Dopamine & Dopaminergic Drugs

Most important sites of dopamine in the brain

substantia nigra

ventral tegmental area

ventral hypothalamus

Dopamine containing cells in the substantia nigra project where (& pathway name)

substantia nigra → striatum

(nigrostriatal pathway)

nigrostriatal pathway function

Movement regulation 

Dopamine containing cells in the ventral tegmental area project where (& pathway name)

ventral tegmental area → nucleus accumbens, frontal cortex and amygdala (mesolimbocortical pathway)

mesolimbocortical pathway function

Reward regulation

Dopamine containing cells in the ventral hypothalamus project where (& pathway name)

ventral hypothalamus → median eminence and pituitary gland (tuberohypophyseal system)

How do the nigrostriatal & mesolimbocortical pathways link up in drugs when treating Parkinson’s

People receiving dopamine to treat Parkinson’s can develop addictions associated with overstimulation of the mesolimbocortical pathway

Tyrosine is taken into the neuron via …….

carrier mediated transport

Tyrosine is converted to dopamine in 2 steps catalysed by what

tyrosine hydroxylase & DOPA decarboxylase

Dopamine is actively/passively packaged into vesicles by _____

Dopamine is actively packaged into vesicles by an amine transporter

Release of dopamine is released via what mechanism

via classical Ca2+-mediated exocytosis

How is dopamine action terminated

Termination is via uptake by a dopamine transporter

How is dopamine degraded

Degradation is via monoamine oxidase, aldehyde dehydrogenase and catechol-o-methyltransferase

Dopamine exerts its effects via 2 types of receptors - name them

D1-type receptors

D2-type receptors

What are the subtypes of D1 & D2 type receptors

D1 type receptor subtypes:

• D1

• D5

D2 type receptor subtypes:

• D2

• D3

• D4

D1-type dopamine receptors act via what G-protein to cause what effect

Gs (stimulates adenylate cyclase → ↑cAMP)

D2-type dopamine receptors act via what G-protein to cause what effect

Gi (inhibits adenylate cyclase → ↓cAMP)

Gq (activates PLC → ↑ IP₃/DAG)

Activation of the D1 type of dopamine receptor mainly causes excitation/inhibition of the pre/post-synaptic neuron

Activation of the D1 type of dopamine receptor mainly causes excitation of the post-synaptic neuron

D2-type receptors location

Widespread in the brain

Located both presynaptically and postsynaptically

Effect of D2-type receptors

Mostly inhibitory effects on presynaptic and postsynaptic neurons. (For example, D2 receptors can be presynaptic inhibitory receptors and/or presynaptic inhibitory autoreceptors supressing release of dopamine from dopaminergic neurons.)

Stimulates/Inhibits hormone release

Dopamine uses 3 pathways of dopaminergic neurons. Name them & their functions

Nigrostriatal pathway → Motor control

Mesolimbocortical pathway → Mediating effects of rewarding stimuli

Tuberohypophyseal pathway → Neuroendocrine function

Dopamine mediates the ‘_____’ impact of natural rewards (e.g. food/sex)

hedonic

What part of mesolimbocortical is the most detrimental to affect

nucleus accumbens

In the tuberohypophyseal pathway, what hormone does dopamine inhibit & what hormone does it promote

Dopamine inhibits prolactin and stimulates growth hormone secretion

Loss of which dopaminergic neurons is associated with Parkinson’s disease

dopaminergic nigrostriatal neurons

First-line therapy for Parkinson’s disease

dopamine replacement: L-DOPA (the DA precursor!)

