PMC

Dopamine Dysfunction in Schizophrenia. A series of studies using positron emission tomography (PET) indicated that presynaptic dopamine synthesis and extracellular dopamine concentrations are increased in unmedicated patients suffering from acute schizophrenia.,,

Proof of Concept That Alterations in Radioligand Binding Can Reflect Endogenous Neurotransmitter Concentrations. A direct negative correlation can be observed between radioligand binding to dopamine D2 receptors (measured with the neuroleptic radioligand tracer IBZM) and endogenous dopamine concentrations (measured with microdialysis) following prefrontal stimulation with amphetamine to mimic stress effects in nonhuman primates (7).

Blockade of Radioligand Binding by Endogenous Neurotransmitter. Competition between radioligand binding to dopamine D2 receptors and endogenous dopamine can be used to measure dopamine concentrations in vivo. (A) Presynaptic dopamine release is depicted on the left side (with dopamine transporters for reuptake), and postsynaptic dopamine D2 receptors are indicated by boxes on the right side. High endogenous dopamine release blocks a considerable amount of dopamine D2 receptors, which then cannot bind a radioligand tracer (eg, the neuroleptic drug [¹²³I]Iodobenzamid [IBZM]), resulting in low radioligand binding. (B) Reduced dopamine release (eg, due to blockade of dopamine synthesis) decreases dopamine concentrations and results in less binding of endogenous dopamine to D2 receptors, which can now be marked by radioligand tracers. Alterations in radioligand binding can be quantified and reflect changes in endogenous dopamine concentrations.

Phasic Dopamine Release Reflects an Error of Reward Prediction. Upper part: When no reward is expected, it comes as a surprise and hence the difference between the received and the expected reward (arbitrarily set at 1) is positive, which according to Schultz and coworkers is reflected in an increase in dopamine firing. Middle part: A conditioned stimulus that reliably predicts that reward is attributed with incentive salience; whenever it appears unexpectedly, it elicits a phasic dopamine response due to a positive difference between the received and the expected value of the cue. Arrival of the reward itself, on the other hand, does not elicit dopamine firing as long as this reward is fully predicted by the preceding salient stimulus (because the reward received is exactly the same as the expected reward). Lower part: When the expected reward fails to be received, the difference between the received and the expected reward is negative, reflected in a phasic decrease of dopamine firing.

Increased Dopamine Release in Acute Schizophrenia Is Hypothetically Due To Altered Cortico-Striatal-Thalamic Neurocircuits. Left panel (A): Dysfunction of the interaction between excitatory glutamatergic and inhibitory GABAergic (γ-aminobutyric acid) neurotransmission in cortical brain areas can disinhibit subcortical dopamine release, as suggested by studies using ketamine to block glutamatergic neurotransmission via NMDA receptors in humans and nonhuman primates.,, Right panel (B): Brain imaging studies suggest that in schizophrenia, low dopamine release in the prefrontal cortex (PFC) results in an upregulation of dopamine D1 receptors, which can destabilize information processing and interfere with a glutamatergic projection to midbrain dopamine neurons. According to Sesack and Carr, these glutamatergic projections can directly stimulate prefrontal dopamine release but inhibit midbrain dopamine neurons projecting to the striatum (via GABAergic interneurons). Dysfunctional glutamatergic input from the PFC can thus (further) impair prefrontal dopamine release while at the same time disinhibiting striatal dopaminergic neurotransmission. Glutamatergic projections are depicted in green and GABAergic in red; reduced neurotransmission is indicated by shaded and dotted lines.

Ventral Striatal Activation During Incentive Anticipation Represents Incentive Salience. Left panel: BOLD response in the bilateral ventral striatum during anticipation of potential monetary reward and loss avoidance compared with the neutral condition in 44 healthy controls (P < .05 family wise error corrected for the whole brain; displayed at Montreal Neurological Institute coordinate y = 6). Right panel upper part: Higher activation during anticipation of larger amounts of monetary gain resp. loss avoidance: Parameter estimates for the different cues indicating different amounts of loss avoidance and reward or no monetary consequences (−3.0€, −0.6€, −0.1€, ±0€, +0.6€, +3.0€, +0.1€): Cues that indicate higher gain or higher loss-avoidance trials elicited stronger activation compared with lower amounts of money (parameter estimates from the peak voxel of the right ventral striatum at x = 15, y = 6, z = −9, t = 7.57). Right panel lower part: Cues that predict higher gains or the possibility to avoid higher losses elicited faster reaction times than cues predicting lower gains (respectably loss avoidance) with the lowest reaction times following neutral cues. This indicated that these stimuli actually represent an incentive to adjust goal-directed behavior according to the predicted gain or loss avoidance.

Hypothesized Association Between Dysfunction of Reward Anticipation and Altered Dopaminergic Neurotransmission in the Hyperdopaminergic State of Acute Schizophrenic Psychosis. Upper part: Task structure for the monetary incentive delay task: During each trial, a cue indicated potential reward, loss avoidance, or a neutral trial. After cue presentation, volunteers waited a variable interval (fixation cross) and then responded to a white target square with a button press. To succeed in a given trial, volunteers had to press the button while the target was visible. Chance of winning was 66% due to an individual adjustment to response performance. After target presentation, feedback appeared, notifying volunteers whether they had successfully won or avoided losing money. Lower part: Firing rate of dopaminergic midbrain neurons according to Schultz et al. A phasic dopamine firing increase occurs during presentation of reward-indicating stimuli once learning has taken place (left panel), which corresponds to the anticipation phase of the Monetary Incentive Delay (MID) task. No increase is observed after the delivery of fully predicted (expected) reward, which corresponds to the feedback phase of the MID task (right panel). Chaotic firing due to the hyperdopaminergic state in unmedicated schizophrenia patients indicated by the red arrows may lead to increased “noise” and “drown out” the neuronal response measured with functional magnetic resonance imaging following the reward-indicating cue.