Lecture 2 - Brain Substrates Flashcards
1
Q
Catecholamines
A
- Psychomotor stimulants (noradrenaline, dopamine, adrenaline, serotonin, acetylcholine)
- Neurotransmitters and hormones derived from the amino acid tyrosine
2
Q
What is the role of catecholamines?
A
- They play key roles in the body’s stress response, regulation of blood pressure, heart rate, and various metabolic processes
- Tyrosine is to do with dopamine synthesis
- Enzymes turn catecholamines (starting with tyrosine) into the following one ^^
- Become addicted to adrenaline/noradrenaline release, not actual behaviour
- One group of drugs that surround adrenaline/noradrenaline
3
Q
Hacking catecholamines
A
- A: potential to bond at dopamine receptor site
- B: full agonist for receptor (neuron passes on electrical signal to do something else)
- C/D: antagonist (not dopamine) (drug attached but no response triggered)
- Lock and key analogy
- Then less sensitive to dopamine because receptors are full of antagonists which aren’t dopamine
4
Q
Illegal drugs
A
- Cocaine = inhibits DA and NA transporters (receptors pick up more dopamine as it can’t be transported away)
- Amphetamines e.g. MDMA = increased DA and NA release into synaptic cleft
5
Q
Legal drugs
A
- Help people struggling to balance neurotransmitter levels
- Risperidone = blocks DA receptors to reduce levels (used in SZ and bipolar treatments)
- Ritalin = blocks DA and NA uptake/transporters (i.e. ADHD)
- Some antidepressants that inhibit monoamines (enzymes that breakdown catecholamines) prolonging catecholamine action
- Reserpine = general catecholamine antagonist. Inhibits VMAT, a protein responsible for moving them back into vesicles (i.e. less to use)
6
Q
Carlsson, Lindqvist & Magnusson (1957)
A
Inject rabbits with drug and found no alertness, excitement, reward (became completely lethargic/major depressive state)
- DOPA is a direct agonist for dopamine (we don’t know if its to do with NA or DA as DOPA is a precursor to both catecholamines)
7
Q
Indirect agonists
A
- Drugs aren’t directly related to dopamine system (interact with and affect levels – catecholamines don’t exist in a vacuum)
- Bloomfield et al. (2016) – THC promotes DA release through cannabinoid receptors (THC not directly influencing dopamine system – becomes behaviourally addictive)
- Long term DA system dulling (weed effects both DA system and cannabinoid system. Indirect – not primary action)
- Reigel et al. (2007) – same results
- Suggests that most drugs have an effect on the DA system, either directly or indirectly
8
Q
Dopamine
A
Most involved neurotransmitter in addiction (most addictive and other drugs directly or indirectly nudge levels up and down)
9
Q
Dopamine pathways
A
- Neural circuits through which dopamine travels to regulate various physical and psychological functions
- These pathways are critical for processes like movement, reward, motivation, emotion and hormonal control
- Routes through which dopamine travels
- Often want to target one or two but not others (people often have an imbalance – want dopamine to be higher in some places and lower in other places)
- Mesocortical (blue) – from dopaminergic neurons in ventral tegmental area (VTA) to cortex
- Mesolimbic (purple) – from VTA to nucleus accumbens (NAC, basal forebrain, ventral striatum)
- Nigrostriatal (yellow) – from substantia nigra to the striatum
- Tuberoinfundibular (green) – from hypothalamic nuclei (arcuate nucleus and periventricular nucleus) to the pituitary
10
Q
Mesocortical
A
- Regulates cognition, decision-making, emotion and social behaviour (PFC)
- Originates in the ventral tegmental area (VTA) but projects to the prefrontal cortex
- Dysfunction or underactivity is associated with negative symptoms of SZ (e.g. apathy, lack of motivation) and cognitive impairments
- Often want to increase levels in the prefrontal cortex e.g. risperidone promotes DA in the PFC (can however result in side effects)
- Risk of SZ symptoms with overstimulation (can be seen in people that overuse psychomotor drugs)
11
Q
Mesocortical drugs
A
- Drugs that target the mesocortical dopamine pathway primarily aim to modulate dopamine activity in the prefrontal cortex (PFC)
- These drugs are used to address cognitive dysfunction, emotion regulation, and negative symptoms in conditions like SZ, ADHD (e.g. Ritalin and Adderall which increase dopamine and NA in PFC) and depression
- E.g. risperidone, which promotes DA in the PFC while controlling hyperactive mesolimbic dopamine (doesn’t touch levels too much elsewhere)
12
Q
Mesolimbic
A
- Involved in reward, motivation and the feeling of pleasure. This pathway plays a central role in reinforcing behaviours and the development of addiction
- Originates in the VTA and projects to the nucleus accumbens and other limbic areas (like the amygdala and hippocampus – reward pathway)
- Overactivity in this pathway is linked to addiction, positive symptoms of SZ (e.g. hallucinations) and other disorders involving reward-processing
- Need a reward system so we do the things that promote survival
- This is primary reinforcement to repeat behaviours
13
Q
Mesolimbic drugs
A
- Drugs that target the mesolimbic dopamine pathway primarily aim to modulate dopamine activity in the reward and motivation system in the brain
- These drugs are commonly used to treat SZ, addiction, depression and Parkinson’s disease
- Decrease activity = (D2 receptor antagonists) antipsychotics e.g. for ADHD where we want high DA/NA in the PFC and low DA/NA here (targeted drugs!)
