Activity in the Dorsomedial Striatum Underlies Serial Reversal Learning Performance Under Probabilistic Uncertainty.

Background: Corticostriatal circuits, particularly the dorsomedial striatum (DMS) and lateral orbitofrontal cortex, are critical for navigating reversal learning under probabilistic uncertainty. These same areas are implicated in the reversal learning impairments observed in individuals with psychosis as well as their psychotic symptoms, suggesting that they may share a common neurobiological substrate. To address this question, we used psychostimulant exposure and specific activation of the DMS during reversal learning in mice to assess corticostriatal activity. Methods: We used amphetamine treatment to induce psychosis-relevant neurobiology in male mice during reversal learning and to examine pathway-specific corticostriatal activation. To determine the causal role of DMS activity, we used chemogenetics to drive midbrain inputs during a range of probabilistic contingencies. Results: Mice treated with amphetamine showed altered punishment learning, which was associated with decreased shifting after losses and increased perseverative errors after reversals. Reversal learning performance and strategies were dependent on increased activity in lateral orbitofrontal cortex to DMS circuits as well as in the DMS itself. Specific activation of midbrain to DMS circuits also decreased shifting after losses and reversal learning performance. However, these alterations were dependent on the probabilistic contingency. Conclusions: Our work suggests that the DMS plays a multifaceted role in reversal learning. Increasing DMS activity impairs multiple reversal learning processes dependent on the level of uncertainty, confirming its role in the maintenance and selection of incoming cortical inputs. Together, these outcomes suggest that elevated dopamine levels in the DMS could contribute to decision-making impairments in individuals with psychosis.

Increasing dopamine synthesis in nigrostriatal circuits increases phasic dopamine release and alters dorsal striatal connectivity: implications for schizophrenia.

One of the most robust neurochemical abnormalities reported in patients with schizophrenia is an increase in dopamine (DA) synthesis and release, restricted to the dorsal striatum (DS). This hyper functionality is strongly associated with psychotic symptoms and progresses in those who later transition to schizophrenia. To understand the implications of this progressive neurobiology on brain function, we have developed a model in rats which we refer to as EDiPs (Enhanced Dopamine in Prodromal schizophrenia). The EDiPs model features a virally mediated increase in dorsal striatal (DS) DA synthesis capacity across puberty and into adulthood. This protocol leads to progressive changes in behaviour and neurochemistry. Our aim in this study was to explore if increased DA synthesis capacity alters the physiology of DA release and DS connectivity. Using fast scan cyclic voltammetry to assess DA release we show that evoked/phasic DA release is increased in the DS of EDiPs rats, whereas tonic/background levels of DA remain unaffected. Using quantitative immunohistochemistry methods to quantify DS synaptic architecture we show a presynaptic marker for DA release sites (Bassoon) was elevated within TH axons specifically within the DS, consistent with the increased phasic DA release in this region. Alongside changes in DA systems, we also show increased density of vesicular glutamate transporter 1 (VGluT1) synapses in the EDiPs DS suggesting changes in cortical connectivity. Our data may prove relevant in understanding the long-term implications for DS function in response to the robust and prolonged increases in DA synthesis uptake and release reported in schizophrenia.

Reversal learning in those with early psychosis features contingency-dependent changes in loss response and learning.

INTRODUCTION: People with psychotic disorders commonly feature broad decision-making impairments that impact their functional outcomes. Specific associative/reinforcement learning problems have been demonstrated in persistent psychosis. But these phenotypes may differ in early psychosis, suggesting that aspects of cognition decline over time. METHODS: The present proof-of-concept study examined goal-directed action and reversal learning in controls and those with early psychosis. RESULTS: Equivalent performance was observed between groups during outcome-specific devaluation, and reversal learning at an 80:20 contingency (reward probability for high:low targets). But when the low target reward probability was increased (80:40) those with early psychosis altered their response to loss, whereas controls did not. Computational modelling confirmed that in early psychosis there was a change in punishment learning that increased the chance of staying with the same stimulus after a loss, multiple trials into the future. In early psychosis, the magnitude of this response was greatest in those with higher IQ and lower clinical severity scores. CONCLUSIONS: We show preliminary evidence that those with early psychosis present with a phenotype that includes altered responding to loss and hyper-adaptability in response to outcome changes. This may reflect a compensatory response to overcome the milieu of corticostriatal changes associated with psychotic disorders.

