Lecture 4 - The Dopaminergic System

dopamine hit

a quick fix of dopamine/enjoyment, in the brain its the change in the neurotransmitter

dopamine

its a neurotransmitter in the monoamine category and fits the catecholamine category

catecholamines

have a similar structure as well as shared synthesis and metabolic pathways (shared drug sensitivity)

synthesis 

the first step in making dopamine, tyrosin is the precursor and the rate limiting step being tyrosine hydroxylase is what allows tyrosine to turn into dopamine, the dopamine B hydroxylase converts dopamine into noradrenaline, then noradrenaline is then used to make adrenaline, they share common pathways,

metabolism

this is done by dopamine B hydroxylase which metabolizes into noradrenaline, this is then used for adrenaline, they share common pathways, breakdown of noradrenaline into catechol-O-methyl-transferase and monoamine oxidase, this is produced through different routes making the metabolite homovanilic acid, the levels of dopamine should correlated to metabolite levels, 

why are metabolites useful?

because they allow us to infer transmitter levels, however the measurement isnt exactly accurate because the fluid compartment levels of a certain metabolism are different from levels found in the brain

spontaneous eye blink rate

favored as another measure of dopamine levels, correlated with cognitive processes and was thought to be correlated with DA levels, the idea is to look at eye blinks to infer dopaminergic tone but it was found to not be a good measure, drugs that affect dopaminergic levels are found to affect eye blinks, there’s a behavioral correlation

individual differences in dopamine

the DA signal may vary between healthy individuals, however the reasons are unclear because it could be genetic variations in COMT or transporter issues, correlations between the DA synthesis and behavior are being explored

vesicular storage

this is the idea that a transmitter can be stored in vesicles so that it can be released later by interacting with the presynaptic terminal

VMAT2

transports dopamine into the vesicles

reserpine

inhibits VMAT2 causing transmitter levels to drop, leading to sedation and depression like behavior

L-DOPA

reverses the effects of VMAT2 inhibition, you use it for treatment in parkinson’s disease so that the neurons can use it to make more dopamine because dopamine cant be administered directly due to the blood brain barrier

dopamine transporter (DAT)

brings extracellular DA back into the cell from synaptic cleft to the presynaptic neuron, many clinical drugs and drugs for abuse affect it

transport

the movement of a transmitter like dopamine from the ECM to some other area, for example, astrocytes have glutamate transporters

D1 family

this includes GS (stimulatory) coupled and excitatory receptors (D1 and D5 receptors)

D2 family receptors

this includes GI coupled and inhibitory receptors, these are the ones that are often linked with movement and disorders like substance abuse

auto receptors

receptor on a neuron that responds to its own transmitters

D2 autoreceptors

cause inhibitory feedback following DA release, it affects K+ channels and voltage gated Ca2+ channels to limit future DA release

peripheral dopamine

this is dopamine that is outside the brain, in other tissues it has specific functions like vascular tone and immune function, this is what ppl refer to as the dopamine hit

neural dopamine

this is the dopamine that is inside the brain, has different functions

dopamine in the body

dopamine does not travel between the peripheral and neural compartments because of the blood brain barrier (it cant cross it), this means that the peripheral levels of dopamine are different from the neural levels, this complicates inference of neural DA through peripheral fluids (not an exact measure)

mesolimbic pathway

this is the pathway that dopamine from the middle of the brain to the limbic system, it is involved in motivation and other functions

mesocortical pathway

this is the dopamine pathway that goes from the middle of the brain to the cortex, it is involved in cognition and other functions

nigrostriatal pathway

this is the dopamine pathway that goes from the substantia nigra to the striatum, it is responsible for movement and likely the most important dopamine pathway because it contains most of the dopamine in the brain (80%)

tuberoinfundibular pathway

this is the pathway that is implicated in hormonal release and prolactin release from the hypothalamus to the pituitary galnd

the nervous system and movement

it involves visual, tactile and proprioceptive input, it is regulated by processing later on

basal ganglia

this is where most movement occurs, it is a group of structures involved in coordinating movement, it has diverse inputs including the frontal cortex for voluntary movement

what is the basal ganglia made up of?

the caudate nucleus, the putamen/dorsal striatum, globus pallidus, subthalamic nucleus and the substantia nigra

substantia nigra

the neurons of this region use DA to signal to other structures, loss of their DA neurons in the defining feature of parkinson’s disease