What type of drugs cause schizophrenia-like symptoms

Drugs which release dopamine (e.g. amphetamine)

Which dopaminergic pathway is affected in Schizophrenia & in what way is it affected

Hyperactivity of mesolimbocortical DAergic pathway

What type of drug is used as treatment for Schizophrenia

dopamine antagonists (esp. D2 receptor)

What is the link between drug addiction & dopamine

Many drugs of abuse (e.g. amphetamine and cocaine which release and block DA reuptake respectively) hijack the DA reward system to mediate their rewarding effects

What type of disease is Parkinson’s

A progressive neurodegenerative disorder

Parkinson’s symptoms

- Tremor at rest

- Muscle rigidity

- Bradykinesia

Parkinson’s affects what % of the population over 65

1%

Parkinson’s is associated with the degeneration of dopaminergic neurons of what pathway

nigrostriatal pathway

Parkinson’s is associated with the formation of what

formation of Lewy bodies (misfolded proteins containing alpha-synuclein)

What is the specific cause of the motor symptoms associated with Parkinson’s

loss of dopamine from the striatum

Symptoms manifest after what % of the nigral dopamine neurons have degenerated & what % of striatal dopamine has been lost

Only after 60% have degenerated & 80% of striatal dopamine has been lost

(our brain can compensate for quite a while so by the time symptoms appear, lots of degeneration has already happened)

Function of treatment for Parkinson’s

All current drug therapy simply provides relief from Parkinsonian symptoms

They do not provide a cure for the disease, nor do they slow the unrelenting degeneration of the nigrostriatal neurons

The symptoms of PD (Parkinson’s) are mainly treated using drugs that enhance dopaminergic transmission by a variety of methods. Name some of these methods

- Drugs that replace dopamine (L-DOPA)

- Drugs that inhibit dopamine metabolism (COMT inhibitors, MAO inhibitors)

- Drugs that mimic dopamine action (dopamine receptor agonists)

- Drugs that release dopamine

Parkinson’s is also treated using drugs that block what receptors

block muscarinic acetylcholine receptors

(cf. acetylcholine as a neurotransmitter)

Most effective treatment for Parkinson’s disease is what specific drug which is a what?

L-DOPA (levodopa) which is a dopamine precursor

L-DOPA (levodopa) is usually given when what, why?

It is usually given with a DOPA decarboxylase inhibitor that is unable to cross the blood-brain barrier (e.g. carbidopa, benserazide) so that conversion to dopamine only occurs in the brain (thus reducing peripheral side effects)

What % of patients respond positively to levodopa with what % restored to virtually normal motor function

About 80% of patients respond positively to levodopa with ~20% restored to virtually normal motor function

Why does the effectiveness of L-DOPA wear off as the disease progresses

intact dopamine neurons are at least partially required for its effectiveness

main side effects of levodopa treatment

Dyskinesias - Abnormal involuntary movements affecting the face and limbs

On-off effects - Rapid fluctuations in clinical state where the symptoms reappear suddenly and can last for minutes to hours

Dyskinesias usually occurs within how long since starting treatment

Manifests in the majority of patients within 2 years of starting levodopa therapy

How is Dyskinesias dealt with

Can be reduced by lowering the levodopa dose but this causes symptoms to reappear

Other than levodopa (DA precursor), what 4 other types of drugs can be sued

Inhibition of dopamine metabolism

Dopamine receptor agonists

Muscarinic cholinergic antagonists

NMDA receptor antagonists

Give 2 drugs that would cause the Inhibition of dopamine metabolism

MAO-B inhibitors e.g. selegiline

COMT inhibitors e.g. entacapone

Give an example of a non-selective, slight selective & selective Dopamine receptor agonists

Non-selective dopamine receptor agonists (e.g. apomorphine)

Slightly selective D2 receptor agonists (e.g. bromocriptine, pergolide, cabergoline)

Selective D2 receptor agonists (e.g. pramipexole, ropinirole)

Give 2 examples of Muscarinic cholinergic antagonists & the reason why they work

Since the cholinergic interneurons in the striatum oppose the effects of dopamine, blocking their actions (e.g. trihexyphenidyl and benztropine) partly overcomes the loss of dopamine

Give an example of an NMDA receptor antagonists

Non-competitive antagonist of the NMDA receptor (e.g. amantadine)

Schizophrenia is a disabling brain disease that affects what % of the population

1%

When does Schizophrenia normally manifest in men/women

Men: late teens / early 20s

Women: late 20s / early 30s

True/False Schizophrenia is a neurodevelopmental disorder

True - It is thought to be a ‘neurodevelopmental’ disorder in which certain brain structures (esp. the cerebral cortex) do not develop properly

Schizophrenia is relapsing & remitting or Chronic & progressive

Both - Schizophrenia can be relapsing & remitting or Chronic & progressive

Clues to the neurochemical nature of schizophrenia came from analysing what

the effects of known anti-schizophrenic drugs

Name 4 Neurotransmitter systems that have been implicated in schizophrenia

-Dopaminergic system 

- Glutamatergic system

- Serotonergic system

- Noradrenergic system

dopamine hypothesis of schizophrenia

overactivity in the dopaminergic system leads to the disease

dopamine hypothesis of schizophrenia is based on two main observations. What are they?