Antagonism of D2 receptors via raclopride ameliorates amphetamine-induced associative learning deficits in male mice.

Dopamine levels in the dorsomedial striatum (DMS) are highly dynamic and are thought to underly the encoding of action-outcome associations. Although it is known that amphetamine disrupts the learning that is required for goal-directed action, the role of D1 and D2 receptors in this process has not been established. In this study, we examined the role of D1 and D2 receptor antagonists on learning in response to amphetamine. We used the outcome-specific devaluation task to examine goal-directed action in male C57BL6/J mice treated systemically with either a D1 antagonist (SCH-23990; 0.01 mg/kg) or a D2 antagonist (raclopride; 0.5 mg/kg) and then administered amphetamine (1 mg/kg). The mice were injected repeatedly throughout the instrumental training phase of the task to assess the impact on the learning of action-outcomes, and the subsequent choice test assessing performance of goal-directed action was conducted drug free. Effects of chronic drug administration on locomotor behaviour was assessed before and after the choice test. Treatment during learning with either amphetamine, or the D1 or D2 antagonists, impaired the subsequent performance of goal-directed action. The amphetamine-induced impairment in goal-directed action was reversed in mice treated with raclopride, but not when treated with SCH-23990. By contrast, amphetamine-induced hyperactivity was reversed in mice treated with SCH-23990, but not in mice treated with raclopride. Taken together, these data support the role of a balance of dopamine receptor signalling after amphetamine treatment. While overall D1 receptor availability is necessary to promote learning, in a state of elevated dopamine, modifying D2 receptor function can ameliorate learning deficits.

Verbal and visual learning ability in patients with treatment-resistant schizophrenia: A 1-year follow-up study.

Objective: In the general population, repeated cognitive testing produces learning effects with potential for improved test performance. It is currently unclear whether the same effect of repeated cognitive testing on cognition pertains to people living with schizophrenia, a condition often associated with significant cognitive impairments. This study aims to evaluate learning ability in people with schizophrenia and-considering the evidence that antipsychotic medication can additionally impair cognitive performance-explore the potential impact of anticholinergic burden on verbal and visual learning. Method: The study included 86 patients with schizophrenia, treated with clozapine, who had persisting negative symptoms. They were assessed at baseline, weeks 8, 24 and 52 using Positive and Negative Syndrome Scale, Hopkins Verbal Learning Test-Revised (HVLT-R) and Brief Visuospatial Memory Test-R (BVMT-R). Results: There were no significant improvements in verbal or visual learning across all measurements. Neither the clozapine/norclozapine ratio nor anticholinergic cognitive burden significantly predicted participants' total learning. Premorbid IQ was significantly associated with verbal learning on the HVLT-R. Conclusions: These findings advance our understanding of cognitive performance in people with schizophrenia and demonstrate limited learning performance in individuals with treatment-refractory schizophrenia.

Activating the dorsomedial and ventral midbrain projections to the striatum differentially impairs goal-directed action in male mice.

The cognitive symptoms of schizophrenia are wide ranging and include impaired goal-directed action. This could be driven by an increase in dopamine transmission in the dorsomedial striatum, a pathophysiological hallmark of schizophrenia. Although commonly associated with psychotic symptoms, dopamine signalling in this region also modulates associative learning that aids in the execution of actions. To gain a better understanding of the role of subcortical dopamine in learning and decision-making, we assessed goal-directed action in male mice using the cross-species outcome-specific devaluation task (ODT). First, we administered systemic amphetamine during training to determine the impact of altered dopaminergic signaling on associative learning. Second, we used pathway-specific chemogenetic approaches to activate the dorsomedial and ventral striatal pathways (that originate in the midbrain) to separately assess learning and performance. Amphetamine treatment during learning led to a dose-dependent impairment in goal-directed action. Activation of both striatal pathways during learning also impaired performance. However, when these pathways were activated during choice, only activation of the ventral pathway impaired goal-directed action. This suggests that elevated transmission in the dorsomedial striatal pathway impairs associative learning processes that guide the goal-directed execution of actions. By contrast, elevated transmission of the ventral striatal pathway disrupts the encoding of outcome values that are important for both associative learning and choice performance. These findings highlight the differential roles of the dorsomedial and ventral inputs into the striatum in goal-directed action and provides insight into how striatal dopamine signaling may contribute to the cognitive problems in those with schizophrenia.

