Reduction of brain kynurenic acid improves cognitive function.

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 α7 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 ketamine-induced 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.

Phosphodiesterase 9A regulates central cGMP and modulates responses to cholinergic and monoaminergic perturbation in vivo.

Cyclic nucleotides are critical regulators of synaptic plasticity and participate in requisite signaling cascades implicated across multiple neurotransmitter systems. Phosphodiesterase 9A (PDE9A) is a high-affinity, cGMP-specific enzyme widely expressed in the rodent central nervous system. In the current study, we observed neuronal staining with antibodies raised against PDE9A protein in human cortex, cerebellum, and subiculum. We have also developed several potent, selective, and brain-penetrant PDE9A inhibitors and used them to probe the function of PDE9A in vivo. Administration of these compounds to animals led to dose-dependent accumulation of cGMP in brain tissue and cerebrospinal fluid, producing a range of biological effects that implied functional significance for PDE9A-regulated cGMP in dopaminergic, cholinergic, and serotonergic neurotransmission and were consistent with the widespread distribution of PDE9A. In vivo effects of PDE9A inhibition included reversal of the respective disruptions of working memory by ketamine, episodic and spatial memory by scopolamine, and auditory gating by amphetamine, as well as potentiation of risperidone-induced improvements in sensorimotor gating and reversal of the stereotypic scratching response to the hallucinogenic 5-hydroxytryptamine 2A agonist mescaline. The results suggested a role for PDE9A in the regulation of monoaminergic circuitry associated with sensory processing and memory. Thus, PDE9A activity regulates neuronal cGMP signaling downstream of multiple neurotransmitter systems, and inhibition of PDE9A may provide therapeutic benefits in psychiatric and neurodegenerative diseases promoted by the dysfunction of these diverse neurotransmitter systems.

Modulation of NMDA receptor function by inhibition of D-amino acid oxidase in rodent brain.

Observations that N-Methyl-D-Aspartate (NMDA) antagonists produce symptoms in humans that are similar to those seen in schizophrenia have led to the current hypothesis that schizophrenia might result from NMDA receptor hypofunction. Inhibition of D-amino acid oxidase (DAAO), the enzyme responsible for degradation of D-serine, should lead to increased levels of this co-agonist at the NMDA receptor, and thereby provide a therapeutic approach to schizophrenia. We have profiled some of the preclinical biochemical, electrophysiological, and behavioral consequences of administering potent and selective inhibitors of DAAO to rodents to begin to test this hypothesis. Inhibition of DAAO activity resulted in a significant dose and time dependent increase in D-serine only in the cerebellum, although a time delay was observed between peak plasma or brain drug concentration and cerebellum D-serine response. Pharmacokinetic/pharmacodynamic (PK/PD) modeling employing a mechanism-based indirect response model was used to characterize the correlation between free brain drug concentration and D-serine accumulation. DAAO inhibitors had little or no activity in rodent models considered predictive for antipsychotic activity. The inhibitors did, however, affect cortical activity in the Mescaline-Induced Scratching model, produced a modest but significant increase in NMDA receptor-mediated synaptic currents in primary neuronal cultures from rat hippocampus, and resulted in a significant increase in evoked hippocampal theta rhythm, an in vivo electrophysiological model of hippocampal activity. These findings demonstrate that although DAAO inhibition did not cause a measurable increase in D-serine in forebrain, it did affect hippocampal and cortical activity, possibly through augmentation of NMDA receptor-mediated currents.

Preclinical pharmacology of the alpha4beta2 nAChR partial agonist varenicline related to effects on reward, mood and cognition.

The pharmacological properties and pharmacokinetic profile of the alpha4beta2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline provide an advantageous combination of free brain levels and functional potencies at the target receptor that for a large part explain its efficacy as a smoking cessation aid. Since alpha4beta2 and other nAChR subtypes play important roles in mediating central processes that control reward, mood, cognition and attention, there is interest in examining the effects of selective nAChR ligands such as varenicline in preclinical animal models that assess these behaviors. Here we describe results from studies on varenicline's effects in animal models of addiction, depression, cognition and attention and discuss these in the context of recently published preclinical and preliminary clinical studies that collected data on varenicline's effects on mood, cognition and alcohol abuse disorder. Taken together, the preclinical and the limited clinical data show beneficial effects of varenicline, but further clinical studies are needed to evaluate whether the preclinical effects observed in animal models are translatable to the clinic.

