Reinstatement of nicotine conditioned place preference in a transgenerational model of drug abuse vulnerability in psychosis: Impact of BDNF on the saliency of drug associations

Rationale: Psychotic disorders such as schizophrenia are often accompanied by high rates of cigarette smoking, reduced quit success, and high relapse rates, negatively affecting patient outcomes. However, the mechanisms underlying altered relapse-like behaviors in individuals diagnosed with psychosis are poorly understood. Objectives: The present study analyzed changes in extinction and reinstatement of nicotine conditioned place preference (CPP) and resulting changes in brain-derived neurotrophic factor (BDNF) in a novel heritable rodent model of psychosis, demonstrating increased dopamine D2 receptor sensitivity, to explore mechanisms contributing to changes in relapse-like behaviors. Methods: Male and female offspring of two neonatal quinpirole-treated (QQ) and two neonatal saline-treated (SS) Sprague-Dawley rats (F1 generation) were tested on an extended CPP paradigm to analyze extinction and nicotine-primed reinstatement. Brain tissue was analyzed 60 min after the last nicotine injection for BDNF response in the ventral tegmental area (VTA), the infralimbic (IfL) and prelimbic (PrL) cortices. Results: F1 generation QQ offspring demonstrated delayed extinction and more robust reinstatement compared to SS control animals. In addition, QQ animals demonstrated an enhanced BDNF response to nicotine in the VTA, IfL and Prl cortices compared to SS offspring. Conclusions: This study is the first to demonstrate altered relapse-like behavior in a heritable rodent model with relevance to comorbid drug abuse and psychosis. This altered pattern of behavior is hypothesized to be related to elevated activity-dependent BDNF in brain areas associated with drug reinforcement during conditioning that persists through the extinction phase, rendering aberrantly salient drug associations resistant to extinction and enhancing relapse vulnerability

Modulation of Metabotropic Glutamate Receptor Type 5 (mGlu5) Reduces the Enhanced Rewarding Effects of Nicotine in a Neonatal Quinpirole Model of Psychosis

Nicotine has been indicated as a prevalent drug for substance abuse comorbidities in mental illness. Tobacco use is elevated in those suffering from psychiatric disorders, most notably in schizophrenia (SZ), where a three-to-five fold increase in usage compared to the general population is observed. Our laboratory has established a rodent model of psychosis. In this model, male and female rats are neonatally treated with quinpirole (NQ), a dopamine (DA) D2-like agonist for 21 days postpartum, resulting in lifelong supersensitization of the DAD2 receptor. Increases in dopamine D2 receptor sensitivity is a hallmark of psychosis. Interestingly, the dopamine D2 receptor forms a triple mutual inhibitor heteromer in the dorsal striatum with the adenosine A(2A) and metabotropic glutamate receptor type 5 (mGlu5), such that stimulation of the A(2A) or mGlu5 receptor results in decreased dopamine D2 signaling. The present study was designed to analyze the role of the mGlu5 receptor in a behavioral task involved in testing the associative aspects of rewarding drugs known as conditioned place preference (CPP). CPP is a behavioral task in which animals are conditioned with a reinforcing drug to prefer a particular environmental context. Male and female rats were neonatally treated with saline (NS) or quinpirole from postnatal day (P) 1 to 21. From P41-51, which is mid-adolescence in a rat, all rats were behaviorally tested on CPP. Results revealed that compared to NS rats, NQ animals administered nicotine demonstrated enhanced CPP, replicating our past work. Groups receiving a positive allosteric modulator to mGlu5, which results in stimulation of the mGlu5 receptor, reduced the enhanced rewarding effects of nicotine in CPP for NQ treated rats equal to control levels. Brain tissue was analyzed for brain-derived neurotropic factor (BDNF), a neurotrophin involved in cell growth, as well cell adhesion molecule cadherin-13 in the ventral tegmental area (VTA), which is a brain area rich in dopamine cell bodies. Results revealed elevations of BDNF in NQ-treated rats given nicotine compared to all other groups, and a sex difference in the increase in cadherin-13, with female NQ rats given nicotine demonstrating increases compared to all other groups. These effects were blocked by the mGlu5 receptor positive allosteric modulator. In addition, we analyzed phospho-p70S6 kinase in the nucleus accumbens (NAcc), which is the dopamine neuronal terminal region in the VTA mitigating drug reward. The NQ group given nicotine demonstrated significant increases in NAcc P70S6 kinase compared to all other groups, suggesting increased synaptic growth, which was also blocked by the positive allosteric modulator to mGlu5. Taken together, these results elucidate mGlu5 as a drug target for reducing the rewarding effects of nicotine via CDPPB administration in a model of substance abuse in psychosis

Analysis of the effects of a novel anti-inflammatory on anxiety, apathy, and cognition in a mouse model of Alzheimer’s Disease

Alzheimer’s Disease (AD) is the most common form of dementia. It is a fatal neurodegenerative disease that leads to both cognitive decline and altered psychological states. There is currently no cure for AD. The pathology of AD includes the clustering of insoluble amyloid-β (Aβ) plaques, tau tangles, and increased neuroinflammation. These pathological manifestations initially occur in the hippocampus (HPC), then continue to the prefrontal cortex (PFC), and occur throughout the brain as the disease progresses. The heightened neuroinflammatory state in AD is an essential point of focus in AD research. In this study, the novel oral anti-inflammatory tumor necrosis factor-α (TNF-α) inhibitor compound PD2244 was tested to observe its effects on sensorimotor gating using prepulse inhibition (PPI), spatial memory using Barnes Maze, anxiety using an elevated-T maze, and apathy by observing nest building behavior in both female and male 3xTg mice. The 3xTg mice are the only triple-transgenic models of AD that have both Aβ plaques and tau tangles and is also an accelerated mouse model of AD pathology onset. A specialized diet containing variable doses of PD2244 was given to 3xTg mice beginning at 6 months of age. The doses given were 0, 1, 3, 10, and 30 mg/kg of PD2244. Testing was then performed at 9, 12, and 15 months, where 15 months equated to thorough AD pathology. Regarding behavioral improvement, it was observed that all doses of PD2244 were effective to alleviate deficits in PPI at 9, 12, and 15 months of age. On the Barnes Maze, at 9 months of age the 10 mg/kg dose of PD2244 was effective to alleviate deficits, whereas at 12 months of age, 3 and 30 mg/kg dose of PD2244 was effective, and finally, at 15 months of age the 3, 10 and 30 mg/kg doses of PD2244 demonstrated efficacy to alleviate deficits in spatial memory performance. On the elevated T-maze, there were no effects at 9 months of age, but the 3 mg/kg dose of PD2244 resulted in anxiolytic effects at 12 and 15 months of age. Nest building behavior is also being observed in 15-month-old mice to determine effects of PD2244 on apathy since it is a common neuropsychiatric prodrome of AD. Finally, analysis of neurobiological markers has revealed that PD2244 reduced increases in the proinflammatory cytokines TNF-α and interkeukin-1β (IL-1β) at 15 months of age in the HPC. In addition, there is currently a project analyzing immunohistological staining of microglial cells in the HPC and PFC in 15-month-old animals. This project is designed to discover a novel, effective, anti-inflammatory treatment for cognitive deficits and increases in anxiety associate with AD