DATKO

dopamine transporter knockout mice, they are shown to move way more

D1RKO

D1 receptor knockout mice, they not only move more but also have altered locomotor responses to cocaine (less responsive), this shows that the receptor plays a role in movement and drug response

parkinson’s disease

this is a progressive disorder of the nervous system affecting movement, it is defined by a loss of substantia nigra dopaminergic neurons so about 60% post mortem, age also plays a huge role in the disorder as well as genetics affecting a-synuclein and environmental factors 

parkinson’s disease symptoms

the idea is that you start with more neurons than you need so in the disorder you lose a certain amount until impairment is seen but at that point you cant regenerate them, patients will show increased risk of impulse control disoders which may be associated with medication, however some symptoms of the disease could actually be due to the treatment rather than the disorder itself 

monoamine oxidase B inhibitors and catechol-O-methyl transferase inhibitors 

these are used as an alternative to L-DOPA because they can limit the metabolism of dopamine so you can administer the precursor and allow it to stay in the brain for longer 

concerns of L-DOPA

it non selectively increase DA levels in the entire brain not just the mesostriatal pathway so other systems are also affected, increased DA elicited by this drug is not as precise as normal healthy DA transmission so sometimes the effects are too strong or too weak, it has unpleasant side effects like nausea, dyskinesia and psychosis

cost

the effort so time and energy you put in to obtain a reward, some are easier to get while others arent

motivation

the drive to obtain a reward, the incentive so the more willing you are to tolerate a high cost 

pleasure

the emotional response to acquisition (liking), it is secondary to the wanting/motivation aspect

key synapse for the reward system/mesolimbic pathway

the ventral tegmental area (VTA) to the nucleus accumbens, DA fibers in this synapse are important for motivation and reinforcement of behavior

phasic DA

these are brief strong bursts, situational, DA hits, they are associated with the increase in dopaminergic firing with the reward

tonic DA

this is weaker, it is the baseline level overtime, it is always there, the activity that is always there

nucleus accumbens

this is thought to play a key role in liking, it contains hedonic hotspots (enhancing the pleasurable reactions to rewards), they could be responsive to many different drugs, the circuit for liking may be small, the circuit for wanting could be larger and involve dopaminergic transmission

wanting vs liking

they are dissociable, motivation to obtain a substance just keeps increasing so wanting increase but the liking doesn’t go up, this is similar to the idea of chasing a high, the first time is always the highest so you just keep searching for that same feeling again

pleasure deafness theory 

this is characterized as the reduction in pleasure following substance use, it is used in a situation where there has been repeated indulgence in a response involving pleasure, the signaling of one neuron to the other is changing meaning that the relationship with the reward and pleasure has changed (when the reward system becomes less responsive to natural rewards)

addiction

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

why is the term addiction problematic?

this is because the idea of brain disease suggests that the focus on the brain is productive so its not a universal view, behavior can refer to many things, harmful is a poorly defined term

gateway drugs

these are drugs that are more socially acceptable that are used first and increase the likelihood of someone using hardcore drugs

substance use disorder risk factors

stability of home environment, early use and peer groups, education, employment, genetics, use and dependence rates are higher in men and overdose rates for some drugs are higher in women, mental health status

comorbidities of substance use disorder

highest is ADHD, bipolar disorder and intermittent explosive disorder

potential neural basis for substance use disorder

assuming that the problem has a basis in the brain, it could be associated with disturbances in systems of mood, affect and personality which involve the PFC and amygdala, when considering motivation and reward which involve the PFC and striatum/DA neurons which is the key pathway of study or it could be cognitive control which involves the PFC and specifically the OFC

DA signal

expect one thing and get something better, prediction error models, might be associated with drugs and many other rewards

craving

having a want for something that is not currently there, might involve a substance, in the case of drugs this is associated with dopamine release in the dorsal striatum and increase in cravings is associated with lower DA receptor availability  for the radioligand

self stimulation

in VTA neurons it is done using implanted electrodes via bar pressing to reinforce them, the reinforcing properties are absent if dopaminergic projection are lesioned, activation of this brain area and fibers is reinforcing so its something you want to do again

self administration tests

assess reinforcing properties via the number of bar presses, the higher the number them more reinforcing it is

conditioned place preference tests

the chamber is associated with a substance, if it is pleasurable the animal will spend more time in that area cause its associated with a pleasurable item or substance, we don’t see this happening with dopamine antagonism

DA signallng in addiction

in many addictions there is reduced release and reduced D2 receptor availability, this may suggest pervasive changes in reward value, PET scan is used to scan this receptor availability 

DA hypothesis evidence

rewards and cravings are accompanied by DA release, stimulation of DA neurons is reinforcing, antagonism of DA receptors can prevent slef administration of substance and abnormalities in DA transmission are common, striatal DA release and D2/3 receptor availability is reduced

DA hypothesis problems

there is a kind of chicken vs egg issue cause we don’t know if its the neural changes that cause the disorder or if its the other way around, studies in humans are fewer and correlational so DA changes could be before or after, the best evidence comes from drugs that affect the DA system so effects are small/non existent for non DA drugs, DA release associated with a drug does not predict its pleasurable/addictive properties

