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.

Behavioral changes and growth deficits in a CRISPR engineered mouse model of the schizophrenia-associated 3q29 deletion

“…Female and male B6.Del16 +/Bdh1-Tfrc mice showed attenuated sensitivity to amphetamine-induced locomotor activity at a high dose of drug, suggesting perturbations in the dopaminergic system and demonstrating a shared behavior phenotype. Disruptions in dopamine signaling have been shown to confer risk for both ASD and SZ (30,31). We also demonstrated that B6.Dlg1 +/mice did not share any of the behavioral phenotypes that are observed in B6.Del16 +/Bdh1-Tfrc mice.…”

Role of basal ganglia neurocircuitry in the pathology of psychiatric disorders

“…Accordingly, levels of the dopamine‐synthesizing enzyme tyrosine hydroxylase in the SNr and baseline and stimulant‐induced levels of dopamine in the striatum have been reported to be increased in schizophrenia patients compared with healthy controls . More recently, alterations in striatal dopamine release were found to be particularly localized to the associative striatum, and are hypothesized to contribute to the misattribution of salience to certain environmental stimuli, associated with psychosis . PET studies have also reported an increase in dopamine D2 receptors in both the NAc and the SNr of schizophrenic patients, suggesting increased D2‐signalling may contribute to schizophrenia symptoms .…”

“…A recently proposed theory of schizophrenia suggests that excessive dopamine signaling in the striatum may directly lead to psychotic symptoms by compromising the integration of cortical inputs . This might explain why antipsychotics binding at D2 receptors are effective in ameliorating the positive symptoms of schizophrenia, associated with altered dopaminergic function in the striatum, but are often unsuccessful in treating cognitive impairments in schizophrenics .…”

Use of tobacco in schizophrenia: A double‐edged sword

“…A study involving Chinese FES patients reported similar results to those obtained in the present study (Zhang et al, ). We assume that the potential mechanism is an elevated release and utilization of dopamine in the mesolimbic dopaminergic system by nicotine, which has been strongly associated with positive symptoms (Brody et al, ; Kesby, Eyles, McGrath, & Scott, ; Li et al, ; Montgomery, Lingford‐hughes, Egerton, Nutt, & Grasby, ). The other potential reason is self‐medication hypothesis.…”