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Kappa-opioid receptors (KOR) control dopamine (DA) levels in the striatum and contribute significantly to the progression of drug addiction. Repeated exposure to psychostimulants has been associated with up-regulated KOR activity and increased DA levels in dorsal striatum. However, it has not been tested if both processes are linked. In this work, we studied if a mechanism mediated by KOR is contributing to the increase in DA levels in the dorsolateral striatum (DLS) after amphetamine (AMPH) sensitization. The AMPH sensitization was assessed after single or repeated once-a-day AMPH injections (1 mg/kg). Only repeated AMPH exposure produced a significant locomotor sensitization. No-net flux microdialysis was used to assess basal DA dialysate, DA extracellular concentration (C ext ), and DA uptake in DLS of anesthetized rats. The role of KOR on DA dynamics in DLS was evaluated by local perfusion (250 μM) and systemic administration (10 mg/kg) of the KOR antagonist nor-binaltorphimine. A significant decrease in DA C ext is observed in the DLS after an AMPH challenge in rats exposed to a single dose of AMPH. The decrease in DA C ext was associated with both a decreased basal DA dialysate and an increased DA uptake. Conversely, the expression of AMPH sensitization was accompanied by a significant increase in DA C ext associated with an increased basal DA dialysate and an attenuation in DA uptake. Both local and systemic administration of nor-binaltorphimine reversed changes in DLS after AMPH pre-treatment. These findings indicate that endogenous KOR system tunes DLS DA dynamics during the progression to AMPH sensitization., (© 2018 International Society for Neurochemistry.)

Rationale: Amphetamine enhances dopamine (DA) transmission and induces psychotic states or exacerbates psychosis in at-risk individuals. Amphetamine sensitization of the DA system has been proposed as a rodent model of schizophrenia-like symptoms. In humans, excessive nonphysiologic drinking or primary polydipsia is significantly associated with a diagnosis of schizophrenia. In rodents, nonphysiologic drinking can be induced by intermittent presentation of food in the presence of a drinking spout to a hungry animal; this phenomenon is termed, 'schedule-induced polydipsia' (SIP). Objective: This study aims to determine the effects of amphetamine sensitization on SIP. Methods: We injected rats with amphetamine (1.5 mg/kg) daily for 5 days. Following 4 weeks of withdrawal, animals were food restricted and exposed to the SIP protocol (noncontingent fixed-time 1-min food schedule) for daily 2-h sessions for 24 days. Results: Results showed that previously amphetamine-injected animals drank more in the SIP protocol and drank more than controls when the intermittent food presentation schedule was removed. Conclusions: These findings suggest that hyperdopaminergia associated with schizophrenia may contribute to the development of polydipsia in this population. Whether animals that develop SIP have DA dysfunction or aberrant activity of other circuits that modulate DA activity has yet to be clearly defined. [ABSTRACT FROM AUTHOR]

Abstract: In the present work, we assessed dopamine extracellular levels in the medial Prefrontal Cortex of rats repeatedly treated with amphetamine during early abstinence. Rats were injected once daily with amphetamine for five consecutive days. A sensitized locomotor response was observed in 55% of animals treated. After two days of abstinence, an amphetamine challenge dose was given to all rats and locomotor activity was measured to assess expression of sensitization. A persistence of heightened locomotor response to amphetamine was observed in rats that developed sensitization. Twenty four hours after amphetamine challenge, microdialysis experiments were carried out to evaluate basal and stimulated dopamine extracellular levels in the medial Prefrontal Cortex. Rats that developed and expressed amphetamine locomotor sensitization showed a significantly greater high potassium-stimulated dopamine release compared to Non-sensitized and Saline rats. These results show that the increased dopamine releasability in the medial Prefrontal Cortex occurs soon after development of amphetamine locomotor sensitization, and might be underlying the early expression of sensitization. [Copyright &y& Elsevier]

