Pharmacokinetic, pharmacodynamic, and transcriptomic analysis of chronic levetiracetam treatment in 5XFAD mice: A MODEL-AD preclinical testing core study.

Introduction: Hyperexcitability and epileptiform activity are commonplace in Alzheimer's disease (AD) patients and associated with impaired cognitive function. The anti-seizure drug levetiracetam (LEV) is currently being evaluated in clinical trials for ability to reduce epileptiform activity and improve cognitive function in AD. The purpose of our studies was to establish a pharmacokinetic/pharmacodynamic (PK/PD) relationship with LEV in an amyloidogenic mouse model of AD to enable predictive preclinical to clinical translation, using the rigorous preclinical testing pipeline of the Model Organism Development and Evaluation for Late-Onset Alzheimer's Disease Preclinical Testing Core. Methods: A multi-tier approach was applied that included quality assurance and quality control of the active pharmaceutical ingredient, PK/PD modeling, positron emission tomography/magnetic resonance imaging (PET/MRI), functional outcomes, and transcriptomics. 5XFAD mice were treated chronically with LEV for 3 months at doses in line with those allometrically scaled to the clinical dose range. Results: Pharmacokinetics of LEV demonstrated sex differences in Cmax, AUC0-∞, and CL/F, and a dose dependence in AUC0-∞. After chronic dosing at 10, 30, 56 mg/kg, PET/MRI tracer 18F-AV45, and 18F-fluorodeoxyglucose (18F-FDG) showed specific regional differences with treatment. LEV did not significantly improve cognitive outcomes. Transcriptomics performed by nanoString demonstrated drug- and dose-related changes in gene expression relevant to human brain regions and pathways congruent with changes in 18F-FDG uptake. Discussion: This study represents the first report of PK/PD assessment of LEV in 5XFAD mice. Overall, these results highlighted non-linear kinetics based on dose and sex. Plasma concentrations of the 10 mg/kg dose in 5XFAD overlapped with human plasma concentrations used for studies of mild cognitive impairment, while the 30 and 56 mg/kg doses were reflective of doses used to treat seizure activity. Post-treatment gene expression analysis demonstrated LEV dose-related changes in immune function and neuronal-signaling pathways relevant to human AD, and aligned with regional 18F-FDG uptake. Overall, this study highlights the importance of PK/PD relationships in preclinical studies to inform clinical study design. Highlights: Significant sex differences in pharmacokinetics of levetiracetam were observed in 5XFAD mice.Plasma concentrations of 10 mg/kg levetiracetam dose in 5XFAD overlapped with human plasma concentration used in the clinic.Drug- and dose-related differences in gene expression relevant to human brain regions and pathways were also similar to brain region-specific changes in 18F-fluorodeoxyglucose uptake.

Prophylactic evaluation of verubecestat on disease- and symptom-modifying effects in 5XFAD mice.

Introduction: Alzheimer's disease (AD) is the most common form of dementia. Beta-secretase (BACE) inhibitors have been proposed as potential therapeutic interventions; however, initiating treatment once disease has significantly progressed has failed to effectively stop or treat disease. Whether BACE inhibition may have efficacy when administered prophylactically in the early stages of AD has been under-investigated. The present studies aimed to evaluate prophylactic treatment of the BACE inhibitor verubecestat in an AD mouse model using the National Institute on Aging (NIA) resources of the Model Organism Development for Late-Onset Alzheimer's Disease (MODEL-AD) Preclinical Testing Core (PTC) Drug Screening Pipeline. Methods: 5XFAD mice were administered verubecestat ad libitum in chow from 3 to 6 months of age, prior to the onset of significant disease pathology. Following treatment (6 months of age), in vivo imaging was conducted with 18F-florbetapir (AV-45/Amyvid) (18F-AV45) and 18-FDG (fluorodeoxyglucose)-PET (positron emission tomography)/MRI (magnetic resonance imaging), brain and plasma amyloid beta (Aß) were measured, and the clinical and behavioral characteristics of the mice were assessed and correlated with the pharmacokinetic data. Results: Prophylactic verubecestat treatment resulted in dose- and region-dependent attenuations of 18F-AV45 uptake in male and female 5XFAD mice. Plasma Aß40 and Aß42 were also dose-dependently attenuated with treatment. Across the dose range evaluated, side effects including coat color changes and motor alterations were reported, in the absence of cognitive improvement or changes in 18F-FDG uptake. Discussion: Prophylactic treatment with verubecestat resulted in attenuated amyloid plaque deposition when treatment was initiated prior to significant pathology in 5XFAD mice. At the same dose range effective at attenuating Aß levels, verubecestat produced side effects in the absence of improvements in cognitive function. Taken together these data demonstrate the rigorous translational approaches of the MODEL-AD PTC for interrogating potential therapeutics and provide insight into the limitations of verubecestat as a prophylactic intervention for early-stage AD.

