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Decades of research have highlighted the importance of optimal stimulation of cortical dopaminergic receptors, particularly the D1R receptor (D1R), for prefrontal-mediated cognition. This mechanism is particularly relevant to the cognitive deficits in schizophrenia, given the abnormalities in cortical dopamine (DA) neurotransmission and in the expression of D1R. Despite the critical need for D1R-based therapeutics, many factors have complicated their development and prevented this important therapeutic target from being adequately interrogated. Challenges include determination of the optimal level of D1R stimulation needed to improve cognitive performance, especially when D1R expression levels, affinity states, DA levels, and the resulting D1R occupancy by DA, are not clearly known in schizophrenia, and may display great interindividual and intraindividual variability related to cognitive states and other physiological variables. These directly affect the selection of the level of stimulation necessary to correct the underlying neurobiology. The optimal mechanism for stimulation is also unknown and could include partial or full agonism, biased agonism, or positive allosteric modulation. Furthermore, the development of D1R targeting drugs has been complicated by complexities in extrapolating from in vitro affinity determinations to in vivo use. Prior D1R-targeted drugs have been unsuccessful due to poor bioavailability, pharmacokinetics, and insufficient target engagement at tolerable doses. Newer drugs have recently become available, and these must be tested in the context of carefully designed paradigms that address methodological challenges. In this paper, we discuss how a better understanding of these challenges has shaped our proposed experimental design for testing a new D1R/D5R partial agonist, PF-06412562, renamed CVL-562.

Background: Converging evidence suggests concomitant abnormalities in NMDA-dependent processes in schizophrenia in addition to dopaminergic disturbances. These include the robust and replicable deficits in mismatch negativity (MMN), an NMDA-dependent event-related potential to unexpected auditory events, and MR spectroscopy findings showing increased glutamate in untreated SCZ in several cortical and subcortical regions (thalamus, striatum, hippocampus, and medial prefrontal cortex). Studies of medicated patients have shown a glutamate- or glutamine-lowering effect of antipsychotic medications. We also recently measured a deficit in cortical dopamine release using PET and the amphetamine challenge. Taken together these findings suggest that dopamine and glutamate may be both affected in the cortex and raise a special therapeutic challenge. Furthermore, in the striatum glutamate and dopamine have both been found to be abnormal.

Background Molecular imaging with Positron Emission Tomography (PET) has the unique capability of examining molecules in the brains of human subjects in real time. This has been well exploited in the study of dopaminergic transmission in schizophrenia. The results have on one hand confirmed some predictions, and on the other hand they have brought up unexpected findings, that have the potential to affect drug development in a major way. Methods PET studies of dopamine release, synthesis, storage, receptors and transporters across labs and different experiments will be reviewed to extract findings that differ from preconceived notions. These have the capability of re-focusing drug development based on new evidence. Results Expected findings that PET studies have confirmed are those of striatal dopaminergic excess, measured as enhanced presynaptic release capacity and presynaptic enzymatic synthesis capacity. Also expected was hypodopaminergic transmission in the dorso-lateral prefrontal cortex. The unexpected findings from PET have been as follows: 1) the striatal excess is most predominant in the associative striatum, rather than the limbic striatum. 2) hypodopaminergia is generalized to all extrastriatal areas of the brain These observations of opposite presynaptic dopaminergic dysfunction between striatal and extrastriatal regions suggest that the striatal excess may not be driven by activity levels of midbrain DA cells but may result from abnormal striatal local regulation of presynaptic DA release, affecting specifically the associative striatum, region which shows largest magnitude of excess DA. Furthermore alterations in dopaminergic signaling in opposing directions may have a dual effect on learning across functional domains by weakening learning from salient or relevant signals and reinforcing stimulus independent signals, thus explaining different symptom domains. Discussion More work is needed to understand the cellular mechanisms of dopaminergic dysfunction in schizophrenia. The evidence presented here, while limited, highlights the challenges of drug development in the absence of real in vivo information from patients, and the need for multidisciplinary cross talk to address these challenges.

Background In schizophrenia (SCH), proton MRS studies of the medial prefrontal cortex (MPFC) show elevated glutamine (Gln) or the combination of Glu and Gln (Glx) in unmedicated patients. Studies in healthy human subjects demonstrate ketamine-induced acute increases in MPFC Glu or Gln. Together, these findings raise the question of potential disturbances in excitation-inhibition balance in the illness, possibly arising from NMDA receptor deficits in GABAergic interneurons. We investigated these questions following acute ketamine administration by using repeated 15-minute MRS acquisitions of Glx and GABA with simultaneous EEG and comparing the results with the same modalities acquired in SCH. Methods We enrolled 11 healthy volunteers (age 18–55) who were given a constant i.v. infusion of ketamine 0.5 mg/kg over 40 min during a combined EEG and 1H MRS study. Glx and GABA were acquired in the pregenual MPFC using a 3T GE system and a J-edited PRESS sequence. Sequential MRS acquisitions each of 15 min duration (90 min total) were obtained before, during, and following the infusion. EEG was recorded using an MRI-compatible 64-channel system with direct current BrainAmp MR amplifiers (Brain Products GmbH). Post-ketamine EEG data were analyzed in frontal electrodes for gamma and delta alterations. EEG and MRS data were also acquired in 12 patients with SCH with these systems. Results Neurochemicals Glx and GABA showed acute increases within 15–30 minutes following the initiation of ketamine infusion, more pronounced for GABA (13% increase, p = .04 by paired t test). Gamma amplitude in left and right frontal electrodes increased in the first 15-minute average after initiation of ketamine (p < .05), with no evidence of earlier gamma decrease. Left delta amplitude decreased linearly following ketamine (p < .01). Peak GABA concentration correlated inversely with average left delta amplitude in the immediately subsequent 15-minute acquisition. Data in SCH showed similar elevations in GABA and gamma amplitude. Discussion These data show the feasibility of attaining time resolution of Glx and GABA changes in the several-minutes range with standard PRESS J-edited 1H MRS, and simultaneous sub-second resolution with EEG. There were no indications in these frontal electrodes of very early GABAergic inhibition leading to disinhibition of Glx, which may occur in other brain regions following ketamine administration. The GABA, Glx, and EEG alterations found here following ketamine administration are consistent with stable alterations reported in unmedicated patients with SCH and are compatible with an NMDA receptor deficit mechanism in the illness. They show homeostatic rebalancing at elevated levels as found in SCH itself. Excitation-inhibition rebalancing at abnormally elevated levels may pose a risk of neuronal damage that persists in untreated psychosis.