The Effects of a Novel Non-catechol Dopamine Partial Agonist on Working Memory in the Aged Rhesus Monkey.

Aged-related declines in cognition, especially working memory and executive function, begin in middle-age and these abilities are known to be mediated by the prefrontal cortex (PFC) and more specifically the dopamine (DA) system within the PFC. In both humans and monkeys, there is significant evidence that the PFC is the first cortical region to change with age and the PFC appears to be particularly vulnerable to age-related loss of dopamine (DA). Therefore, the DA system is a strong candidate for therapeutic intervention to slow or reverse age related declines in cognition.

D1 Agonist Improved Movement of Parkinsonian Nonhuman Primates with Limited Dyskinesia Side Effects.

Parkinson's disease is a progressive neurodegenerative disease characterized by striatal dopaminergic loss. L-DOPA treatment replaces lost dopamine and enables motor function; however, eventually, fluctuating efficacy and side effects associated with its use become challenging for many patients. Here, we demonstrate, in a clinically translatable nonhuman primate model of parkinsonian motor symptoms, that treatment with the partial D1 receptor agonist CVL-751, formerly known as PF-06649751, is just as effective as L-DOPA in enabling movement and reducing disability.

In Vivo Modulation of Hippocampal Excitability by M4 Muscarinic Acetylcholine Receptor Activator: Implications for Treatment of Alzheimer's Disease and Schizophrenic Patients.

Abnormal hippocampal activity has been linked to impaired cognitive performance in Alzheimer's disease and schizophrenia, leading to a hypothesis that normalization of this activity may be therapeutically beneficial. Our work suggests that one approach for hippocampal normalization may be through activation of the M4 muscarinic acetylcholine receptor. We used a brain penetrant M4 muscarinic acetylcholine receptor selective activator, PT-3763, to show dose-dependent attenuation of field potentials in Schaffer collateral (CA3-CA1) and recurrent associational connections (CA3-CA3) ex vivo in hippocampal slices.

α5 nAChR modulation of the prefrontal cortex makes attention resilient.

A loss-of-function polymorphism in the α5 nicotinic acetylcholine receptor (nAChR) subunit gene has been linked to both drug abuse and schizophrenia. The α5 nAChR subunit is strategically positioned in the prefrontal cortex (PFC), where a loss-of-function in this subunit may contribute to cognitive disruptions in both disorders. However, the specific contribution of α5 to PFC-dependent cognitive functions has yet to be illustrated.

Nicotinic receptor subtypes differentially modulate glutamate release in the dorsal medial striatum.

The dorsal medial striatum is a crucial part of the neural network that subserves dynamic, goal-directed behaviors. Functional output of this nucleus is shaped, in part, by the influence of glutamatergic inputs. Striatal cholinergic systems have the capacity to modulate these excitatory inputs through presynaptic nicotinic acetylcholine receptors (nAChRs); however, the individual contribution of the two major nicotinic receptor subtypes, α4β2 and α7, to such modulation is not well characterized.

Cross-site strain comparison of pharmacological deficits in the touchscreen visual discrimination test.

The low rate of success for identifying effective treatments for cognitive dysfunction has prompted recent efforts to improve pharmaceutical discovery and development. In particular, investigators have emphasized improving translation from pre-clinical to clinical research. A specific area of focus has been touchscreen technology; this computer-automated behavioral testing method provides an objective assessment of performance that can be used across species.

MAM (E17) rodent developmental model of neuropsychiatric disease: disruptions in learning and dysregulation of nucleus accumbens dopamine release, but spared executive function.

Rationale: Gestational day 17 methylazoxymethanol (MAM) treatment has been shown to reproduce, in rodents, some of the alterations in cortical and mesolimbic circuitries thought to contribute to schizophrenia.

Objective: We characterized the behavior of MAM animals in tasks dependent on these circuitries to see what behavioral aspects of schizophrenia the model captures. We then characterized the integrity of mesolimbic dopamine neurotransmission in a subset of animals used in the behavioral experiments.

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.

A systemically-available kynurenine aminotransferase II (KAT II) inhibitor restores nicotine-evoked glutamatergic activity in the cortex of rats.

Kynurenic acid (KYNA) is a tryptophan metabolite that acts in the brain as an endogenous antagonist at multiple receptors, including glutamate and α7 nicotinic acetylcholine receptors. Increased levels of KYNA have been demonstrated in the brain of patients with a range of neurocognitive disorders, including schizophrenia, and are hypothesized to contribute to cognitive symptoms. Reducing KYNA levels by administering inhibitors of enzymes of the kynurenine pathway, particularly kynurenine aminotransferase II (KAT II), has been proposed as a treatment for such cognitive impairments.

Modulators in concert for cognition: modulator interactions in the prefrontal cortex.

Research on the regulation and function of ascending noradrenergic, dopaminergic, serotonergic, and cholinergic systems has focused on the organization and function of individual systems. In contrast, evidence describing co-activation and interactions between multiple neuromodulatory systems has remained scarce. However, commonalities in the anatomical organization of these systems and overlapping evidence concerning the post-synaptic effects of neuromodulators strongly suggest that these systems are recruited in concert; they influence each other and simultaneously modulate their target circuits.

Toward a neuro-cognitive animal model of the cognitive symptoms of schizophrenia: disruption of cortical cholinergic neurotransmission following repeated amphetamine exposure in attentional task-performing, but not non-performing, rats.

Impairments in attentional functions and capacities represent core aspects of the cognitive symptoms of schizophrenia. Attentional performance has been demonstrated to depend on the integrity and activity of cortical cholinergic inputs. The neurobiological, behavioral, and cognitive effects of repeated exposure to psychostimulants model important aspects of schizophrenia.

Increased striatal dopamine synthesis is associated with decreased tissue levels of tyrosine.

Tyrosine levels do not generally affect indices of dopamine (DA) synthesis or efflux under basal conditions, but can do so when DA synthesis is increased. One possibility is that a high rate of DA synthesis depletes the normally adequate pool of endogenous tyrosine. To study this, we administered drugs known to preferentially increase striatal DA synthesis and examined DOPA levels in striatal microdialysate during perfusion with NSD-1015.

Clozapine-induced dopamine release in the medial prefrontal cortex is augmented by a moderate concentration of locally administered tyrosine but attenuated by high tyrosine concentrations or by tyrosine depletion.

Rationale: Tyrosine availability can affect indices of dopamine (DA) release in activated central DA systems. There are, however, inconsistencies between studies. One possibility is that the relationship between tyrosine availability and DA release is non-linear.