Emerging Electroencephalographic Biomarkers to Improve Preclinical to Clinical Translation in Alzheimer's Disease.

Continually emerging data indicate that sub-clinical, non-convulsive epileptiform activity is not only prevalent in Alzheimer's disease (AD) but is detectable early in the course of the disease and predicts cognitive decline in both humans and animal models. Epileptiform activity and other electroencephalographic (EEG) measures may hold powerful, untapped potential to improve the translational validity of AD-related biomarkers in model animals ranging from mice, to rats, and non-human primates. In this review, we will focus on studies of epileptiform activity, EEG slowing, and theta-gamma coupling in preclinical models, with particular focus on its role in cognitive decline and relevance to AD. Here, each biomarker is described in the context of the contemporary literature and recent findings in AD relevant animal models are discussed.

Comprehensive Evaluation of the 5XFAD Mouse Model for Preclinical Testing Applications: A MODEL-AD Study.

The ability to investigate therapeutic interventions in animal models of neurodegenerative diseases depends on extensive characterization of the model(s) being used. There are numerous models that have been generated to study Alzheimer's disease (AD) and the underlying pathogenesis of the disease. While transgenic models have been instrumental in understanding AD mechanisms and risk factors, they are limited in the degree of characteristics displayed in comparison with AD in humans, and the full spectrum of AD effects has yet to be recapitulated in a single mouse model. The Model Organism Development and Evaluation for Late-Onset Alzheimer's Disease (MODEL-AD) consortium was assembled by the National Institute on Aging (NIA) to develop more robust animal models of AD with increased relevance to human disease, standardize the characterization of AD mouse models, improve preclinical testing in animals, and establish clinically relevant AD biomarkers, among other aims toward enhancing the translational value of AD models in clinical drug design and treatment development. Here we have conducted a detailed characterization of the 5XFAD mouse, including transcriptomics, electroencephalogram, in vivo imaging, biochemical characterization, and behavioral assessments. The data from this study is publicly available through the AD Knowledge Portal.

Chronic antipsychotic treatment exerts limited effects on the mania-like behavior of dopamine transporter knockdown mice.

BACKGROUND: Bipolar disorder is a life-threatening disorder linked to dopamine transporter (DAT) polymorphisms, with reduced DAT levels seen in positron emission tomography and postmortem brains. AIMS: The purpose of this study was to examine the effects of approved antipsychotics on DAT dysfunction-mediated mania behavior in mice. METHODS: DAT knockdown mice received either D2-family receptor antagonist risperidone or asenapine and mania-related behaviors were assessed in the clinically-relevant behavioral pattern monitor to assess spontaneous exploration. RESULTS: Chronic risperidone did not reverse mania-like behavior in DAT knockdown mice. Chronic asenapine reduced mania behavior but this effect was more pronounced in wild-type littermates than in DAT knockdown mice. CONCLUSION: Taken together, these findings suggest that while acute antipsychotic treatment may be beneficial in management of bipolar mania, more targeted therapeutics may be necessary for long-term treatment. Specific investigation into DAT-targeting drugs could improve future treatment of bipolar mania.

Converging evidence that short-active photoperiod increases acetylcholine signaling in the hippocampus.

