Dopamine disease

4 main dopaminergic pathways in the brain:

1) nigrostriatal, ~75% of dopaminergic neurones, cell bodies largely in the substantia nigra with axons running in the medial forebrain bundle and terminating in the corpus striatum

2) mesolimbic, cell bodies are in the midbrain ventral tegmental area (VTA), axons project in the medial forebrain bundle to parts of the limbic system

3) mesocortical, cell bodies in the VTA, but project via the medial forebrain bundle to the frontal cortex

4) tuberohypophyseal/tuberofundibular, projection neurones, run from the ventral hypothalamus to the median eminence and pituitary gland

What is the functional role of dopaminergic pathways?

involved in motor control (nigrostriatal), emotion/behaviour (mesocortical and mesolimbic) and endocrine regulation (tuberohypophyseal)

Schizophrenia

condition in which sufferers often exhibit signs of psychosis (e.g. delusions and hallucinations)

What are the 3 main characteristics of schizophrenia?

1) positive symptoms – delusions (often persecutory), hallucinations (often auditory), disorganised behaviour and speech (e.g. repetitive/stereotyped movement).

2) negative symptoms – alogia (inability to speak), affective blunting (restricted range and intensity of emotions), asociality (withdrawal from social circle), anhedonia (reduced experience of pleasure), and avolition (reduced desire and persistence to perform tasks) and catatonia (immobility).

3) cognitive symptoms – impaired attention and memory, problems of prioritising and difficulty with problem solving

Drugs

levodopa

bromocriptine

bromocriptine

Chlorpromazine

amphetamine

(enters vesicles via VMAT to displace DA and thus cause increased DA in the brain) can induce behaviour in humans similar to that seen in acute schizophrenia

bromocriptine

DA receptor agonists

PD can be hallucinogenic

Antipsychotic drugs

chlorpromazine

haloperidol

clozapine

Aripiprazole- atypical antipsychotics

Glutamate hypothesis

Parkinson’s disease

underlying cause of PD is often unknown and idiopathic PD is the most common form, but cerebral ischaemia, viruses or other pathological damage are potential underlying factors.

Post- mortem brains show less than 10% of normal levels of DA and this is due to a loss of cell bodies in the substantia nigra and degeneration of dopaminergic terminals in the corpus striatum

PD symptoms

The main symptoms that PD patients display are:

- tremor, usually at rest, starts in the hands, but is suppressed during voluntary movement

- rigidity, increased resistance to passive limb movement

- slowness/suppression of movement (bradykinesia), partly due to rigidity, but also due to inertia of the motor system, such that once a movement is started it is difficult to stop, as well as initiate

- other issues experienced by PD patients include: tiredness, depression, pain and constipation

What may cause the loss of dopaminergic neurones in PD

- imbalance in the production and elimination of reactive oxygen species (ROS): DA metabolism, either by MAO or auto-oxidation, produces ROS that can damage lipids and proteins, and impair mitochondrial function, and thus a shift in the balance of production and elimination could lead to dopaminergic neuronal death

- accumulation and aggregation of α-synuclein: although its function is poorly understood, it appears to be involved in synaptic vesicle function and abnormal accumulation of α-synuclein results in aggregates that appear particularly toxic to dopaminergic neurones; certain inherited forms of PD are due to mutations in the gene encoding α-synuclein. Aggregates containing α-synuclein are referred to as Lewy bodies. It is also possible that when formed in aggregates α-synuclein can no longer perform its role in synaptic vesicle function leading to decreased vesicular storage of DA and thus leading to more DA being available in the cytoplasm for degradation to ROS.

- decreased proteasome and autophagy activity: proteasomes and autophagosomes degrade misfolded and aggregated proteins and aggregated proteins are toxic to cells, therefore a decrease in proteasome/autophagosome activity leads to increased propensity of cell death

drugs

Levodopa

carbidopa

domperidone

clozapine

selegiline

safinamide

entacapone

tolcapone

Ropinirole

bromocriptine

amantadine

Levodopa

carbidopa

domperidone

clozapine

selegiline

safinamide

entacapone

tolcapone

Ropinirole

romocriptine

amantadine