Neural Circuitry of Salience and Reward Processing in Psychosis.

The processing of salient and rewarding stimuli is integral to engaging our attention, stimulating anticipation for future events, and driving goal-directed behaviors. Widespread impairments in these processes are observed in psychosis, which may be associated with worse functional outcomes or mechanistically linked to the development of symptoms. Here, we summarize the current knowledge of behavioral and functional neuroimaging in salience, prediction error, and reward. Although each is a specific process, they are situated in multiple feedback and feedforward systems integral to decision making and cognition more generally. We argue that the origin of salience and reward processing dysfunctions may be centered in the subcortex during the earliest stages of psychosis, with cortical abnormalities being initially more spared but becoming more prominent in established psychotic illness/schizophrenia. The neural circuits underpinning salience and reward processing may provide targets for delaying or preventing progressive behavioral and neurobiological decline.

Biopsychology of Physical Activity in People with Schizophrenia: An Integrative Perspective on Barriers and Intervention Strategies.

People with severe mental illness such as schizophrenia experience high physical comorbidity, leading to a 15-20-year mortality gap compared with the general population. Lifestyle behaviours such as physical activity (PA) play important roles in the quest to bridge this gap. Interventions to increase PA engagement in this population have potential to be efficacious; however, their effectiveness can be hindered by low participant engagement, including low adherence and high drop-out, and by implementation of interventions that are not designed to compensate for the cognitive and motivational impairments characteristic for this group. Moreover, and importantly, the negative symptoms of schizophrenia are associated with neurobiological changes in the brain, which-based on principles of biopsychology-can contribute to poor motivation and impaired decision-making processes and behavioural maintenance. To increase PA levels in people with schizophrenia, better understanding of these neurological changes that impact PA engagement is needed. This has the potential to inform the design of interventions that, through enhancement of motivation, could effectively increase PA levels in this specific population. Incorporating strategies that address the dopamine dysregulation associated with schizophrenia, such as boosting the role of reward and self-determined motivation, may improve long-term PA maintenance, leading to habitual PA. Consideration of motivation and behavioural maintenance is also needed to impart health benefits such as prevention of chronic disease, which is associated with currently low PA levels in this high metabolic risk population. Taking a biopsychological perspective, we outline the neural pathways involved in motivation that are impacted by schizophrenia and propose strategies for promoting motivation for and PA engagement from adoption to habit formation.

Impairments in goal-directed action and reversal learning in a proportion of individuals with psychosis.

Cognitive impairment in psychosis is one of the strongest predictors of functional decline. Problems with decision-making processes, such as goal-directed action and reversal learning, can reflect cortico-striatal dysfunction. The heterogenous symptoms and neurobiology observed in those with psychosis suggests that specific cognitive phenotypes may reflect differing causative mechanisms. As such, decision-making performance could identify subgroups of individuals with more severe cortico-striatal dysfunction and help to predict their functional decline. The present work evaluated the relationship between goal-directed action, reversal learning, and symptom profiles in those with psychosis. We assessed decision-making processes in healthy controls (N = 34) and those with persistent psychosis (N = 45), subclassifying subjects based on intact/impaired goal-directed action. Compared with healthy controls (<20%), a large proportion (58%) of those with persistent psychosis displayed impaired goal-directed action, predicting poor serial reversal learning performance. Computational approaches indicated that those with impaired goal-directed action had a decreased capacity to rapidly update their prior beliefs in the face of changing contingencies. Impaired decision-making also was associated with reduced levels of grandiosity and increased problems with abstract thinking. These findings suggest that prominent decision-making deficits, indicative of cortico-striatal dysfunction, are present in a large proportion of people with persistent psychosis. Moreover, these impairments would have significant functional implications in terms of planning and abstract thinking.