Seasonal variations in environmental light influence switches between moods in seasonal affective disorder (SAD) and bipolar disorder (BD), with depression arising during short active (SA) winter periods. Light-induced changes in behavior are also seen in healthy animals and are intensified in mice with reduced dopamine transporter expression. Specifically, decreasing the nocturnal active period (SA) of mice increases punishment perseveration and forced swim test (FST) immobility. Elevating acetylcholine with the acetylcholinesterase inhibitor physostigmine induces depression symptoms in people and increases FST immobility in mice. We used SA photoperiods and physostigmine to elevate acetylcholine prior to testing in a probabilistic learning task and the FST, including reversing subsequent deficits with nicotinic and scopolamine antagonists and targeted hippocampal adeno-associated viral administration. We confirmed that physostigmine also increases punishment sensitivity in a probabilistic learning paradigm. In addition, muscarinic and nicotinic receptor blockade attenuated both physostigmine-induced and SA-induced phenotypes. Finally, viral-mediated hippocampal expression of human AChE used to lower ACh levels blocked SA-induced elevation of FST immobility. These results indicate that increased hippocampal acetylcholine neurotransmission is necessary for the expression of SA exposure-induced behaviors. Furthermore, these studies support the potential for cholinergic treatments in depression. Taken together, these results provide evidence for hippocampal cholinergic mechanisms in contributing to seasonally depressed affective states induced by short day lengths.

Short-active photoperiod gestation induces psychiatry-relevant behavior in healthy mice but a resiliency to such effects are seen in mice with reduced dopamine transporter expression.

A higher incidence of multiple psychiatric disorders occurs in people born in late winter/early spring. Reduced light exposure/activity level impacts adult rodent behavior and neural mechanisms, yet few studies have investigated such light exposure on gestating fetuses. A dysfunctional dopamine system is implicated in most psychiatric disorders, and genetic polymorphisms reducing expression of the dopamine transporter (DAT) are associated with some conditions. Furthermore, adult mice with reduced DAT expression (DAT-HT) were hypersensitive to short active (SA; 19:5 L:D) photoperiod exposure versus their wildtype (WT) littermates. Effects of SA photoperiod exposure during gestation in these mice have not been examined. We confirmed adult females exhibit a heightened corticosterone response when in SA photoperiod. We then tested DAT-HT mice and WT littermates in psychiatry-relevant behavioral tests after SA or normal active (NA; 12:12 L:D) photoperiod exposure during gestation and early life. SA-born WT mice exhibited sensorimotor gating deficits (males), increased reward preference, less immobility, open arm avoidance (females), less motivation to obtain a reward, and reversal learning deficits, vs. NA-born WT mice. DAT-HT mice were largely resilient to these effects, however. Future studies will determine the mechanism(s) by which SA photoperiod exposure influences brain development to predispose toward emergence of psychiatry-relevant behaviors.

Oxytocin improves probabilistic reversal learning but not effortful motivation in Brown Norway rats.

Deficits in cognition and motivation are common and debilitating aspects of psychiatric disorders, yet still go largely untreated. The neuropeptide oxytocin (OT) is a potential novel therapeutic for deficits in social cognition and motivation in psychiatric patients. However, the effects of OT on clinically relevant domains of non-social cognition and motivation remain under studied. The present study investigated the effects of acute and chronic (21-day) administration of subcutaneous OT (0.04, 0.2, and 1 mg/kg) in cross-species translatable operant paradigms of reward learning and effortful motivation in male and female Brown Norway (BN) rats (n = 8-10/group). Reward learning was assessed using the probabilistic reversal learning task (PRLT) and effortful motivation was measured using the progressive ratio breakpoint task (PRBT). As predicted, BN rats exhibited baseline deficits in the detection of reversals of reward contingency in the PRLT relative to Long Evans (LE) rats. The two strains performed equally in the PRBT. Thirty minutes after a single OT injection (1 mg/kg), measures of both initial probabilistic learning (trials to first criterion) and subsequent reversal learning (contingency switches) were significantly improved to levels comparable with LE rats. The OT effect on switches persisted in male, but not female, BN rats 30 min, 24 h, and 6 days after long-term OT administration, suggesting the induction of neuroplastic changes. OT did not affect effortful motivation at any time-point. The beneficial effects of OT on reward learning in the absence of increased effortful motivation support the development of OT as a novel therapeutic to improve cognitive functioning.

DREADD-mediated modulation of locus coeruleus inputs to mPFC improves strategy set-shifting.

