Cholinergic neurons originating from the basal forebrain innervate the entire cortical mantle. Choline-sensitive microelectrodes were used to measure the synaptic release of cortical acetylcholine (ACh) at a subsecond resolution in rats performing a task involving the detection of cues. Cues that were detected, defined behaviorally, evoked transient increases in cholinergic activity (at the scale of seconds) in the medial prefrontal cortex (mPFC), but not in a nonassociational control region (motor cortex). In trials involving missed cues, cholinergic transients were not observed. Cholinergic deafferentation of the mPFC, but not motor cortex, impaired cue detection. Furthermore, decreases and increases in precue cholinergic activity predicted subsequent cue detection or misses, respectively. Finally, cue-evoked cholinergic transients were superimposed over slower (at the timescale of minutes) changes in cholinergic activity. Cortical cholinergic neurotransmission is regulated on multiple timescales to mediate the detection of behaviorally significant cues and to support cognitive performance.

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Selective activation of dopamine D1 receptors (D1Rs) has been pursued for 40 years as a therapeutic strategy for neurologic and psychiatric diseases due to the fundamental role of D1Rs in motor function, reward processing, and cognition. All known D1R-selective agonists are catechols, which are rapidly metabolized and desensitize the D1R after prolonged exposure, reducing agonist response. As such, drug-like selective D1R agonists have remained elusive. Here we report a novel series of selective, potent non-catechol D1R agonists with promising in vivo pharmacokinetic properties. These ligands stimulate adenylyl cyclase signaling and are efficacious in a rodent model of Parkinson's disease after oral administration. They exhibit distinct binding to the D1R orthosteric site and a novel functional profile including minimal receptor desensitization, reduced recruitment of β-arrestin, and sustained in vivo efficacy. These results reveal a novel class of D1 agonists with favorable drug-like properties, and define the molecular basis for catechol-specific recruitment of β-arrestin to D1Rs.

The elevation of kynurenic acid (KYNA) observed in schizophrenic patients may contribute to core symptoms arising from glutamate hypofunction, including cognitive impairments. Although increased KYNA levels reduce excitatory neurotransmission, KYNA has been proposed to act as an endogenous antagonist at the glycine site of the glutamate NMDA receptor (NMDAR) and as a negative allosteric modulator at the ␣7 nicotinic acetylcholine receptor. Levels of KYNA are elevated in CSF and the postmortem brain of schizophrenia patients, and these elevated levels of KYNA could contribute to NMDAR hypofunction and the cognitive deficits and negative symptoms associated with this disease. However, the impact of endogenously produced KYNA on brain function and behavior is less well understood due to a paucity of pharmacological tools. To address this issue, we identified PF-04859989, a brain-penetrable inhibitor of kynurenine aminotransferase II (KAT II), the enzyme responsible for most brain KYNA synthesis. In rats, systemic administration of PF-04859989 dose-dependently reduced brain KYNA to as little as 28% of basal levels, and prevented amphetamine-and ketamineinduced disruption of auditory gating and improved performance in a sustained attention task. It also prevented ketamine-induced disruption of performance in a working memory task and a spatial memory task in rodents and nonhuman primates, respectively. Together, these findings support the hypotheses that endogenous KYNA impacts cognitive function and that inhibition of KAT II, and consequent lowering of endogenous brain KYNA levels, improves cognitive performance under conditions considered relevant for schizophrenia.

Previous research has demonstrated that attentional performance depends on the integrity of the cortical cholinergic input system and that such performance is associated with increases in cortical acetylcholine (ACh) release. The present experiment tested the hypothesis that the attentional impairments produced by bilateral basal forebrain infusions of the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV) are associated with attenuation of performance-associated increases in ACh release. Rats were trained in a sustained attention task and equipped with three guide cannula for the bilateral infusion of the NMDA receptor antagonist APV (0, 3, 20 nmol) and for the insertion of a dialysis probe into the medial prefrontal cortex (mPFC). APV or vehicle was infused remotely following completion of the first of five blocks of trials. During the first block, attentional performance was associated with a 140% increase in ACh efflux. Infusions of APV decreased the animals' ability to detect signals and augmented the increases in ACh efflux observed prior to infusions. These data indicate a dissociation between levels of attentional performance and increases in mPFC ACh release. Augmentation of performance-associated increases in mPFC cholinergic transmission is hypothesized to mediate the increased demands on attentional 'effort' that are required to maintain performance under challenging conditions.

Schizophrenia is associated with impaired attention. The top-down control of attention, defined as the ability to guide and refocus attention in accordance with internal goals and representations, was identified by the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative as an important construct for task development and research. A recent CNTRICS meeting identified three tasks commonly used with rodent models as having high construct validity and promise for further development: The 5-choice serial reaction time task, the 5-choice continuous performance task, and the distractor condition sustained attention task. Here we describe their current status, including data on their neural substrates, evidence for sensitivity to neuropharmacological manipulations and genetic influences, and data from animal models of the cognitive deficits of schizophrenia. A common strength is the development of parallel human tasks to facilitate connections to the neural circuitry and drug development research done in these animal models. We conclude with recommendations for the steps needed to improve testing so that it better represents the complex biological and behavioral picture presented by schizophrenia.

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