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35.Schizophrenia 3. Substrates.doc

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Department
Pharmacology
Course
PCL475Y1
Professor
Mac Burnham
Semester
Winter

Description
SCHIZOPRENIA 3: SUBSTRATES A confused field, with conflicts. Need to explain both positive symptoms and negative symptoms. ANATOMY: • Traditional: Not much discussed these days! o schizophrenia = left temporal focus?  Recall: chronic temporal lobe epilepsy can lead to schizophrenia and a tonic-clonic seizure can cause forced-normalization (a temporary period of being normal after tonic-clonic seizure) o Whereas depression = right temporal focus? Query: Exactly what is wrong in schizophrenics? Is there an anatomical “site” of abnormality? Perhaps two or more. **************** • Bio ψ – perspective (an odd grab bag of symptoms) so we probably won’t just find ONE anatomical sites, probably many.  For example: its not isolated like too much anxiety, too much depression, too much voluntary movement or too little voluntary movement like the next topics we’ll discuss o Delusions – a limbic mistake? (delusions not open to logical discussion) o Hallucinations – cortical? (but not like epileptic hallucinations – not open to discussion) o Feelings of threat (amygdala?) o Feelings of grandeur (?) o Thought disorder (s). Not easy to explain like “anxiety syndrome = neuropathic anxiety).  Could there be multiple sites? Possibly. There are in Huntington’s chorea. ***************** What anatomical sites could be affected in schizophrenia? Cell loss studies suggest that there is widespread cell loss in schizophrenia, and that a number of sites could be involved. Carlson shows pictures of the brains of schizophrenic and non-schizophrenic twins. The schizophrenic twin shows a number of sites in the cortex that are smalled and enlarged ventricles are enlarged, indicating cell loss.  Below shows enlarged lateral ventricles (suggesting cell loss) Which two sites actually cause the symptoms? Carlson: nucleus accumbens and prefrontal cortex 1) The Nucleus Accumbens: (nucleus accumbens septi) o Is one some ways related to the amygdala (receives dopaminergic projection from the ventral tegmental area – VTA). They have the same supply of dopaminergic neurons! What is the Nucleus accumbens (n. acc.)? • It is in the subcortical forebrain (telencephalon) and is next to the septal area –not blantantly limbic or BG; sometimes both (classically defined) o The septal area is found in front of the thalamus, near the basal ganglia. They provide cholinergic and GABAergic input to the hippocampus – thought to be the wakeup for the hippocampus (particularly the cholinergic input) o The nucleus accumbens is small, so do testing in the caudate nucleus (dorsal striatum) – both have strong dopaminergic projections. It differs from the n. acc because the abnormalities associated with it are often blatantly motor (basal ganglia disorders). • A part of the “ventral striatum” (which also contains the olfactory tubercle – sometimes classified as part of the BG) • Target or dopaminergic axons from the VTA (floor of the mesencephalon and right next to the substantia nigra; mesolimbic pathway) o Carlson: VTA → N. Acc + Amyg + frontal cortex  VTA  n. acc + amyg is the mesolimbic pathway (subcortical)  VTA  cortex is the mesocortical pathway Note: The amygdala might produce feelings of threat that give rise to the delusions of persecution. –Fibiger ************** Puzzle of the N. Accumbens? “Reward” (site of reinforcement)? Anxiety? Schizophrenia? • Carlson tries to tie the development of delusions of persecution to an overactive reinforcement. So basically, an overactive nucleus accumbens is accidently reinforcing ideas of grandeur and persecution. ************** Support for the nucleus accumbens: dopamine hypothesis (below) 2) The Prefrontal Neocortex  Another Postulated Site of Abnormality What is the Prefrontal Neocortex? • Frontal lobe: contains a variety of limbic cortices plus neocortex • Prefrontal neocortex = premotor = anterior association area = planning and strategy (imaging non-present things) = dlPFC  Support for the Prefrontal Cortex: Carlson argues that schizophrenics resemble people with prefrontal brain damage  Recent papers have identified the hippocampus as being another structure that is abnormal PHYSIOLOGY • Are these structures overactive or underactive? According to Carlson, the positive symptoms relate to the nucleus accumbens and perhaps amygdala (overactive?) and negative symptoms relate to the prefrontal cortex (hypoactive) • Positive symptoms o Excess activity in DA circuits that connects to the n. acc.  don’t know if hyper- or hypofunctional; implication is hyperfunctional o In other words, excess activity in mesolimbic paths, leading to the positive symptoms  Projecting to the n.acc and amygdala o Model – discuss later o Query: Is the n. acc. overactive therefore? Not clear.  Would depend on the receptors. When dealing with the motor systems (caudate nucleus of striatum), they have both D1 and D2 receptors. • D1 are excitatory and D2 are inhibitory o receptors in the striatum are D2 family: they are inhibitory • Negative Symptoms o Carlson relates these to hypofunction in the prefrontal cortex  He postulates prenatal brain damage which makes the child somewhat abnormal from birth: this seems to cause behavioral abnormalities in pre- schizophrenic children  Symptoms of children with this prenatal brain damage (Seen in several brain damage syndromes though) o catatonia, facial dyskinesia, too much or too little blinking, poor visual pursuit, etc.  After puberty, further cell loss occurs (pruning; loss of axons) which leads to severe PFC hypofunction and the onset of negative and then positive symptoms Query: If there is widespread cell loss, why is the prefrontal cortex especially affected? We don’t know. Query: HPC? Another Strucure. Some theorists now postulate that the HPC is overactive in Schiz and that that causes excess DA release in the N. Acc. NEUROCHEMISTRY Background Review (Dr. Mitchell’s lecture)  The striatum is one structure in lower animals. o Becomes caudate + putamen in higher.  VTA and substantia nigra lie in the floor of the midbrain. • DA Paths: o SN (substantia nigra) → Striatum (C/PU) o VTA (mesolimbic, mesocortical) → N. Acc Amyg, Cx (cortex), etc DA Receptors: al
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