Antipsychotic drugs Flashcards
Dopamine Hypothesis of Schizophrenia
Abnormality in brain function in schizophrenics is due to overactivity in brain dopaminergic pathways, especially in mesolimbic pathway
Most developed hypotheses for schizophrenia
Moderate success in explanation of disease
Not adequate to explain all aspects of the disease, especially the cognitive impairment.
Provided the basis for much of the early rationale for antipsychotic therapy.
Limitations of the dopamine hypothesis of schizophrenia
Postmortem and in vivo imaging studies show diminished DA activity in cortical and hippocampal regions that may underlie negative symptoms and cognitive impairment
Clozapine is weak D2 blocker but still is an effective antipsychotic agent
Evidence exists for role of serotonin (5-HT) and glutamate neurotransmitter systems (via modulation of dopamine neurotransmission [?])
Mesolimbic pathway
Integration of sensory input and motor responses with affective or emotional data.
Hyperactivity contributes to the occurrence of positive symptoms.
Are most conventional antipsychotics (D2 receptor blockers) better at treating positive or negative symptoms?
positive
Mesocortical pathways
involved in communication and social abilities
Hypoactivity due to cell loss in the prefrontal cortex contributes to presence of negative symptoms (poverty of speech, anhedonia, lack of motivation, social isolation).
What class of meds are better for treating negative symptoms?
Atypical antipsychotic agents such as clozapine or olanzapine (via additional block of 5HT2A receptors)
Nigrostriatal pathways
central role in planned, coordinated movement
Loss of dopamine in this region results in dysregulation of movement (Parkinson’s disease, hypoactivity, bradykinesia, and tremor).
Tuberoinfundibular pathway and side effects it causes from antipsychotics
Hypothalamic neurons release DA in pituitary to inhibit prolactin release.
Antipsychotic drug use (via D2 dopamine receptor blockade) can cause side effects of hyperprolactinemia as well as interference with regulation of body temperature (poikilothermia) and alteration of eating behavior (weight gain)
Serotonin Hypothesis
Activation of 5HT2A receptors is the basis for the hallucinatory effects
Hallucinogens (mescaline – LSD) act in CNS as serotonin agonists.
Brain Serotonin Pathways
Projections from brainstem nuclei to prefrontal cortical areas, limbic region, and striatum have important modulatory actions on dopamine and glutamate neurons
Activation of 5HT2A receptors on DA neurons in the PFC
Decrease DA release
Cause negative symptoms
Activation of 5HT2A receptors on glutamate pyramidal cells in the PFC (not shown here)
Result in stimulation of DA neurons in VTA
Increase DA release in the mesolimbic pathway
Can cause positive symptoms
How to treat both positive and negative symptoms in Schizophrenia?
Using an antagonist of both 5HT2A and D2 receptors
Glutamate Hypothesis
Hypofunction of NMDA receptors located on GABAergic interneurons in the PFC leads to diminished inhibitory influences that affect both mesolimbic and mesocortical dopamine pathways
Gives rise to both positive and negative symptoms.
Direct Brain Glutamate Pathway
Cortical - Brainstem VTA
[increased cortical output leads to increased mesolimbic DA release]
Cortical glutamate neurons to VTA directly innervate and stimulate the mesolimbic DA neurons. Activation of the cortical glutamate neurons leads to activation of mesolimbic DA neurons. NMDA receptors on cortical GABA interneurons mediate inhibition of cortical glutamate output.
Hypofunction in these cortical NMDA-Glu neurons can result in loss of cortical GABA inhibition and increased activity of cortical glutamate neurons resulting in hyperactivity in the mesolimbic pathway and positive symptoms of schizophrenia.