1) All anti-schizophrenic drugs act as antagonists at dopamine receptors and clinical potency correlates with D2 receptor affinity

2) Amphetamine (which releases dopamine from neurons) causes schizophrenic-like symptoms in users

All antipsychotic drugs act as agonists/antagonists at what dopamine receptor

All antipsychotic drugs act as antagonists at dopamine D2 receptors

In addition to the dopaminergic system, antipsychotic drugs may also affect other what 4 other neurotransmitter systems

Noradrenergic, histaminergic, cholinergic, serotonergic

(mostly contribute to the side effects of antipsychotics)

Activity of antipsychotic drugs at what receptor provides clinical benefit / reduced side effects 

activity at 5-HT receptors (serotonin)

They can act as antagonists at 5-HT2A and as agonists at 5-HT1A receptors

Explain the difference between the acute & chronic mechanisms of action of anti-schizophrenic drugs

Acute: antagonists at dopamine D2 receptors → block the effects of dopamine released from the mesolimbic pathway (reduced positive symptoms). Initial spike in DAergic neuron activity.

Chronic: Long term decrease in DAergic neuron activity.

Antipsychotic effects require ~__% block of D2 receptors

80%

Anti-schizophrenic drugs are also known as what 3 names

antipsychotic drugs

neuroleptic drugs

major tranquillisers

How many anti-schizophrenic drugs are currently in clinical use

40

Antipsychotic drugs limitations

Only effective in ~70% of patients (The remaining ~30% are ‘treatment-resistant') 

They can only control the positive symptoms of schizophrenia - don’t control the negative symptoms

Name the 4 Classical ‘typical’ antipsychotics

- Chlorpromazine

- Haloperidol

- Thioradazine

- Flupenthixol

Name the 5 Recently-developed ‘atypical’ antipsychotics

- Sulpiride

- Clozapine

- Risperidone

- Sertindole

- Quetiapine

In what ways are the atypical’ antipsychotics better than the classical ones

atypical have:

• Lower incidence of side effects

• Higher efficacy in treatment resistant patients

• Higher efficacy against negative symptoms

• Better selectivity for the dopamine D2 receptor

Blocking of what 2 pathways causes side effects in anti-schizophrenic drugs? What are the side effects?

Blocking effects of the nigrostriatal pathway:

→ Acute (first few weeks of treatment) dystonia (Parkinsonian-like syndrome with involuntary movements)

→ Tardive dyskinesia (Severe disabling involuntary movements affecting the face and limbs after months or years of treatment (tardive))

Blocking the tuberohypophyseal pathway:

→ Increase in plasma prolactin concentration → breast swelling, pain & lactation (gynecomastia) in men & women

Which of the side effects are & are not reversible on stopping treatment (dystonia & dyskinesia)

Acute dystonia → Reversible on stopping treatment

Tardive dyskinesia → Often gets worse on stopping treatment

How do neuroleptics cause the side effect: Sedation (what does this lead to?)

due to H1 block

(Often causing daytime drowsiness and difficulty in concentrating)

How do neuroleptics cause the side effect: Anticholinergic effects (what does this lead to?)

due to muscarinic block

(Dry mouth, constipation, blurred vision, urinary retention etc

How do neuroleptics cause the side effect: Postural hypotension

due to a-adrenoceptor block

Neuroleptic malignant syndrome due to neuroleptics side effects leads to?

Muscle rigidity, fever, autonomic instability, delerium

What are some Miscellaneous reactions that can be side effects of anti-schizophrenic drugs

Jaundice, urticaria (hives), leucopenia/agranulocytosis (reduction in white blood cells), antipsychotic malignant syndrome