antipsychotics and schizophrenia Flashcards
what kind of NTs are thought to be the problem in schizophrenia, and what do they do?
amine neurotransmitters
these include:
Noradrenaline, a catecholamine, peripheral sympathetic nervous system but also in CNS
Dopamine, v. important (parkinson’s = loss of dopamine etc…)
5HT / serotonin - regulation of mood (more so to do with depression)
ACh - used in CNS as well as peripheral nervous system
noradrenaline - where are these receptors mostly found in the CNS, and what are it’s main kinds of receptors?
Found mostly in locus coeruleus, axons are sent from here to many areas including hippocampus, amygdala and cortex
Alpha 1 - motor control, cognition and fear (GPCRs)
Alpha 2 - blood pressure (red flag), targets for sedation and analgesia
Beta 1 - antidepressant targets
dopamine - where is it found/which pathways is it important for?
- Nigrostriatal pathway - fine motor control (substantia nigra to striatum)
- Tuberohypophyseal pathway - pituitary hormone secretion
- Mesocortical and mesolimbic pathways - neurons in the ventral tegmental area - reward behaviours, motivation. Targeted in mood disorders, but all pathways listed here will be affected
which of the three pathways dopamine is involved in do we want to target in schizophrenia?
the mesocortical and mesolimbic pathways - issues in these pathways are what cause the symptoms seen in schizophrenia, but it is important to know the other pathways dopamine is heavily involved in to know what potential side effects to except
how is dopamine synthesised and released?
released - more to do with where are these enzymes
Tyrosine, converted by tyrosine hydroxylase to L-DOPA, DOPA decarboxylase converts to dopamine (DOPA can be used for Parkinson’s - loss of dopaminergic neurons)
The NT or the precursors are stored in vesicles that may have these enzymes for conversion on
Released by exocytosis
note - From dopamine, dopamine B-hydroxylase converts to NA which can be converted to adrenaline
how are amine NTs taken back up into the cell and broken down (include metabolic waste products)?
Reuptake back into the neurons the NTs were made at, via plasma membrane transporters
MAO (monoamine oxidase) attached to mitochondria, COMT found in cytosol, these enzymes terminate/breakdown amine NTs (these enzymes can be found outside the neuron too)
These enzymes produce metabolic products DOPAC and HVA, can be used to monitor function as they are excreted in urine
how do amphetamines work?
they cause an increase of DA and NA in CNS, because amphetamines are taken up by transporters at P.membrane, then displace the amine NTs like DA and NA from their vesicles.
So these NTs (DA and NA) build in conc. Inside the neuron, and are secreted by P.membrane transporters as they begin to work in reverse due to conc. gradient
how does cocaine work?
cocaine inhibits the reuptake of amine neurotransmitters - especially dopamine - increasing motor activity and prolonging stimulation of reward pathways
dopamine receptors - how many are there and how are they grouped?
five genes (five types of receptors) split into two groups based on the G-protein:
type 1 = D1 and D5 = Gs protein, so these receptors typically cause an increase in excitability (more cAMP etc…)
type 2 = D2, D3, D4 = Gi protein = typically inhibitory, with effects such as activating K+ channels (GIRKs), inhibiting V-gated Ca channels. D2 are the main target for schizophrenia - antagonists of D2 to be specific
what are the symptoms of schizophrenia and what neurological pathway are they related to?
divided into two different categories:
positive - hallucinations, delusions, paranoia, aggression. these are thought to be a result of hyperactivity of the mesolimbic pathway
negative - blunting of emotions, anhedonia (cannot enjoy things) and reluctance to perform everyday tasks. thought to be a result of decreased activity in the mesocortical pathway
commonly accompanied by anxiety and cognitive deficits
what is thought to be the cause of schizophrenia?
associated with a reduction in dendrites/branching of glutaminergic neurons
Genetic component - over 100 genes identified
xombined with environmental cues e.g. associated with excessive cannabis consumption
Considered a neurodevelopmental disorder (starts in utero and slowly develops) believed to be a defect in synaptic plasticity
in schizophrenia, what is going on in the mesolimbic pathway?
causes the +ve symptoms observed
it is overactive as a result of increased D2 activity (so D2 antagonists are useful)
also thought that NMDA hypOfunction contributes to the increased DA signalling (because here, NMDA receptors are inhibitory, so hypofunction = less inhibition)
what is thought to be going on in the mesocortical pathway in schizophrenia?
causes -ve symptoms
it is a decrease in activity of this pathway, associated with reduction in D1 receptor activity
here NMDA hypOfunction seen again, but REDUCES DA signalling (NMDA not inhibitory in this area?) contributing to the negative symptoms
aside from glutamate and dopamine - what is being looked at as a target for schizophrenia treatments, again related to a drug of abuse?
Agonists of 5 HT2A receptors are involved in hallucinations (for example, LSD) so antagonists are being looked into
(tho many D2 antagonists used to treat schizophrenia also block this receptor, also new developments in antagonists of this receptor are being developed)
aside from dopamine, what is an important target in schizophrenia and what recreational drugs are involved?
as in what drugs mimic schizophrenia as a result of this important targe
glutamate is an important target - hypofunction of NMDA receptors (which are glutaminergic) is associated with schizophrenia
similarly, ketamine and phencyclidine are NMDA antagonists (so reduce NMDA activity) and cause hallucinations/similar to +ve symptoms of schizophrenia