Appropriate modification of behavior in response to our dynamic environment is essential for adaptation and survival. This adaptability allows organisms to maximize the utility of behavior-related energy expenditure. Modern theories of locus coeruleus (LC) function implicate a pivotal role for the noradrenergic nucleus in mediating switches between focused behavior during periods of high utility (exploit) versus disengagement of behavior and exploration of other, more rewarding opportunities. Two modes of activity in LC neurons have been characterized as elements in an Adaptive Gain Theory (AGT) of LC function. In this theory, during periods of accurate and focused behavior, LC neurons exhibit task-related phasic bursts. However, as behavioral utility wanes, phasic activity is suppressed and baseline (tonic) impulse activity increases to facilitate exploration. Our experiments sought to exogenously induce an elevated pattern of activity in LC neurons and their medial prefrontal cortical (mPFC) targets to test the tenets of the AGT. This theory posits that tonic activation immediately following a rule change should increase exploration and thereby improve performance on a set-shifting task. Indeed, DREADD mediated stimulation of LC terminals within mPFC decreased trials to reach criterion. However, this effect resulted from improved application of the new rule once the original rule is jettisoned rather than earlier disengagement from the old, ineffective strategy. Such improvements were not seen with global manipulation of LC, consistent with the view that LC-mediated exploration involves specific sub-circuits targeting mPFC. These findings extend our understanding of the role of LC in PFC and flexible behavior.

Chemogenetic Manipulations of Ventral Tegmental Area Dopamine Neurons Reveal Multifaceted Roles in Cocaine Abuse.

Ventral tegmental area (VTA) dopamine (DA) neurons perform diverse functions in motivation and cognition, but their precise roles in addiction-related behaviors are still debated. Here, we targeted VTA DA neurons for bidirectional chemogenetic modulation during specific tests of cocaine reinforcement, demand, and relapse-related behaviors in male rats, querying the roles of DA neuron inhibitory and excitatory G-protein signaling in these processes. Designer receptor stimulation of Gq signaling, but not Gs signaling, in DA neurons enhanced cocaine seeking via functionally distinct projections to forebrain limbic regions. In contrast, engaging inhibitory Gi/o signaling in DA neurons blunted the reinforcing and priming effects of cocaine, reduced stress-potentiated reinstatement, and altered behavioral strategies for cocaine seeking and taking. Results demonstrate that DA neurons play several distinct roles in cocaine seeking, depending on behavioral context, G-protein-signaling cascades, and DA neuron efferent targets, highlighting their multifaceted roles in addiction.SIGNIFICANCE STATEMENT G-protein-coupled receptors are crucial modulators of ventral tegmental area (VTA) dopamine neuron activity, but how this metabotropic signaling impacts the complex roles of dopamine in reward and addiction is poorly understood. Here, we bidirectionally modulate dopamine neuron G-protein signaling with DREADDs (designer receptors exclusively activated by designer drugs) during a variety of cocaine-seeking behaviors, revealing nuanced, pathway-specific roles in cocaine reward, effortful seeking, and relapse-like behaviors. Gq and Gs stimulation activated dopamine neurons, but only Gq stimulation robustly enhanced cocaine seeking. Gi/o inhibitory signaling reduced some, but not all, types of cocaine seeking. Results show that VTA dopamine neurons modulate numerous distinct aspects of cocaine addiction- and relapse-related behaviors, and point to potential new approaches for intervening in these processes to treat addiction.

Dopamine transporter knockdown mice in the behavioral pattern monitor: A robust, reproducible model for mania-relevant behaviors.

Efforts to replicate results from both basic and clinical models have highlighted problems with reproducibility in science. In psychiatry, reproducibility issues are compounded because the complex behavioral syndromes make many disorders challenging to model. We develop translatable tasks that quantitatively measure psychiatry-relevant behaviors across species. The behavioral pattern monitor (BPM) was designed to analyze exploratory behaviors, which are altered in patients with bipolar disorder (BD), especially during mania episodes. We have repeatedly assessed the behavioral effects of reduced dopamine transporter (DAT) expression in the BPM using a DAT knockdown (KD) mouse line (~10% normal expression). DAT KD mice exhibit a profile in the BPM consistent with acutely manic BD patients in the human version of the task-hyperactivity, increased exploratory behavior, and reduced spatial d (Perry et al., 2009). We collected data from multiple DAT KD BPM experiments in our laboratory to assess the reproducibility of behavioral outcomes across experiments. The four outcomes analyzed were: 1) transitions (amount of locomotor activity); 2) rearings (exploratory activity); 3) holepokes (exploratory activity); and 4) spatial d (geometrical pattern of locomotor activity). By comparing DAT KD mice to wildtype (WT) littermates in every experiment, we calculated effect sizes for each of the four outcomes and then calculated a mean effect size using a random effects model. DAT KD mice exhibited robust, reproducible changes in each of the four outcomes, including increased transitions, rearings, and holepokes, and reduced spatial d, vs. WT littermates. Our results demonstrate that the DAT KD mouse line in the BPM is a consistent, reproducible model of mania-relevant behaviors. More work must be done to assess reproducibility of behavioral outcomes across experiments in order to advance the field of psychiatry and develop more effective therapeutics for patients.

