• maternal infection

• Paternal age

• adolescent cannabis use

Gene x environment interactions