Aberrant dopamine-mediated behaviours are a hallmark of a number of psychiatric disorders, including substance use disorders and schizophrenia. It has been demonstrated recently that rodent models of these diseases display enhanced dopamine neuron activity throughout the ventral tegmental area (VTA). It is known, however, that the VTA is not a homogeneous structure, and that the dopamine neuron population provides discrete, topographical innervation of nucleus accumbens subregions. In addition, these ventromedial and ventrolateral dopamine systems are known to subserve complementary but distinct aspects of goal-directed behaviour. Using in-vivo extracellular recordings of identified dopamine neurons in chloral hydrate-anaesthetized rats, we examined the level of dopamine neuron population activity across the mediolateral extent of the VTA following amphetamine sensitization or gestational methylazoxymethanol acetate (MAM) treatment, a verified rodent model of schizophrenia. Here we demonstrate that both models display an augmented medial VTA-ventromedial striatal dopamine system function that correlates with the augmented locomotor response to amphetamine observed in both models. In contrast, only MAM-treated rats exhibit an increase in VTA-ventrolateral striatal dopamine system function. This latter finding is consistent with human imaging studies in schizophrenia patients. In summary, we demonstrate that, although a number of disorders involving a hyperdopaminergic state demonstrate an increase in dopamine neuron population activity, there is divergence in the exact populations of neurons affected. This distinction probably underlies the observed differences in disease symptomatology. [ABSTRACT FROM AUTHOR]

Abstract: Exposure to an intermittent, escalating dose of amphetamine induces a sensitized state that, both behaviourally and neurochemically, mirrors several features linked to the positive symptoms of schizophrenia. Increasingly it is being realized that cognitive deficits are a core component of schizophrenia; therefore we sought to assess the effects of inducing an amphetamine-sensitized state on memory (working and long-term) and cognitive flexibility, two cognitive domains impaired in schizophrenia. Rats were exposed to a sensitizing regimen of amphetamine (1–5mg/kg; three times per week for 5 weeks; escalating at 1mg/kg per week) or saline. In experiment 1, animals were tested on an operant delayed non-match to position task (working memory). Experiment 2 used a standard fixed-platform location water maze task (long-term memory), while experiment 3 used a variable-platform location water maze task (long-term memory and working memory). Amphetamine-sensitized animals were not impaired on any of these tasks. In experiment 4, animals were assessed on a strategy selection task in which they were first required to learn to locate a food reward using a particular learning strategy (place or response) then to learn to shift to an alternate learning strategy (response or place). Amphetamine-sensitized animals were not impaired on this task. In the final experiment animals were found to be impaired in performance of the extra-dimensional shift component of an attentional set-shifting task. These results suggest that while amphetamine sensitization does not produce memory impairments similar to those seen in schizophrenia, it does produce strong impairments in set-shifting, suggesting changes in prefrontal function similar to those seen in schizophrenia. [Copyright &y& Elsevier]

Amphetamine (AMPH) sensitization in the nonhuman primate induces persistent aberrant behaviors reminiscent of the hallmark symptoms of schizophrenia, including hallucinatory-like behaviors, psychomotor depression, and profound cognitive impairment. The present study examined whether AMPH sensitization induces similarly long-lasting morphologic alterations in prefrontal cortical pyramidal neurons. Three to 3½ years postsensitization, sensitized, and AMPH-naïve control monkeys were killed. Blocks of prefrontal cortex were Golgi-impregnated for elucidation of pyramidal dendritic morphology in layers II/superficial III (II/IIIs), deep III, and V/VI. In AMPH-sensitized animals as compared to AMPH-naïve controls, pyramidal dendrites in layer II/IIIs exhibited reduced overall dendritic branching and reduced peak spine density (22%) on the apical trunk. Across all layers, the distance from soma to peak spine density along the apical trunk was decreased (126.38±7.65 μm in AMPH-sensitized compared to 162.98±7.26 μm in AMPH-naïve controls), and basilar dendritic length was reduced (32%). These findings indicate that chronic dopamine dysregulation, consequent to AMPH sensitization, results in enduring, atrophic changes in prefrontal pyramidal dendrites that resemble the pathologic alterations described in patients with schizophrenia and may contribute to the persistence of schizophrenia-like behavioral changes and cognitive dysfunction associated with sensitization. These findings may also provide key insights into the etiologic origin of the pronounced behavioral disturbances and cognitive dysfunction associated with schizophrenia.Neuropsychopharmacology (2007) 32, 919–931. doi:10.1038/sj.npp.1301179; published online 16 August 2006 [ABSTRACT FROM AUTHOR]