Antipsychotics - Putting the hypotheses together Flashcards
Which symptoms develop first, positive or negative?
Schizophrenia develops gradually, first with negative symptoms, then the emergence of positive symptoms. This gives an indication of the neuropathology of schizophrenia.
Which brain regions begin deteriorating in utero?
Limbic structures and prefrontal regions. Continues throughout childhood.
Describe the deterioration of brain structures throughout development.
Continues throughout childhood, getting fast tracked during the synaptic pruning that takes place prior to and during adolescence.
What does the synaptic pruning during adolescence lead to?
progressive and substantial loss of glutamate synapses, resulting in NMDA receptor hpoactivity and glutamate dysregulation.
Describe the relationship between glutamate and DA systems.
Glutamate neuron cell bodies in the PFC have axons that project to the VTA. There, they synapse with dopaminergic neurons that form both the mesocortical and mesolimbic pathways. Cortical glutamate nerons projecting to the VTA produce a tonic excitation of mesocorticalDA neurons. These DA neurons, in turn, project their axons back to the PFC (this is the mesocortical pathway) where they release DA in response to this excitation.
Describe the relationship between glutamatergic neurons and GABAergic interneurons.
Prefrontal cortical glutamatergic neurons form synapses with GABAergic interneurons within the VTA. The axons of these GABAergic interneurons project to and inhibit the activity of the dopaminergic neurons that, in turn, project their axon to the Nucleus accumbens (this is the mesolimbic pathway). Stimulation of glutamate neurons in the PFC results in the inhibition of DA neurons that form the mesolimbic pathway, due to the presence of the GABAergic neurons that act as a chronic braking system.
What are the negative and cognitive symptoms of schizophrenia thought to be a result of?
Hypoactivity in the mesocortical pathway.
What are the positive symptoms of schizophrenia thought to be a result of?
Hyperactivity of the mesolimbic dopamine pathway.
What happens when cortical glutamate activity is diminished due to neurodevelopmental pathology?
Loss of NMDA receptors or glutamate connectivity, VTA DA neurons are understimulated. As a result, the mesocortical DA pathway becomes hypoactive, and at the same time, the mesolimbic DA pathway becomes hyperactive. this results in the negative and positive symptoms of schizophrenia respectively.
