Lecture 3: Schizophrenia & Psychoses

• Schizophrenics have deficits in sensorimotor gating which makes them unable to respond appropriately to environmental stimuli
• What type of test measures deficits on sensorimotor gating in schizophrenics?

  The prepulse inhibition test
• In the prepulse inhibition test, the warning prepulse inhibits startle to the next loud tone in normal individuals but does not inhibit the startle response in individuals with schizophrenia. This is evidence of deficits in sensorimotor gating.
• Deficits in sensorimotor gating may also be responsible

  for the lack of ‘theory of mind’ in schizophrenics, including difficulty gauging the mental state of others.
• The role of dopamine in the striatal region (prefrontal cortex to basal ganglia) is to recognise things that are salient and filter information that you should pay attention to.

  People with schizophrenia have too much dopamine in the PFC-BG, so they are unable to filter out unimportant stimuli.
• The main neurotransmitters implicated in schizophrenia are: dopamine, serotonin, glutamate and GABA
• Drugs that increase dopamine levels in the nucleus accumbens exacerbate or produce positive psychotic symptoms

  e.g. Amphetamine, cocaine, dopamine receptor agonists
• Chlorpromazine reduces the positive symptoms of schizophrenia
• Schizophrenics have increased dopamine in the nucleus accumbens and decreased dopamine in the prefrontal cortex (hypofrontality)
• Cognitive deficits and negative symptoms = Decreased dopamine in PFC

  Positive symptoms = Increased dopamine in NA - often hallucinations are preceded by feelings of euphoria
• Hypofrontality = decreased dopamine in the PFC, causing cognitive deficits and negative symptoms
• The positive psychotic symptoms are produced by increased Dopamine in the nucleus accumbens (mesolimbic dopamine)
• The negative and cognitive symptoms are produced by decreased Dopamine in the prefrontal cortex (mesocortical dopamine)
• In Schizophrenia, there is an increased number of dopamine D2 receptors in the mesolimbic system
• Where are D2 receptors located - pre-synaptically, post-synaptically, or both?

  Both
• Enhanced dopamine neurotransmission at D2 receptors in the mesolimbic system causes what type of symptoms in schizophrenia?

  Positive
• First generation antipsychotics are also called?

  Typical or neuroleptics
• Which 1st generation antipsychotics mostly lack antihistaminic (sedative), anticholinergic & adrenaline-like effects (ie ‘sympathetic’ effects)?

  Butyrophenones & Diphenylbutylpiperidines e.g. Haloperidol, Droperidol
• The main action of 1st generation antipsychotics?

  antagonise dopamine receptors
• Phenothiazines (e.g. chlorpromazine) and thioxanthines (e.g. flupentixol) have what side effects?

  antihistaminic, anticholinergic and adrenaline-like effects (i.e. sympathetic effects)
• Fill in the drug class:

  Chlorpromazine = phenothiazine

  Periciazine = phenothiazine

  Prochlorperazine = phenothiazine

  Zuclopenthixol = thioxanthine

  Flupentixol = thioxanthine

  Haloperidol, droperidol = Butyrophenones/Diphenylbutylpiperidines
• What is the problem with typical (1st gen) antipsychotics?

  Non-specificity - antagonises D1 and D2 receptors, among others
• Do 1st Gen antipsychotics have any effect on negative or cognitive symptoms?

  No
• Intolerable side effects of 1st gen antipsychotics?

  EPSE and cardiotoxicity
• D1 receptor family = D1, D5

  D2 receptor family = D2, D3, D4
• D2 receptors in the nucleus accumbens produce positive psychotic symptoms

  
  

  D1 receptors are very important for normal movement
• Typical neuroleptics block D1, D2, or both families of receptors?

  Both D1 and D2 families
• Decreased DA in nigrostriatal causes Parkinson’s Symptoms
• 80 % of D2 receptors need to be blocked for antipsychotic effect
• Amisulpride is highly selective for D2 receptors and has less EPSEs
• Serotonin modulates the mesocorticolimbic dopamine system.

  Encourages dopamine deficit in prefrontal cortex?
• Serotonin can also increase dopamine release - 5-HT2A receptors. Encourages increased dopamine in nucleus accumbens (NAc)?
• There are also changes in serotonin receptor levels in the prefrontal cortex. Hyperactivity of 5HT2A receptors (too much 5HT release or more receptors) on glutamate neurons in the PFC stimulates their activity – will then drive DA to Nac/Ventral Striatum.

  Drugs that are agonists at 5HT2 receptors (like LSD) produce positive & negative symptoms
• In Schizophrenia:

  
  

  Serotonin levels in prefrontal cortex are unaltered

  Prefrontal cortex serotonin receptor levels are altered

  Drugs activating 5-HT2 receptors produce schizophrenia-like symptoms

  Serotonin modulates dopamine systems
• Newer Atypical Antipsychotics also act as 5-HT2 antagonists

  5-HT2 antagonism helps with the negative symptoms of schizophrenia
• True or false: Targetting D4 receptors in schizophrenia is effective?


  False, need to target both D2 and D4
• Clozapine blocks both D2 and D4 receptors, as well as 5HT2, muscarinic, histamine and adrenergic receptors
• Clozapine attentuates which symptoms of schizophrenia?

  Both positive and negative
• Clozapine does not have EPSEs
• Current antipsychotics antagonise mainly which two receptors?

  5HT and D2 receptors