Cognitive Phenotypes for Biomarker Identification in Mental Illness: Forward and Reverse Translation.

Psychiatric illness has been acknowledged for as long as people were able to describe behavioral abnormalities in the general population. In modern times, these descriptions have been codified and continuously updated into manuals by which clinicians can diagnose patients. None of these diagnostic manuals have attempted to tie abnormalities to neural dysfunction however, nor do they necessitate the quantification of cognitive function despite common knowledge of its ties to functional outcome. In fact, in recent years the National Institute of Mental Health released a novel transdiagnostic classification, the Research Domain Criteria (RDoC), which utilizes quantifiable behavioral abnormalities linked to neurophysiological processes. This reclassification highlights the utility of RDoC constructs as potential cognitive biomarkers of disease state. In addition, with RDoC and cognitive biomarkers, the onus of researchers utilizing animal models no longer necessitates the recreation of an entire disease state, but distinct processes. Here, we describe the utilization of constructs from the RDoC initiative to forward animal research on these cognitive and behavioral processes, agnostic of disease. By linking neural processes to these constructs, identifying putative abnormalities in diseased patients, more targeted therapeutics can be developed.

Mice with reduced DAT levels recreate seasonal-induced switching between states in bipolar disorder.

Developing novel therapeutics for bipolar disorder (BD) has been hampered by limited mechanistic knowledge how sufferers switch between mania and depression-how the same brain can switch between extreme states-described as the "holy grail" of BD research. Strong evidence implicates seasonally-induced switching between states, with mania associated with summer-onset, depression with winter-onset. Determining mechanisms of and sensitivity to such switching is required. C57BL/6J and dopamine transporter hypomorphic (DAT-HY 50% expression) mice performed a battery of psychiatry-relevant behavioral tasks following 2-week housing in chambers under seasonally relevant photoperiod extremes. Summer-like and winter-like photoperiod exposure induced mania-relevant and depression-relevant behaviors respectively in mice. This behavioral switch paralleled neurotransmitter switching from dopamine to somatostatin in hypothalamic neurons (receiving direct input from the photoperiod-processing center, the suprachiasmatic nucleus). Mice with reduced DAT expression exhibited hypersensitivity to these summer-like and winter-like photoperiods, including more extreme mania-relevant (including reward sensitivity during reinforcement learning), and depression-relevant (including punishment-sensitivity and loss-sensitivity during reinforcement learning) behaviors. DAT mRNA levels switched in wildtype littermate mice across photoperiods, an effect not replicated in DAT hypomorphic mice. This inability to adjust DAT levels to match photoperiod-induced neurotransmitter switching as a homeostatic control likely contributes to the susceptibility of DAT hypormophic mice to these switching photoperiods. These data reveal the potential contribution of photoperiod-induced neuroplasticity within an identified circuit of the hypothalamus, linked with reduced DAT function, underlying switching between states in BD. Further investigations of the circuit will likely identify novel therapeutic targets to block switching between states.

Modafinil improves attentional performance in healthy, non-sleep deprived humans at doses not inducing hyperarousal across species.