Varenicline has antidepressant-like activity in the forced swim test and augments sertraline's effect.

Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist developed as a smoking cessation aid, showed antidepressant-like activity in the forced swim test in two mouse strains. In addition, a low varenicline dose significantly enhanced the effects of moderately active doses of the selective serotonin reuptake inhibitor sertraline. These findings are consistent with the notion that reducing alpha4beta2 nicotinic acetylcholine receptor activity either by antagonists or by partial agonists that can partially activate or desensitize acetylcholine receptors is associated with antidepressant-like properties. These data suggest that varenicline may have antidepressant potential and can, when combined, augment antidepressant responses of selective serotonin reuptake inhibitors.

CP-809,101, a selective 5-HT2C agonist, shows activity in animal models of antipsychotic activity.

CP-809,101 is a potent, functionally selective 5-HT(2C) agonist that displays approximately 100% efficacy in vitro. The aim of the present studies was to assess the efficacy of a selective 5-HT(2C) agonist in animal models predictive of antipsychotic-like efficacy and side-effect liability. Similar to currently available antipsychotic drugs, CP-809,101 dose-dependently inhibited conditioned avoidance responding (CAR, ED(50)=4.8 mg/kg, sc). The efficacy of CP-809,101 in CAR was completely antagonized by the concurrent administration of the 5-HT(2C) receptor antagonist, SB-224,282. CP-809,101 antagonized both PCP- and d-amphetamine-induced hyperactivity with ED(50) values of 2.4 and 2.9 mg/kg (sc), respectively and also reversed an apomorphine induced-deficit in prepulse inhibition. At doses up to 56 mg/kg, CP-809,101 did not produce catalepsy. Thus, the present results demonstrate that the 5-HT(2C) agonist, CP-809,101, has a pharmacological profile similar to that of the atypical antipsychotics with low extrapyramidal symptom liability. CP-809,101 was inactive in two animal models of antidepressant-like activity, the forced swim test and learned helplessness. However, CP-809,101 was active in novel object recognition, an animal model of cognitive function. These data suggest that 5-HT(2C) agonists may be a novel approach in the treatment of psychosis as well as for the improvement of cognitive dysfunction associated with schizophrenia.

CP-465,022, a selective noncompetitive AMPA receptor antagonist, blocks AMPA receptors but is not neuroprotective in vivo.

BACKGROUND AND PURPOSE: Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition has been hypothesized to provide neuroprotective efficacy after cerebral ischemia on the basis of the activity in experimental ischemia models of a variety of compounds with varying selectivity for AMPA over other glutamate receptor subtypes. CP-465,022 is a new, potent, and selective noncompetitive AMPA receptor antagonist. The present study investigated the ability of this compound to reduce neuronal loss after experimental cerebral ischemia to probe the neuroprotective potential of AMPA receptor inhibition. METHODS: To demonstrate that CP-465,022 gains access to the brain, the effects of systemic administration of CP-465,022 were investigated on AMPA receptor-mediated electrophysiological responses in hippocampus and on chemically induced seizures in rats. The compound was then investigated for neuroprotective efficacy in rat global and focal ischemia models at doses demonstrated to be maximally effective in the electrophysiology and seizure models. RESULTS: CP-465,022 potently and efficaciously inhibited AMPA receptor-mediated hippocampal synaptic transmission and the induction of seizures. However, at comparable doses, CP-465,022 failed to prevent CA1 neuron loss after brief global ischemia or to reduce infarct volume after temporary middle cerebral artery occlusion. CONCLUSIONS: Given the high selectivity of CP-465,022 for AMPA over kainate and N-methyl-D-aspartate subtypes of glutamate receptors, the lack of neuroprotective efficacy of the compound calls into question the neuroprotective efficacy of AMPA receptor inhibition after ischemia.