Treating cognitive impairment in schizophrenia with GLP-1RAs: an overview of their therapeutic potential.

INTRODUCTION: Schizophrenia is a neuropsychiatric disorder that affects approximately 1% of individuals worldwide. There are no available medications to treat cognitive impairment in this patient population currently. Preclinical evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve cognitive function. There is a need to evaluate how GLP-1 RAs alter specific domains of cognition and whether they will be of therapeutic benefit in individuals with schizophrenia. AREAS COVERED: This paper summarizes the effects of GLP-1 RAs on metabolic processes in the brain and how these mechanisms relate to improved cognitive function. We provide an overview of preclinical studies that demonstrate GLP-1 RAs improve cognition and comment on their potential therapeutic benefit in individuals with schizophrenia. EXPERT OPINION: To understand the benefits of GLP-1 RAs in individuals with schizophrenia, further preclinical research with rodent models relevant to schizophrenia symptomology are needed. Moreover, preclinical studies must focus on using a wider range of behavioral assays to understand whether important aspects of cognition such as executive function, attention, and goal-directed behavior are improved using GLP-1 RAs. Further research into the specific mechanisms of how GLP-1 RAs affect cognitive function and their interactions with antipsychotic medication commonly prescribed is necessary.

Developmental Inhibition of Long Intergenic Non-Coding RNA, HOTAIRM1, Impairs Dopamine Neuron Differentiation and Maturation.

The dopaminergic (DA) system is important for a range of brain functions and subcortical DA development precedes many cortical maturational processes. The dysfunction of DA systems has been associated with neuropsychiatric disorders such as schizophrenia, depression, and addiction. DA neuron cell fate is controlled by a complex web of transcriptional factors that dictate DA neuron specification, differentiation, and maturation. A growing body of evidence suggests that these transcriptional factors are under the regulation of newly discovered non-coding RNAs. However, with regard to DA neuron development, little is known of the roles of non-coding RNAs. The long non-coding RNA (lncRNA) HOX-antisense intergenic RNA myeloid 1 (HOTAIRM1) is present in adult DA neurons, suggesting it may have a modulatory role in DA systems. Moreover, HOTAIRM1 is involved in the neuronal differentiation in human stem cells suggesting it may also play a role in early DA neuron development. To determine its role in early DA neuron development, we knocked down HOTAIRM1 using RNAi in vitro in a human neuroblastoma cell line, and in vivo in mouse DA progenitors using a novel in utero electroporation technique. HOTAIRM1 inhibition decreased the expression of a range of key DA neuron specification factors and impaired DA neuron differentiation and maturation. These results provide evidence of a functional role for HOTAIRM1 in DA neuron development and differentiation. Understanding of the role of lncRNAs in the development of DA systems may have broader implications for brain development and neurodevelopmental disorders such as schizophrenia.

Positive symptom phenotypes appear progressively in "EDiPS", a new animal model of the schizophrenia prodrome.

An increase in dopamine (DA) synthesis capacity in the dorsal striatum (DS) during the prodromal stage of schizophrenia becomes more pronounced as patients progress to the full disorder. Understanding this progression is critical to intervening in disease course. We developed an animal model-Enhanced Dopamine in Prodromal Schizophrenia (EDiPS)-which uses a genetic construct to increase DA synthesis capacity in the DS of male rats. We assessed pre-pulse inhibition (PPI) and amphetamine (AMPH)-induced locomotion (0.6 mg/kg) in EDiPS animals longitudinally after post-natal day 35 (when the EDiPS construct is administered). We also assessed their response to repeated acute restraint stress. In adult EDiPS animals, we measured baseline and evoked extracellular DA levels, and their stereotyped responses to 5 mg/kg AMPH. AMPH-induced hyperlocomotion was apparent in EDiPS animals 6-weeks after construct administration. There was an overall PPI deficit in EDiPS animals across all timepoints, however the stress response of EDiPS animals was unaltered. Adult EDiPS animals show normal baseline and potassium-evoked DA release in the DS. These findings suggest that key behavioural phenotypes in EDiPS animals show a progressive onset, similar to that demonstrated by patients as they transition to schizophrenia. The EDiPS model could therefore be used to investigate the molecular mechanisms underlying the prodrome of schizophrenia.