The wake-promoting drug modafinil is frequently used off-label to improve cognition in psychiatric and academic populations alike. The domain-specific attentional benefits of modafinil have yet to be quantified objectively in healthy human volunteers using tasks validated for comparison across species. Further, given that modafinil is a low-affinity inhibitor for the dopamine and norepinephrine transporters (DAT/NET respectively) it is unclear if any effects are attributable to a non-specific increase in arousal, a feature of many catecholamine reuptake inhibitors (e.g., cocaine, amphetamine). These experiments were designed to test for domain-specific enhancement of attention and cognitive control by modafinil (200 and 400 mg) in healthy volunteers using the 5-choice continuous performance task (5C-CPT) and Wisconsin Card Sort Task (WCST). An additional cross-species assessment of arousal and hyperactivity was performed in this group and in mice (3.2, 10, or 32 mg/kg) using species-specific versions of the behavioral pattern monitor (BPM). Modafinil significantly enhanced attention (d prime) in humans performing the 5C-CPT at doses that did not affect WCST performance or induce hyperactivity in the BPM. In mice, only the highest dose elicited increased activity in the BPM. These results indicate that modafinil produces domain-specific enhancement of attention in humans not driven by hyperarousal, unlike other drugs in this class, and higher equivalent doses were required for hyperarousal in mice. Further, these data support the utility of using the 5C-CPT across species to more precisely determine the mechanism(s) underlying the pro-cognitive effects of modafinil and potentially other pharmacological treatments.

The Five-Choice Continuous Performance Task (5C-CPT): A Cross-Species Relevant Paradigm for Assessment of Vigilance and Response Inhibition in Rodents.

Deficits in the domains of attention and response inhibition are central to many psychiatric disorders. As such, animal models of disorders purporting to replicate these behavioral deficits first require tests that can accurately assess the behaviors with high fidelity. The gold-standard clinical test of attention and response inhibition is the continuous performance test (CPT). Although there are a number of CPTs, all share the premise of responding to target stimuli and inhibiting from responding to non-target stimuli. The recently developed rodent five-choice CPT (5C-CPT) requires similar behavioral responses, enabling signal detection parameter calculations. With demonstrable feasibility for rodent testing, the 5C-CPT permits/facilitates: (1) delineation of neural mechanisms underlying these behaviors; (2) multifactorial analyses of the complex interplay between genetic and environmental manipulations relevant to psychiatric disorders; and hence (3) development of novel targeted treatments. All data to date indicate that the rodent 5C-CPT described here has direct translatability to clinical CPTs, producing equivalent measures of behavior in experimental animals to those assessed in humans. The 5C-CPT task provides an important tool toward delineating these mechanisms and developing treatments. However, it is also complex, with long training times and nuances requiring a thorough understanding before utilization. This unit will enable researchers to avoid potential missteps, greatly increasing the likelihood of success. © 2017 by John Wiley & Sons, Inc.

Premature responses in the five-choice serial reaction time task reflect rodents' temporal strategies: evidence from no-light and pharmacological challenges.

RATIONALE: The five-choice serial reaction time task (5-CSRTT) is regularly used to study attention and impulsivity. In the 5-CSRTT, rodents initiate a trial, then after an inter-trial interval (ITI), a light appears in one of five holes. Responding in the lit vs. unlit hole reflects attention (accuracy), while responding prematurely before a light appears is suggested to reflect impulsivity/response disinhibition. Comparison of rat and mouse 5-CSRTT performance has raised questions on the validity of premature responses as measuring impulsivity/response inhibition. To minimize effort, rodents may use a temporal strategy, enabling their "timing" of the ITI, minimizing the need to attend during this delay. Greater reliance on this strategy could result in premature responses due to "guesses" if their timing was poor/altered. OBJECTIVES: To assess the degree to which rats and/or mice utilize a temporal strategy, we challenged performance using infrequent no-light trials during 5-CSRTT performance. RESULTS: Even when no light appeared when one was expected, rats responded ~60 % compared to ~40 % in mice, indicating a greater reliance on a temporal strategy by rats than by mice. Consistent with this hypothesis, rats made more premature responses than mice. Additional studies using a temporal discrimination task and a 5-CSRTT variant demonstrated that delta-9-tetrahydrocannabinol, the active ingredient in cannabis, slowed temporal perception and reduced premature responses. CONCLUSIONS: These data provide behavioral and pharmacological evidence indicating that premature responses are heavily influenced by temporal perception. Hence, they may reflect an aspect of waiting impulsivity, but not response disinhibition, an important distinction for translational clinical research.

Chronic methamphetamine self-administration alters cognitive flexibility in male rats.