- Can also be used when low dopamine in the mesolimbic pathway contributes to depression, addiction withdrawal or Parkinson’s disease
- Increase activity = motor agonists (ropinirole for Parkinson’s/depression, psychostimulants for ADHD)
- High dopamine in the mesolimbic pathway results in psychosis, addiction and mania
- Low dopamine in the mesolimbic pathway results in depression, anhedonia, apathy (as seen in Parkinson’s)
14
Q
Nigrostriatal
A
- Crucial for motor control, and drugs that target it are primarily used for Parkinson’s disease, drug-induced movement disorders and Huntingdon’s disease
- Low dopamine in the nigrostriatal pathway -> Parkinson’s disease, drug-induced Parkinsonism
- Lowering DA here = floppy
- Excess dopamine in the nigrostriatal pathway -> tardive dyskinesia (uncontrolled movements e.g. in face, arms, tongue), Huntington’s chorea (stop regulating own movements)
- Drugs not always target perfect and may slightly affect other pathways (not even 100 years into developing drugs) e.g. people taking drugs to lower dopamine in mesolimbic pathway report feeling heavy (inadvertently lowering dopamine in nigrostriatal pathway)
15
Q
Tuberoinfundibular
A
- Regulates the secretion of prolactin from the anterior pituitary gland, playing a role in hormonal control
- Originates in the hypothalamus (arcuate nucleus) and projects to the pituitary gland
- Dysfunction can result in hyperprolactinemia, leading to symptoms such as infertility, sexual dysfunction and galactorrhoea (milk production)
16
Q
Tuberoinfundibular drugs
A
- DA acts as a prolactin antagonist
- Want to ensure dopamine levels don’t get too low (because then prolactin gets too high)
- Increased prolactin (hyperprolactinemia) can lead to infertility, menstrual irregularities, decreased libido and galactorrhoea
- Decreased prolactin is rare and usually not clinically significant unless in conditions like hypopituitarism
17
Q
Other pathways
A
- NA and 5H-T pathways exist
- Projections of that system are very widespread across brain (no real evidence of separate distinct pathways – one single pathway, making it more difficult to target drugs along those pathways)
- More implicated in being aroused and awake, or in an extreme form agitation (similar to DA, but DA agitation is from a reward driven perspective). NA not really implicated in the reward system
18
Q
How do we target drugs?
A
- DA had multiple receptors (dopamine is a single key with multiple receptors)
- D-1 like (D1, D5) and D2-like (D2, D3, D4)
- Target drugs specifically to dopamine receptor types
- Multiple locks for the same key (which have different densities across the 4 dopamine pathways)
- Some activate easily (D3) and others less so (D1)
- Some excite the neuron (D1-like) while others calm it down (D2-like)
- Located in different regions e.g. D1 is key for motivation and movement, while D3 is more involved in addiction and impulse control
- Receptors often located in different densities in different regions e.g. more D3 in mesolimbic pathway and D1 in nigrostriatal
19
Q
Beyond drugs
A
- Giros et al. (1996) – genetic engineering – ability for rats to generate dopamine transporters so lost ability to transport high amounts of dopamine (rate immune to cocaine addiction)
- Potential further implications – a world where people physically can’t get addicted
- From birth, not CRISPA edited
- Heterozygous = 1 deletion
- Homozyhour = double deletion (so you see an effect) – the dopamine transporter would usually remove the dopamine
- Xu, Ghuo, Vorhees & Zhang (2000) = mutant mice lacking D1 receptors are insensitive to cocaine which increased locomotor activity in the wild-type but not the knockout mice
- Many drugs coming in can have drastic side effects in the long run due to the DA system being damaged (e.g. haloperidol)