Sex differences and Tat expression affect dopaminergic receptor expression and response to antioxidant treatment in methamphetamine-sensitized HIV Tat transgenic mice.

Methamphetamine (Meth) abuse is a common HIV comorbidity. Males and females differ in their patterns of Meth use, associated behaviors, and responses, but the underlying mechanisms and impact of HIV infection are unclear. Transgenic mice with inducible HIV-1 Tat protein in the brain (iTat) replicate many neurological aspects of HIV infection in humans. We previously showed that Tat induction enhances the Meth sensitization response associated with perturbation of the dopaminergic system, in male iTat mice. Here, we used the iTat mouse model to investigate sex differences in individual and interactive effects of Tat and Meth challenge on locomotor sensitization, brain expression of dopamine receptors (DRDs) and regulatory adenosine receptors (ADORAs). Because Meth administration increases the production of reactive oxygen species (ROS), we also determined whether the effects of Meth could be rescued by concomitant treatment with the ROS scavenger N-acetyl cysteine (NAC). After Meth sensitization and a 7-day abstinence period, groups of Tat+ and Tat-male and female mice were challenged with Meth in combination with NAC. We confirmed that Tat expression and Meth challenge suppressed DRD mRNA and protein in males and females' brains, and showed that females were particularly susceptible to the effects of Meth on D1-like and D2-like DRD subtypes and ADORAs. The expression of these markers differed strikingly between males and females, and between females in different phases of the estrous cycle, in a Tat -dependent manner. NAC attenuated Meth-induced locomotor sensitization and preserved DRD expression in all groups except for Tat + females. These data identify complex interactions between sex, Meth use, and HIV infection on addiction responses, with potential implications for the treatment of male and female Meth users in the context of HIV, especially those with cognitive disorders.

Subcortical Dopamine and Cognition in Schizophrenia: Looking Beyond Psychosis in Preclinical Models.

Schizophrenia is characterized by positive, negative and cognitive symptoms. All current antipsychotic treatments feature dopamine-receptor antagonism that is relatively effective at addressing the psychotic (positive) symptoms of schizophrenia. However, there is no clear evidence that these medications improve the negative or cognitive symptoms, which are the greatest predictors of functional outcomes. One of the most robust pathophysiological observations in patients with schizophrenia is increased subcortical dopamine neurotransmission, primarily in the associative striatum. This brain area has an important role in a range of cognitive processes. Dopamine is also known to play a major part in regulating a number of cognitive functions impaired in schizophrenia but much of this research has been focused on cortical dopamine. Emerging research highlights the strong influence subcortical dopamine has on a range of cognitive domains, including attention, reward learning, goal-directed action and decision-making. Nonetheless, the precise role of the associative striatum in the cognitive impairments observed in schizophrenia remains poorly understood, presenting an opportunity to revisit its contribution to schizophrenia. Without a better understanding of the mechanisms underlying cognitive dysfunction, treatment development remains at a standstill. For this reason, improved preclinical animal models are needed if we are to understand the complex relationship between subcortical dopamine and cognition. A range of new techniques are facillitating the discrete manipulation of dopaminergic neurotransmission and measurements of cognitive performance, which can be investigated using a variety of sensitive translatable tasks. This has the potential to aid the successful incorporation of recent clinical research to address the lack of treatment strategies for cognitive symptoms in schizophrenia. This review will give an overview on the current state of research focused on subcortical dopamine and cognition in the context of schizophrenia research. We also discuss future strategies and approaches aimed at improving the translational outcomes for the treatment of cognitive deficits in schizophrenia.

Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization.

Methamphetamine (Meth) abuse is common among humans with immunodeficiency virus (HIV). The HIV-1 regulatory protein, trans-activator of transcription (Tat), has been described to induce changes in brain gene transcription that can result in impaired reward circuitry, as well as in inflammatory processes. In transgenic mice with doxycycline-induced Tat protein expression in the brain, i.e., a mouse model of neuroHIV, we tested global gene expression patterns induced by Meth sensitization. Meth-induced locomotor sensitization included repeated daily Meth or saline injections for seven days and Meth challenge after a seven-day abstinence period. Brain samples were collected 30 min after the Meth challenge. We investigated global gene expression changes in the caudate putamen, an area with relevance in behavior and HIV pathogenesis, and performed pathway and transcriptional factor usage predictions using systems biology strategies. We found that Tat expression alone had a very limited impact in gene transcription after the Meth challenge. In contrast, Meth-induced sensitization in the absence of Tat induced a global suppression of gene transcription. Interestingly, the interaction between Tat and Meth broadly prevented the Meth-induced global transcriptional suppression, by maintaining regulation pathways, and resulting in gene expression profiles that were more similar to the controls. Pathways associated with mitochondrial health, initiation of transcription and translation, as well as with epigenetic control, were heavily affected by Meth, and by its interaction with Tat in anti-directional ways. A series of systems strategies have predicted several components impacted by these interactions, including mitochondrial pathways, mTOR/RICTOR, AP-1 transcription factor, and eukaryotic initiation factors involved in transcription and translation. In spite of the antagonizing effects of Tat, a few genes identified in relevant gene networks remained downregulated, such as sirtuin 1, and the amyloid precursor protein (APP). In conclusion, Tat expression in the brain had a low acute transcriptional impact but strongly interacted with Meth sensitization, to modify effects in the global transcriptome.

Brain Reward Function after Chronic and Binge Methamphetamine Regimens in Mice Expressing the HIV-1 TAT Protein.

BACKGROUND: Methamphetamine abuse and human immunodeficiency virus (HIV) are common comorbidities. HIV-associated proteins, such as the regulatory protein TAT, may contribute to brain reward dysfunction, inducing an altered sensitivity to methamphetamine reward and/or withdrawal in this population. OBJECTIVE: These studies examined the combined effects of TAT protein expression and, chronic and binge methamphetamine regimens on brain reward function. METHODS: Transgenic mice with inducible brain expression of the TAT protein were exposed to either saline, a chronic, or a binge methamphetamine regimen. TAT expression was induced via doxycycline treatment during the last week of methamphetamine exposure. Brain reward function was assessed daily throughout the regimens, using the intracranial self-stimulation procedure, and after a subsequent acute methamphetamine challenge. RESULTS: Both methamphetamine regimens induced withdrawal-related decreases in reward function. TAT expression substantially, but not significantly increased the withdrawal associated with exposure to the binge regimen compared to the chronic regimen, but did not alter the response to acute methamphetamine challenge. TAT expression also led to persistent changes in adenosine 2B receptor expression in the caudate putamen, regardless of methamphetamine exposure. These results suggest that TAT expression may differentially affect brain reward function, dependent on the pattern of methamphetamine exposure. CONCLUSION: The subtle effects observed in these studies highlight that longer-term TAT expression, or its induction at earlier stages of methamphetamine exposure, may be more consequential at inducing behavioral and neurochemical effects.

Is there a role for antibodies targeting muscarinic acetylcholine receptors in the pathogenesis of schizophrenia?

