Professional Documents
Culture Documents
Objectives:
Neurotransmitters in Schizophrenia
Dopamine Glutamate Serotonin
1 - DOPAMINE
Caudate Nucleus
Putamen
I - Nigrostriatal Pathway :
It is a part of extrapyramidal system involved in cognitive integration, habituation, sensory-motor coordination and initiation of movement.
Mesolimbic Pathway
Ventral Tegmental Area
Amygdala
Putamen
II - Mesolimbic Pathway :
Involved in pleasure, reward and reinforcing behavior and many drug of abuse interact here. Its overactivity lead to production of positive symptoms.
MesoCortica l Pathway
Dopamine receptors :
D1- like receptors family :
D1
receptors has a wide spread neocortical distribution including the PFC, and also in the striatum. receptors are concentrated in the Hippocampus and entorhinal cortex.
D5
D3 receptors are present in the striatum more in ventral part. D4 receptors are present in the PFC and Hippocampus, but not in the
striatum
Dopaminergic receptors
The action of DA on target neurons should not be viewed in terms of simple excitation or inhibition ... but stimulation of DA G-protein linked receptors induce a cascade of intracellular signaling that results in modifying the response of the cells to OTHER neurotransmitters. Thus DA is not inhibitory nor excitatory, but its action will depend on the state of the neurons at the time of stimulation.
2 - Glutamate
Glutamate the major excitatory transmitter in the CNS may be at least as important as DA in the pathophysiology of Schizophrenia
Cortico-Thalamo-Cortical loops
(Cortex - B.G. - Thalamus)
Pars Compacta
Striatum
D1
Thalamus
Cortex
Glutamate
D2
Pars Reticulata
GABA
Dopamine Internal Part of G.P. Sub Thalamic N.
Cortico-Thalamo-Cortical Pathways
These loops have been further classified into : 1- Limbic loops :
2- Associative loops :
3- Motor Loops :
Ventral Striatum
Ventral pallidum
Ventral Striatum
Glutamat e
Striatum
D1
D2
Cortex
Pars Reticulata
GABAergic filter
Thalamus
DA
Normally
Glutamate from cortex
Noise
Noise
Corte x
Signal Thalamus
GABAergic filter
Both an elevation of DA function in striatum or a decrease in glutamate function (PCP) would lead to relief of striatal inhibition of the thalamus and opening the filter leading to cortical overload (psychosis)
In Schizophrenia
Noise
Noise
Corte x
Signal Thalamus
In Schizophrenia, a hypoactivity in glutamate function will lead to relief of striatal inhibition of the thalamus and opening the filter leading to cortical overload (psychosis)
A future challenge : To develop a partial agonist on NMDA glutamate receptors such as : D-serine and Dcycloserine. They are currently used as augmentation for novel antipsychotics.
3 - SEROTONIN
Interest in 5HT in the pathophysiology of Schizophrenia has been stimulated largely by the observation that many atypical antipsychotic drugs also bind with high affinity to certain Serotonin receptors
5 HT 1A :
This receptor subtype can be considered as functionally antagonistic to 5HT2A, both at the presynaptic and post synaptic levels .
Atypicality of antipsychotics
1) The role of serotonin receptor occupancy 2) D2 receptor-affinity 3) Regional specificity
Atypicality of antipsychotics
1) The role of serotonin receptor occupancy: Theory : Generally Serotonin inhibit the Dopamine release both at the level of DA cell bodies and axon terminals.
Novel Antipsychotics
Block both 5HT and DA receptors
Stimulates DA release by blockade of the more prevalent 5HT2A
5HT2A
Blockade of 5HT2c does not lead to stimulation of DA, so the net result is inhibition of the pathway
D2
Mesocortical pathway
5HT2A
D2
Nigrostriatal pathway
5HT2C
D2
MesoLimbic pathway
Less EPS
2) D2 receptor-affinity:
The hypothesis that can account for atypicity is ; faster dissociation rate K-off from D2 receptors, which results in a lower overall affinity for D2 receptors.
Minimal EPS or prolactin elevation, decreased cognitive impairment, and perhaps greater improvement of secondary negative symptoms
3) Regional Specificity:
Recent reports suggest that atypical antipsychotics show a preferential blockade of the cortical D2 receptors as opposed to striatal D2 receptors, whereas haloperidol shows equal occupancies in the 2 regions.
1st Version :
Proposed that DA levels were increased in patients with schizophrenia but efforts were not confirmatory of increased DA levels, turnover or metabolism by measuring DA and metabolites in peripheral fluids. e.g. : blood, urine, CSF
2nd Version :
There might be increased number of DA receptors in the striatum, primarily D2 receptors, the target of antipsychotics. But the majority of studies of D2 receptors ligand binding both in post mortum tissue and in vivo with PET found no evidence of increased abundance of D2 receptors.
3rd Version :
DA neuronal activity might be abnormal as a downstream effect of a primary cortical abnormality. Proof: Decreased prefrontal cortical DA activity has been found in imaging studies of living subjects and decreased prefrontal DA enervation has been observed in post mortum tissue. Diminished prefrontal DA signaling is one of the factors that lead to a downstream upregulation of striatal DA activity.
Prefrontal Cortex is involved in : Context updating Inhibition of reflexive drive directed behavior Planning Decision making Motivation and emotion Rule detection
One of the functions of the frontal lobes is to find regularities in whatever input patterns arrive from lower level cortical areas. However if something unexpected happens, it may be dangerous (Negative) or rewarding (positive). These two types of evaluations are performed by different brain systems. Negative aspects of incoming information are quickly relayed to the Amygdala where they are associated with fear and anxiety (fight, flight and fright). Whenever something happens that is better than expected then the Dopaminergic reward system becomes activated
Frontal Cortex
DA function
Positive
Negative
Reward system
Amygdala
Dopamine, reward and salience : The Dopaminergic neurons signal the importance and rewordness of the stimulus regardless of its nature. All organisms are bombarded with a large number of stimuli and have to sort out the few that are important from the many that are unimportant. The Dopamine system is thus the signal that become attached to the stimuli when the sorting out function is applied.
Dopamine, reward and salience : Salience : A process in which the events and thoughts come to grab attention, drive action and influence goal directed behavior due to their association with reword or punishment. The mesolimbic DA system is a critical component in the attribution of Salience.
In schizophrenia, the DA system is dysfunctional in that it is no longer appropriately fine tuned, becoming either hyperactive in the acute phase of the illness or hypoactive during more chronic states.
In acute phase : Delusions : Aberrant salience experiences (Noises) reaching the cortex are cognitively explained in the form of delusions. Since delusions are constructed by the individual they are colored by the psychodynamic themes relevant to the individual and his cultural background. This explains how the same neurochemical dysregulation lead to variable phenomenological expression.
In the chronic state : A hyperactive DA system no longer produces much (or any) meaningful experience. Even stimuli which are normally meaningful and worth further consideration, such as social interactions become uninteresting and boring and hence dont capture cognitive resources. This process could be the biological correlate of certain of the core negative symptoms of schizophrenia such as blunted affect and social withdrawal.
THANK YOU