Neurotransmitter dysfunction Flashcards
What do Monoamines comprise of ? ( C + I)
3 Catecholamines
2 Indolamines
What are the 3 Catecholamines ( DAN)
Dopamine
Noradrenaline
Adrenaline
What are the 2 Indolamines ( S + M)
Serotonin
Melatonin
- Histamine
See Diag P 54
What does monoamine system dysfunction refer to ? ( Stimulant abuse > Psychosis + ? )
Repeated psychostimulant drug abuse:
Paranoid Psychosis ( * Like Schizophrenia)
Seizures
Depression/ Anxiety/ Parkinsons like symptoms
Describe 3 Core Schizophrenia symptoms ? ( +ve, -ve, Cog.)
- Psychotic ‘positive’ symptoms (episodic) Delusions, hallucinations, thought disorders
- Deficit ‘negative’ symptoms (chronic)
disturbances in: motivation, experience of pleasure, social interactions, spontaneous speech, mood expression - Cognitive impairment (chronic)
intellectual, memory, executive function, attention
What are the 3 psychotic Positive symptoms?
( HED)
- Hallucinations - usually auditory (single or multiple)
Delusions (paranoid) - persecution, grandiosity, - external control, thoughts inserted or removed, mind read Thought disorder - (tangential, loosening associations)
- Disorganised thinking and behaviour - trouble with simple tasks
What are the 4 main NT involves in Schizophrenia?
D- S-G -G
- Dopamine (DA)
- Serotonin (5-HT)
- Glutamate
- GABA
What is the dopamine Hypothesis of schizophrenia? (
- Drugs which increase dopamine levels (in “nucleus accumbens”) produce positive psychotic symptoms
-**Amphetamine, cocaine, dopamine receptor agonists
- Drugs which block dopamine transmission alleviate some symptoms (dopamine ***antagonists)
- 1950s Chlorpromazine (developed as antihistamine) reduced positive symptoms of schizophrenia - (blocks dopamine receptors)
-Dopamine neurotransmission is involved in psychosis
* see P 56
Is Meso- cortico- limbic dopamine system abnormal in schizophrenic ?
Yes
Explain the above meso-cortico-limbic system above ( up or down dopamine)
positive psychotic symptoms:due 2 INcreased Dopamine (mesolimbic dopamine)
The negative and cognitive symptoms due to DEcreased Dopamine in the PFC (mesocortical)
Explain Meso- limbic Dopamine System ( INV D2 receptors : +ve symptoms. Schizop.)
The nucleus accumbens directly influences output of the dorsal striatum (Caudate & Putamen) - weakens the ‘filter’
Increased NO. of dopamine D2 receptors (mesolimbic system) with schizophrenia
Enhanced dopamine neurotransmission at Dopamine D2 receptors > positive symptoms of schizop.
Ø Use a dopamine D2 receptor antagonist to prevent psychoses
First Generation Antipsychotic neuroleptics are ? ( Chlorpromazine + …)
Chlorpromazine, Haloperidol
- BLOCK dopamine D2 receptors : effective at reducing psychotic symptoms
Better binding to D2 receptors = better clinical potency
What is down side of Typical Antispsychotics above? ( No effect, relapse, Excarebate, Intolerant)
antagonise both Dopamine D1 / D2 receptors (and many other receptors!!)
- no effect on NEG or COG symptoms - ineffective in 30 % patients
- Exacerbate symptoms in some
- 20 % relapse rate
- 5-10% have intolerable side effects (due to many receptors involved) - cardiotoxicity
- Extrapyramidal Side Effects (EPS)
- Diag p58
What are the extrapyramidal effects of antipsychotics? ( Parkinson, Dystonias, Tardive Dyskinesia)
80% of D2 receptors need to be blocked - Ø80% of D2 receptors blocked also effect D1 receptors
Parkinson’s like symptoms (reduced dopamine transmission in Caudate Nucleus)
Acute dystonias (involuntary movements)
muscle spasms, protruding tongue
May cause development of Tardive Dyskinesia (20-40% over years) Debilitating movement disorder - involuntary movements: jaw/lips/limbs
New antipsychotics that are more selective for D2 receptors? ( SILPIRIDE)
Silpiride
- BUT Still no effect on negative or cognitive symptoms…. Need to address prefrontal cortex deficits
What do and dont Dopamine antagonists do?
- Reduction*of dopamine in PFC
- Dopamine D2 antagonists : reduce +ve symptoms
-Serotonin: mediate negative and cognitive symptoms
-Glutamate antagonists produce psychosis
**Reduced function of GABA neurons in the prefrontal cortex in schiz.
What are the 8 symptoms of Depression ? (DAR DRS Feelings)
Depressed mood
Reduced interest in pleasure
Sleep disorders :Loss of energy
Feelings of guilt or worthlessness
Decreased attention
Altered eating patterns
Recurrent thoughts of death *15 % suicide rate if left untreated
What is the monoamine Hypothesis ? ( “monoamine oxidase inhibitor” to elevate mood in depressed)
effectiveness of “monoamine oxidase inhibitor” to elevate mood in depressed pats. indicated depletion of monoamines contributed to the pathology of depression
Name some Monoamines?SND)
Serotonin Noradrenaline (norepinephrine) Dopamine
Tryptophan and link to depression? ( low > depression)
Depletion of dietary tryptophan produces symptoms of depression
What are the 4 areas of the brain associated with Depression? (VAP Hippo Nuc)
PFC
Hippocampus
Nucleus accumbent
VTA
Amygdala
What are some meds or actions to enhance Monoamine NT? ( anti-depressants: “monoamine oxidase inhibitor” - block
- First Generation Anti-depressants
- Tricyclic Antidepressants (TCAs)
- Block re-uptake of all monoamines
- Monoamine Oxidase Inhibitors
- Block the metabolism of active monoamines
Diag p63-67
Side effects of Tricyclic Antidepressants ?
Amitryptyline!!!
Side Effects:
(sympathetic/antimuscarinic)
Dry mouth, impaired vision, increased heart rate, difficult to pee
Memory and learning impairments (antihistamine)
Sedation
(blocks alpha 1 adrenoceptors - periphery)
Postural hypotension (low blood pressure on standing)
CARDIOTOXIC (blocks ability for heart to pump) 15 % depressed patients suicide - 25% by TCA overdose
What are monoamine Oxidase Inhibitors? ( PPIT)
Phenelzine, pargyline, isocarboxazid, tranylcypromine : drugs block breakdown of all monoamines
What are side effects of above? ( Tremors, excitement, insomnia, hypertension, headaches, food / drug interaction: avoid cheese, yeast, redwine
Tremors, excitement, insomnia (CNS overstimulation:convulsions) Food & drug interactions
Foods to avoid: Cheese/Concentrated yeast products/red wine that contain Tyramine Hypertension - headaches or intracranial haemorrhage Cardiotoxic (less than TCA’s)
(SSRI’s) Selective Re-uptake Inhibitors Second Generation Antidepressants: their role? reuptake of serotonin and ? )
These focus on the re-uptake of serotonin or noradrenaline or both (Reduced Dopamine is not a major problem in depression)
Selective Serotonin Reuptake Inhibitors (SSRIs)
Noradrenaline Reuptake Inhibitors (NRIs) Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs)
p 69