RATIONALE: Methamphetamine (meth) addiction is a chronically relapsing disorder that often produces persistent cognitive deficits. These include decreased cognitive flexibility, which may prevent meth addicts from altering their habitual drug abuse and leave them more susceptible to relapse. Multiple factors including low rates of compliance with research study participation and varied drug use patterns make the relationship between cognitive flexibility and relapse difficult to establish in clinical populations. OBJECTIVES: Here, we combined an extended-access meth self-administration paradigm with an automated set-shifting task in rats to directly compare cognitive flexibility performance with meth-seeking behavior. METHODS: Rats were pre-trained on an automated visual discrimination task, followed by 14 days of extended access (6 h/day) of meth or sucrose self-administration. They were then tested in the set-shifting task on strategy shift and reversal and subsequently assessed for cue-induced reinstatement of meth seeking. RESULTS: Rats with a history of meth, but not sucrose, self-administration had selective deficits in reversal learning. Specifically, meth rats had an increase in the total number of errors and perseverative errors (corresponding to the old stimulus-reward association) following the reversal shift, which correlated with prior stable meth self-administration. However, no relationship was seen between errors during the reversal and cue-induced reinstatement. CONCLUSION: The lack of association between meth-induced reversal deficits and cue-induced reinstatement to meth seeking indicates that these two domains may constitute independent pathologies of meth addiction.

Amphetamine increases activity but not exploration in humans and mice.

RATIONALE: Cross-species quantification of physiological behavior enables a better understanding of the biological systems underlying neuropsychiatric diseases such as bipolar disorder (BD). Cardinal symptoms of manic BD include increased motor activity and goal-directed behavior, thought to be related to increased catecholamine activity, potentially selective to dopamine homeostatic dysregulation. OBJECTIVES: The objective of this study was to test whether acute administration of amphetamine, a norepinephrine/dopamine transporter inhibitor and dopamine releaser, would replicate the profile of activity and exploration observed in both humans with manic BD and mouse models of mania. METHODS: Healthy volunteers with no psychiatric history were randomized to a one-time dose of placebo (n = 25), 10 mg d-amphetamine (n = 18), or 20 mg amphetamine (n = 23). Eighty mice were administered one of four doses of d-amphetamine or vehicle. Humans and mice were tested in the behavioral pattern monitor (BPM), which quantifies motor activity, exploratory behavior, and spatial patterns of behavior. RESULTS: In humans, the 20-mg dose of amphetamine increased motor activity as measured by acceleration without marked effects on exploration or spatial patterns of activity. In mice, amphetamine increased activity, decreased specific exploration, and caused straighter, one-dimensional movements in a dose-dependent manner. CONCLUSIONS: Consistent with mice, amphetamine increased motoric activity in humans without increasing exploration. Given that BD patients exhibit heightened exploration, these data further emphasize the limitation of amphetamine-induced hyperactivity as a suitable model for BD. Further, these studies highlight the utility of cross-species physiological paradigms in validating biological mechanisms of psychiatric diseases.

Schizophrenia and substance abuse comorbidity: nicotine addiction and the neonatal quinpirole model.

This review focuses on nicotine comorbidity in schizophrenia, and the insight into this problem provided by rodent models of schizophrenia. A particular focus is on age differences in the response to nicotine, and how this relates to the development of the disease and difficulties in treatment. Schizophrenia is a particularly difficult disease to model in rodents due to the fact that it has a plethora of symptoms ranging from paranoia and delusions of grandeur to anhedonia and negative affect. The basis of these symptoms is believed to be due to neurochemical abnormalities and neuropathology in the brain, which most models have attempted to emulate. A brief review of findings regarding nicotine use and abuse in schizophrenics is presented, with findings using rodent models that have been able to provide insight into the mechanisms of addiction. A common clinical approach to the treatment of nicotine addiction in the schizophrenic population has been that these drugs are used for self-medication purposes, and it is clear that self-medication may actually be directed at several symptoms, including cognitive impairment and anhedonia. Finally, our laboratory has reported across a series of studies that neonatal treatment with the dopamine D(2)/D(3) receptor agonist quinpirole results in long-term increases in dopamine-like receptor sensitivity, consistent with data reporting increases in dopamine D(2) receptor function in schizophrenia. Across these studies, we have reported several behavioral, neurochemical, and genetic consistencies with the disease, and present a hypothesis for what we believe to be the basis of psychostimulant addiction in schizophrenia.