OBJECTIVE: Muscarinic receptor dysfunction has been suggested to play an important role in the pathophysiology of schizophrenia. Recently, it has also become clear that immune reactivity directed against neurotransmitter receptors may play a pathogenic role in some cases of schizophrenia. The aim of this review is to summarize the case for muscarinic receptor dysfunction in schizophrenia and the evidence supporting the hypothesis that this dysfunction is related to the development of muscarinic receptor-targeting antibodies. METHOD: The article reviews studies of muscarinic receptors and the presence and potential role(s) of anti-muscarinic acetylcholine receptor antibodies in people with schizophrenia. RESULTS: There is accumulating evidence that altered or deficient muscarinic signalling underlies some of the key clinical features of schizophrenia. Although the number of studies investigating anti-muscarinic acetylcholine receptor antibodies in schizophrenia is relatively small, they consistently demonstrate that such antibodies are present in a proportion of patients. This evidence suggests that these antibodies could have pathogenic effects or exist as a biomarker to an unknown pathophysiological process in schizophrenia. CONCLUSION: The presence of elevated levels of anti-muscarinic acetylcholine receptor antibodies may identify a subgroup of people with schizophrenia, potentially informing aetiopathogenesis, clinical presentation and treatment. To date, all studies have examined antibodies in participants with chronic schizophrenia, who have likely received antipsychotic medication for many years. As these medications modulate immune functions and regulate receptor densities, it is recommended that future studies screen for the presence of anti-muscarinic antibodies in people experiencing their first episode of psychosis.

Effects of HIV-1 TAT protein and methamphetamine exposure on visual discrimination and executive function in mice.

Mild neurocognitive impairments are common in people with human immunodeficiency virus (HIV) infection. HIV-encoded proteins, such as trans-activator of transcription (TAT), contribute to neuropathology and cognitive function in medicated subjects. The combination of TAT and comorbid methamphetamine use may further impair neurocognitive function in HIV-positive individuals by affecting dopaminergic systems in the brain. The current study examined the effects of TAT protein expression and methamphetamine exposure on cognitive function and dopamine systems in mice. Transgenic mice with inducible brain expression of the TAT protein were exposed to a binge methamphetamine regimen. TAT expression was induced via a doxycycline-containing diet during the final stage of the regimen and maintained throughout cognitive testing. Learning and executive function were assessed using an operant visual discrimination protocol, with a strategy switch and reversal. TAT expression and methamphetamine exposure improved visual discrimination learning. Combined TAT expression and methamphetamine exposure increased perseverative errors during reversal learning. TAT expression altered reversal learning by improving early stage, but impairing late stage, learning. TAT expression was also associated with an increase in dopamine transporter expression in the caudate putamen. These results highlight that TAT expression and methamphetamine exposure likely affect a range of selective cognitive processes, with some potentially improving function under certain conditions.

Modeling human methamphetamine use patterns in mice: chronic and binge methamphetamine exposure, reward function and neurochemistry.

Different methamphetamine use patterns in human subjects may contribute to inconsistent findings regarding the effects of methamphetamine abuse on brain and behavior. The present study investigated whether human-derived chronic and binge methamphetamine use patterns have differential effects on reward and neurochemistry in mice. Brain reward function in mice was evaluated during acute/prolonged withdrawal, and in response to methamphetamine challenge using the intracranial self-stimulation procedure. Brain dopaminergic, serotonergic and glutamatergic neurochemistry was determined with high-performance liquid chromatography. Chronic and binge regimens induced withdrawal-related decreases in reward function that were more severe during the binge regimen during cycles 1-2. Despite large differences in methamphetamine dose, both regimens induced similar reward deficits during cycles 3-4. Neither methamphetamine regimen led to persistent alterations in the sensitivity to the reward-enhancing effects of acute methamphetamine challenge. The binge regimen severely depleted striatal dopamine levels and increased brain glutamine levels. The chronic regimen had milder effects on striatal dopamine levels and altered cortical dopamine and serotonin levels. This work highlights that the magnitude of acute/prolonged withdrawal may not reflect amount or frequency of methamphetamine intake. In contrast, the array of underlying neurochemical alterations was methamphetamine regimen dependent. Thus, stratifying methamphetamine-dependent individuals based on use pattern may help to cater therapeutic interventions more appropriately by targeting use pattern-specific neurotransmitter systems.