Dopamine, psychosis and schizophrenia: the widening gap between basic and clinical neuroscience

Abstract

The stagnation in drug development for schizophrenia highlights the need for better translation between basic and clinical research. Understanding the neurobiology of schizophrenia presents substantial challenges but a key feature continues to be the involvement of subcortical dopaminergic dysfunction in those with psychotic symptoms. Our contemporary knowledge regarding dopamine dysfunction has clarified where and when dopaminergic alterations may present in schizophrenia. For example, clinical studies have shown patients with schizophrenia show increased presynaptic dopamine function in the associative striatum, rather than the limbic striatum as previously presumed. Furthermore, subjects deemed at high risk of developing schizophrenia show similar presynaptic dopamine abnormalities in the associative striatum. Thus, our view of subcortical dopamine function in schizophrenia continues to evolve as we accommodate this newly acquired information. However, basic research in animal models has been slow to incorporate these clinical findings. For example, psychostimulant-induced locomotion, the commonly utilised phenotype for positive symptoms in rodents, is heavily associated with dopaminergic activation in the limbic striatum. This anatomical misalignment has brought into question how we assess positive symptoms in animal models and represents an opportunity for improved translation between basic and clinical research. The current review focuses on the role of subcortical dopamine dysfunction in psychosis and schizophrenia. We present and discuss alternative phenotypes that may provide a more translational approach to assess the neurobiology of positive symptoms in schizophrenia. Incorporation of recent clinical findings is essential if we are to develop meaningful translational animal models.

Fig. 1. Functional subdivisions of the dopamine system across species.

Midbrain dopamine neurons are the source of dopamine projections to the striatum in primates (left) and rodents (right). Important neuroanatomical differences exist, especially when considering functional subdivisions of the striatum. In the primate, the limbic system (orange) originates in the dorsal tier of the substantia nigra (the ventral tegmental area equivalent). In the rodent, the limbic system originates in ventral tegmental area, which sits medially to the substantia nigra. The midbrain projections to the associative striatum (yellow) and sensorimotor striatum (blue) follow a dorsomedial-to-ventrolateral topology

Fig. 2. Network implicated in psychotic symptoms and schizophrenia.

Dysfunction in a variety of brain regions can elicit psychotic symptoms. A primary circuit involved in psychosis includes the thalamus and prefrontal cortex (yellow) feeding into the associative striatum. Alterations in the thalamus and prefrontal cortex are involved in hallucinations and also insight for delusional symptoms. Expression of psychotic symptoms in most cases requires increased activity in the associative striatum and specifically excessive D2 receptor stimulation (red). Other limbic regions such as the hippocampus and amygdala (green) can feed into this circuit contributing to altered sensory perception and emotional context

Fig. 3. Psychosis: a consequence of severe circuit specific cognitive impairment.

This schematic representation highlights the potential for cognitive symptoms to feed into psychosis networks and create positive feedback loops that spiral to psychosis. Non-specific and heterogeneous deficits in auxiliary neurocircuitry (in the context of psychosis) lead to broad cognitive impairments unique to each individual. These systems feed into the primary psychosis networks leading to destabilisation of associative striatal dysfunction and further cognitive impairment. In most individuals with schizophrenia, excessive dopamine signalling in the associative striatum leads to positive symptoms. Antipsychotics antagonise downstream D2 receptor signalling to blunt the expression of symptoms. In treatment-refractory patients (those who do not respond to first-line antipsychotics) blocking D2 receptors is insufficient to blunt positive symptoms suggesting further upstream dysfunction in the associative striatum or psychosis networks. Clozapine may lead to improvement in some of these individuals by stabilising function throughout these networks in addition to D2 receptor antagonism. Positive symptoms in treatment-refractory patients who fail to respond to clozapine may be the result of severe impairment throughout psychosis networks (and the associative striatum) that are independent of dopamine dysfunction. Thus, our current treatments for positive symptoms act downstream of the source of cognitive impairments, hence their ineffectiveness in treating cognitive symptoms. While the expression of psychotic symptoms may be a discrete outcome, separate to impairments in cognitive function, the upstream cause of these symptoms may share common neuropathology

Fig. 4. Comparisons for cognitive tests in humans and rodents.

Humans and rodents can both perform cognitive tasks that feature actions to obtain rewards (a) The primary differences in testing are that humans can receive monetary rewards whereas rodents tend to be given food rewards. Furthermore, rodents require more initial training to learn the action (i.e., lever pressing or nose poking). To test for goal-directed action (b) both humans and rodents are trained to associate two actions (left and right button/lever presses) with two separate food rewards. One of these rewards is then devalued through an aversive video (cockroaches on the food item) for humans or feeding to satiety in rodents. Healthy controls will demonstrate outcome-specific devaluation by biasing their response towards the food reward that was not devalued. Serial reversal learning (c) requires the subject to learn a simple discrimination between two choices of which one is associated with a reward. Once certain criteria are met, the contingencies are reversed so that the non-rewarded stimulus is now rewarded and the previously rewarded stimulus does not attain a reward. This is classified as the first reversal. Once the criteria are met for the new contingencies, the rewarding stimulus is switched again (back to the original pairings) for the second reversal. This switching back and forth continues until completion of the test

Fig. 5. Behavioural tests to probe associative striatal function.

a The neurocircuitry involved in goal-directed action can be split into three primary circuits. The associative system (red), including the PFC and ACC, is required for the acquisition and expression of goal-directed action, which is sensitive to outcome devaluation. In contrast, the limbic system (green) is critical for the formation of associations between reward predictive stimuli and action. Habitual behaviours rely on the sensorimotor system (purple). b Behavioural flexibility involves OFC and PFC inputs to the associative striatum. The OFC is critical for reversal learning whereas the PFC is required when shifting to new rules or strategies. The associative striatum is the only common region required for goal-directed action that is sensitive to outcome devaluation and serial reversal learning. OFC orbitofrontal cortex, PFC prefrontal cortex, ACC anterior cingulate cortex, vm ventromedial, m medial, dl dorsolateral, lat lateral