Addiction, Tumours and Genetic Influences

Question 1

Reinforcement

Answer 1

• Process by which an event increases the probability of a given response
• Positive reinforcement: use drugs to feel relaxed
• Negative reinforcement: use drugs not to feel withdrawal symptoms

Question 2

Habit

Answer 2

• Impact of conditioned negative and positive reinforcement

- relapse due to stress or environmental causes

Question 3

Tolerance

Answer 3

Neuronal Changes:

• changes in receptor populations
• desensitisation of receptors
• changes in neurotransmitter vesicle content
• changes in signalling pathways

Question 4

Criteria for substance use disorder

Answer 4

• A problematic pattern of alcohol use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring with a 12 month period
• Larger amounts or over longer period
• Persistent desire or unsuccessful efforts to cut down
• Time
• Craving
• Failure to fulfil major role obligations at work, school or home
• Continued use regardless of problems (social etc)
• Physically hazardous situations eg. drink driving

Question 5

Stimulants

Answer 5

• amphetamines, cocaine, nicotine

Question 6

Depressants

Answer 6

• Heroin, alcohol

Question 7

Composite addiction cycle

Answer 7

1. use/intoxication -> withdrawal -> craving

- Each stage involves discrete neuronal circuits

Question 8

Addiction Involvement

Answer 8

• All involve mesolimbic dopamine pathway, either directly or indirectly effected
• Brain areas: VTA, nucleus accumbens, prefrontal cortex, amygdala, hippocampus
• Many neurotransmitter systems
• Stress axis (CRF, CORT)
• Autonomic regulation (vagal)
• Immune system (glia, cytokines)

Question 9

Symptoms: Brain Tumour

Answer 9

• Headache (morning)
• Seizure
• Sensory deficits: vision impaired, taste, smell
• Motor deficits
• Nausea/vomiting
• Behavioural/personality changes

Question 10

Diagnosis

Answer 10

• Neurological exam
• Imaging: MRI and DWI
• Biopsy

Question 11

Grade and Prognosis

Answer 11

I - excellent - juveniile pilocyctic astrocytoma
II - variable - astrocytoma
III - poor - anaplastic astrocytoma
IV - aggressive - glioblastoma

Question 12

Types: Brain Tumour

Answer 12

• Glial: astrocytoma, oligodendroglioma, ependymoma

- Metastatic: lung, breast, melanoma, colorectal

Question 13

Astrocytoma

Answer 13

• 80% of all adult primary brain tumours
• Pilocytic astrocytoma (I) -> fibrillary astrocytoma (II) -> anaplastic astrocytoma (III) -> glioblastoma multiforme (GBM - IV)

Question 14

Pilocytic astrocytoma

Answer 14

• low grade, relatively benign
• children and young adults
• located in the cerebellum and sometimes the cerebral hemispheres
• very slow growing
• good prognosis

Question 15

Fibrillary astrocytoma

Answer 15

• Grade II
• 10-15% of astrocytic brain tumours
• Peak incidence 30-40yrs
• Mean survival 6-8 years
• Length of disease affected by rate of progression to GBM
• No current predictor of when or whether progression will occur

Question 16

Genetics: brain tumours

Answer 16

• > 60% show TP53 mutation
• > 80% in germistocytic astrocytomas
• PDGFR-a increase mRNA expression - gene amplification specific to low grade astocytomas

Question 17

Anaplastic Astrocytoma

Answer 17

• Stage III
• multinucleated cells, abnormal mitosis
• High frequency of TP53 mutations similar to diffuse astrocytomas in addiction
• Intermediate stage on the way to GBM
• Strong tendency to progress

Question 18

GBM

Answer 18

• Grade IV
• Most common adult primary neoplasm
• 45-75 yrs
• variable in appearance
• haemorrhage and necrosis present
• poor prognosis of 8-10 months
• 10% have 2 year survival rate

Question 19

Phenotype

Answer 19

• Observed genetic trait eg. chronic pain
• Functional effect of genetic changes
• Something that can be measured in a person

Question 20

Genotype

Answer 20

• Trait at gene level

- Determined by direct testing of DNA

Question 21

Central Immune System: Glia

Answer 21

• 90% of CNS cells: Microglia and astrocytes
• Immunocompetent cells: respond to different signal and mount an immune response
• Important in modulating neuronal responses:
• Pain signalling: neurological disease -> chronic pain
• Infection/sickness: neurological disease -> epilepsy

Question 22

Glial Neuronal Cross talk

Answer 22

• TLR4 (innate immune receptor) on glial cells get activated
• > release IL-1 (-> activates other glial cells to also release IL-1)
• > IL-1 activated neurones -> response

Question 23

Stages of Glial Cells

Answer 23

1. Naive glia
   - Priming signals: stress, drug, infection
2. Primed glia
   - > release proinflam cytokines
3. Neuronal response
4. Primed glia
   - Activator signals: stress, infection, drugs
5. Activated glia: increased expression of TLR4 -> increased release of cytokines
6. Increased neuronal response

Question 24

Chronic Pain

Answer 24

• Immune/non-classical component
• Glia:
• Pivotal role in generation and maintenance of enhanced pain states
• Activation of TLR, innate immune receptors
• release of inflammatory factors

Question 25

Chronic Pain: Contributing Factors

Answer 25

- Sex: females - Environmental triggers: sleep patterns - Genetic variability: SNPs in inflammatory factors

Question 26

Immune genetics and pain severity

Answer 26

- Worst day: no SNPs were related to pain severity | - Best day: 28% pain related to immune genetics

Question 27

Summary points for pain study

Answer 27

- Environmental factors explained a higher proportion of pain score variability in patients with FMS - Immune genetics explained more pain score variability when patients had least amount of pain ie best day - Genetic variability in number of genes: TGF-b and MYD88 and pain scores: support immune system involvement in pain

Question 28

Glia and epilepsy

Answer 28

1. Role of TLR4 activation and glial signalling in two models of epilepsy: decreased no and frequency of seizures with TLR4 antagonist 2. IL-1B expression increases after seizures: epileptic focus and frontal brain