DA in wanting rather than liking

what we call change in wanting could be changing in VTA or dopaminergic connection, tolerance may explain some of the reduction in liking

role of the PFC in substance use disorder

reduced activity, particularly in the orbitofrontal cortex, may be associated with reduced ability to assess value and control behavior

treating SUD

there are many barriers that exist like stigma, legal implications of admitting addiction, the idea of addiction as a disease has implications for treatment efficacy and quality of life  so beliefs vary by country, prognosis is good so majority seeking treatment recover, treatment can take on many forms like psychological or drug treatment

pharmacological treatments

drug vaccines can be used but they are controversial and efficacy is uncertain, now they are switching to a less active/longer half life form of drug so it stays longer in the system, treatment could counteract pleasurable effects of the drug or they could mitigate withdrawal effects of the rug

methadone

used to treat opioid use disorder

varenicline and nicotine patches

used to get smokers to quit smoking

naltrexone

used to treat opioid use disorder and alcoholism , it counteracts the pleasurable effects of the drug by blocking certain receptors

acamprosate

used to mitigate withdrawal effects of the drug, it affects glutamatergic transmission, getting off alcohol is very dangerous and needs to be monitored because it could often cause seizures

positive symptoms of schizophrenia

hallucinations, delusions and disorganized speech, they are similar to effects of drugs that stimulate DA signaling like amphetamines and L-DOPA, these symptoms are reduced by drugst that block DA signalling like DA antagonists and antipsychotics like haloperdiol, they are associated with higher DA activity in the mesolimbic system

negative symptoms of schizophrenia

lack of emotion, impaired social interaction, they are associated with lower DA activity in the mesocortical pathway

cognitive deficits in schizophrenia

impaired attention, memory and executive function

why are schizophrenia symptoms grouped?

because each cluster/group has its own mechanism of action, co-occurrence and shared pathways

features of schizophrenia

it occurs in 1% of ppl, onset and severity differs by sex so males are affected earlier and have worse outcomes, many risk factors like cannabis use, with increase to access there is an emergence in schizophrenia cases, it is thought that a lot of it is genetic and heritable

neural features of schizophrenia

cortical atrophy in the temporal cortex, HPC and PFC, abnormal cell organization in the HPC and hypo frontality so low frontal cortex activity

dopamine hypothesis of schizophrenia

higher levels of DA metabolites/homovanilic acid, more D2 receptors, higher DA activity in the mesolimbic pathway associated with positive symptoms and lower DA activity in the mesocortical pathway associated with negative symptoms

prefrontal cortex

provides info that ultimately regulates both the mesocortical and mesolimbic pathway, their neurons are less active in schizophrenia due to hypofrontality, this causes increased mesolimbic system activity so higher DA and lower DA in the mesocortical systems

antipsychotics

most will block D2 receptors, they are typically selective in this action, there are atypical and conventional ones,

atypical antipsychotics

they don’t affect D2 receptors directly but they do it from an alternative pathway by blocking other related targets, examples include clozapine and risperidone, weight gain is a common side effect

conventional antipsychotics

they cause extrapyramidal motor symptoms especially tardive dyskinesia, they reduce movement and produce lots of prolactin due to the tuberoinfundibular pathway

DA memory and cognition

in monkeys, DA depletion in the PFC impairs WM and effects are reversed in agonists but in humans these agonists have complex effects like enhancement in ppl with poorer undrugged performance, it has no benefit in ppl with strong undrugged performance, the right level of DA is important

relationship between dopamine in PFC functions

too little dopamine and norepinephrine leads to fatugue and too high levels of dopamine and norepinephrine leads to stress, the right amount leads to an alert states, increased levels leads to different complements of receptors

ADHD

it is made up of two symptoms that manifest differently, inattention and hyperactivity/impulsivity 

inattention (ADHD)

causes lack of attention to details or careless mistakes, does not seem to listen when spoken to directly

hyperactivity/impulsivity

causes excessive fidgeting, running, climbing, restlessness in inappropriate situations

neural features of ADHD

reduced PFC volume/maturation, low DA signaling with is related to the reward deficiency theory so not lower dopamine levels but lower dopamine transporter levels, it is treated with psychostimulants like DAT and NAT blockers as well as non stimulants

psychostimulants

includes NAT and DAT blockers like amphetamine (adderall) and methylphenidate (ritalin), most work by increasing DA or NA transmission, long term effects could include changes in DAT levels

non stimulant use for ADHD

30% of ppl may respond to stimulants, other ppl might be at risk for interactions, non stimulants include atomoxetine, guanfacine and clonidine, there are different side effects for these particular drugs

atomoxetine

ADHD non stimulant drug that targets noradrenaline re-uptake

guanfacine and clonidine

ADHD non stimulant drugs that target a2 receptors activated by noradrenaline

can ADHD drugs help ppl who dont have it?

4-8% of college and uni students report non medical use to enhance performance, cognitive benefits in healthy ppl are modest, there are no strong associations of use with academic performance, benefits may go beyond cognition like reducing fatigue and increase motivation but could decrease quality, an important factor may be initial DA levels

other effects of DA drugs

altered perception with dopaminergic drugs (faster with agonists and slower with inhibitors), may contribute to altered temporal perception with ADHD