Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia

Abstract

Schizophrenia is characterized by profound cognitive deficits that are not alleviated by currently available medications. Many of these cognitive deficits involve dysfunction of the newly evolved, dorsolateral prefrontal cortex (dlPFC). The brains of patients with schizophrenia show evidence of dlPFC pyramidal cell dendritic atrophy, likely reductions in cortical dopamine, and possible changes in dopamine D₁ receptors (D₁R). It has been appreciated for decades that optimal levels of dopamine are essential for dlPFC working memory function, with many beneficial actions arising from D₁R stimulation. D₁R are concentrated on dendritic spines in the primate dlPFC, where their stimulation produces an inverted-U dose response on dlPFC neuronal firing and cognitive performance during working memory tasks. Research in both academia and the pharmaceutical industry has led to the development of selective D₁ agonists, e.g., the first full D₁ agonist, dihydrexidine, which at low doses improved working memory in monkeys. Dihydrexidine has begun to be tested in patients with schizophrenia or schizotypal disorder. Initial results are encouraging, but studies are limited by the pharmacokinetics of the drug. These data, however, have spurred efforts toward the discovery and development of improved or novel new compounds, including D₁ agonists with better pharmacokinetics, functionally selective D₁ ligands, and D₁R positive allosteric modulators. One or several of these approaches should allow optimization of the beneficial effects of D₁R stimulation in the dlPFC that can be translated into clinical practice.

Keywords: D(1) agonist; D(2) receptors; Executive function; Prefrontal cortex; Schizophrenia; Working memory.

Figure 1. Schematic illustration of DA D₁R influences on Delay cell firing in layer III of the primate dlPFC

A. Localization of D₁R in layer III dlPFC pyramidal cell networks. Pyramidal cells interconnect via NMDAR synapses on spines, with permissive actions from nicotinic α7 receptors (nic- α7R). Immunoelectron microscopy has shown that D₁R are concentrated on dendritic spines, where they can be seen directly within the synapse (magenta), and near the synapse where they often co-localize with HCN or KCNQ potassium channels (red). The open state of both of these channels is increased by cAMP-PKA signaling. Physiological recordings from monkeys indicate that D₁R activates feedforward cAMP-PKA-calcium signaling, which opens K⁺ channels and weakens nearby synaptic inputs (red). At optimal doses this sculpts away noise from irrelevant inputs, but at higher doses, e.g. as occurs during stress, it causes nonspecific suppression of Delay cell firing and loss of working memory. Feedforward cAMP-calcium signaling is held in check by the phosphodiesterase, PDE4A, which is anchored in place by DISC1 (Disrupted In Schizophrenia). Studies in nonprimate species suggest that D₁R within the synapse phosphorylate NMDAR via activation of cAMP-PKA and PKC signaling; this maintains NMDAR in the synaptic membrane and strengthens connections (magenta). There are also D₁R on glutamate axon terminals that may reduce glutamate release (purple). For detailed description, see Arnsten et al, 2015. The asterisk indicates the spine apparatus, the extension of the smooth endoplasmic reticulum into the spine. B. A schematic illustration of the DA D₁R inverted U influence on the “memory fields” of dlPFC Delay cells. For details, see (5). Under optimal arousal conditions, Delay cells generate persistent representations of visual space, displaying high rates of firing (orange-red) to the memory of one spatial location, and low rates of firing (blue) to the memory of all other spatial locations. When there is no D₁R stimulation, Delay cells have little firing. Low levels of D₁R stimulation appear to be excitatory, e.g. phosphorylating NMDAR to increase their trafficking into the synapse (7). This can produce noisy firing for all directions, as represented by the generalized green-orange coloring of the memory field. With optimal levels of D₁R stimulation, there are additional sculpting actions, gating out “noise”, e.g. by opening a subset of HCN channels. At still higher levels of D₁R stimulation (e.g. as occurs during stress), there is excessive HCN channel opening and Delay cell firing is generally suppressed. Under these conditions the neuron is not able to generate persistent representations of visual space.

Figure 2. Structures of selective D₁ antagonists and PET ligands

The site of radiolabeling is shown by the asterisk. The most pharmacologically active isomer is shown, although these compounds are sometimes used as racemates.

Figure 3. Examples of important experimental D₁ agonists

[Top Row] SKF-38393 (partial agonist) and SKF-82958 (full agonist) are phenylbenzazepines. SKF-89626 had higher intrinsic activity than SKF-38393, but lacked BBB permeability. CY208243 is a high D₁ intrinsic activity ergoline. [Bottom row] Four full D₁ agonists from four different chemotypes: A-77636, A-86829 (the active compound of the diacetyl prodrug ABT-431), dihydrexidine (DAR-0100A), and dinapsoline. The most pharmacologically active isomer is shown in all cases, although these compounds are sometimes used as racemates.

Figure 4. Structures of D₁ positve allosteric modulators (PAMs)

PAMs may offer an advantage over orthosteric (direct) agonists by interacting with endogenous dopamine tone, and as such, may possibly avoid biphasic effects currently seen with direct D₁ agonists.