1

schizophrenia

positive symptoms

negative symptoms

anx/dep aggressive symptoms cognitive

symptoms

10-1 Stahl S M, Essential Psychopharmacology (2000)

Positive Symptoms of Schizophrenia

Negative Symptoms of Schizophrenia

2

10-20 Stahl S M, Essential Psychopharmacology (2000)

100%

50%

0

15 20 40 60

Age in years

Functional Status

hypothalamus

d

c

Nucleus accumbens

Tegmentum

bSubstantia nigra

Basal Ganglia

a

DOPAMINE PATHWAYS

10-7 Stahl S M, Essential Psychopharmacology (2000)

mesolimbic overactivity = positive symptoms of psychosis

10-9 Stahl S M, Essential Psychopharmacology (2000)

3

Mesolimbic Dopaminergic Hyperactivity in Schizophrenia

Laruelle et al., Ann NY Acad Sci (2003)

Relationship Between Affinity for Dopamine D2 Receptors and Daily Dose for Treating Schizophrenia

primary dopamine deficiency

D2 receptor blockade

secondary dopamine deficiency

mesocortical pathway

increase in negative symptoms

10-11 Stahl S M, Essential Psychopharmacology (2000)

4

Hypofunction of Mesocortical Dopaminergic Transmission in Schizophrenia

Laruelle et al., Ann NY Acad Sci (2003)

Dopamine Dyregulation in Schizophrenia

PFCNAc

VTA

DADA

PFC Glutamatergic transmission

Tonic inhibition of DA in NAc

Tonic excitation of DA in PFC

Mesolimbic systemMesocortical system

Normal Schizophrenia ?

PFCNAc

VTA

DADA

PFC Glutamatergic lesion

Increases DA in NAc

Decreases DA in PFC

Dysfunctional mesolimbic systemDysfunctional mesocortical system

DA-mediated motivational system functioning normally DA-mediated motivational reward-system deficiency

Courtesy of Alan I. Green, M.D.

Glutamate-Dopamine Interactions in Schizophrenia

Takahata and Moghaddam, J Neurochem (2000)

5

Kaplan and Hammer, Am Psychiatric Press Inc, 2002

Thesis- Dopamine Dysregulation in Schizophrenia

MechanismMechanism SchizophreniaSchizophrenia SxsSxs

1.1. HypoactivityHypoactivity of PFCof PFC Negative/CognitiveNegative/CognitiveDA Systems DA Systems Sxs Sxs

2. Hyperactivity of 2. Hyperactivity of NAc NAc Positive Positive SxsSxsDA Systems DA Systems

3. 3. Neuroleptic Neuroleptic inducedinduced Improves PositiveImproves Positive SxsSxsDA blockade DA blockade Worsens Negative Worsens Negative SxsSxs