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Background: Bipolar disorder (BD) and substance use disorders share common symptoms, such as behavioral sensitization. Amphetamine-induced behavioral sensitization can serve as an animal model of BD. Neurotrophic factors have an important role in BD pathophysiology. This study evaluated the effects of amphetamine sensitization on behavior and neurotrophic factor levels in the brains of rats.Methods: Wistar rats received daily intraperitoneal (i.p) injections of dextroamphetamine (d-AMPH) 2 mg/kg or saline for 14 days. After seven days of withdrawal, the animals were challenged with d-AMPH (0.5 mg/kg, i.p) and locomotor behavior was assessed. In a second protocol, rats were similarly treated with d-AMPH (2 mg/kg, i.p) for 14 days. After withdrawal, without d-AMPH challenge, depressive- and anxiety-like behaviors were evaluated through forced swimming test and elevated plus maze. Levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NT-3), neurotrophin 4/5 (NT-4/5) and glial-derived neurotrophic factor (GDNF) were evaluated in the frontal cortex, hippocampus, and striatum.Results: D-AMPH for 14 days augmented locomotor sensitization to a lower dose of d-AMPH (0.5 mg/kg) after the withdrawal. d-AMPH withdrawal induced depressive- and anxious-like behaviors. BDNF, NGF, and GDNF levels were decreased, while NT-3 and NT-4 levels were increased in brains after d-AMPH sensitization.Limitations: Although d-AMPH induces manic-like behavior, the mechanisms underlying these effects can also be related to phenotypes of drug abuse.Conclusions: Together, vulnerability to mania-like behavior following d-AMPH challenge and extensive neurotrophic alterations, suggest amphetamine-induced behavioral sensitization is a good model of BD pathophysiology. [ABSTRACT FROM AUTHOR]

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 (Cext), 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 Cext is observed in the DLS after an AMPH challenge in rats exposed to a single dose of AMPH. The decrease in DA Cext 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 Cext 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. We proposed that dynorphin contributes to dopamine (DA) dynamics during progression to amphetamine (AMPH) sensitization modifying DA transporter activity. A significant decrease in DA extracellular levels is observed in the dorsolateral striatum (DLS) after a single dose of AMPH. The decrease in DA extracellular is associated with an increased DA uptake. Conversely, the expression of AMPH sensitization is accompanied by a significant increase in DA extracellular levels associated with attenuation in DA uptake. The administration of nor‐BNI reverses the changes in DLS after AMPH pre‐treatment tending to normalize DA extracellular levels modifying DA uptake activity. [ABSTRACT FROM AUTHOR]

The psychogenetically selected Roman high- (RHA) and low-avoidance (RLA) rats are being proposed as a valuable animal model of individual vulnerability to the two distinct neurobiological mechanisms of behavioral sensitization to psychostimulants, namely induction and expression. Most hallmarks of their divergent phenotypes are also found in the inbred RHA (RHA-I) and RLA (RLA-I) strains. For instance, they differ in the expression of sensitization to amphetamine. However, the pattern of spontaneous activity of the inbred rats seems to differ from that of outbred Roman strains. The present work shows the relevance of analyzing spontaneous activity as a covariant in order to determine the significance of day effect in the induction of behavioral sensitization to amphetamine (regime: 11 days, 1 mg/kg, i.p.) in the inbred strains and, for comparison, the standard low activity Sprague-Dawley (SD) strain. Our results also confirm that, in parallel to the outbred strains, only inbred RHA rats showed sensitization during the induction phase, here detectable from day 9 of treatment, while RLA-I and SD strains did not. Inbred RLA rats provide an interesting model to study individual resistance to sensitization, with nuances due to their underlying high spontaneous activity phenotype. [ABSTRACT FROM AUTHOR]

A single exposure to amphetamine induces neurochemical sensitization in striatal areas. The neuropeptide angiotensin II, through AT 1 receptors (AT 1 -R) activation, is involved in these responses. However, amphetamine-induced alterations can be extended to extra-striatal areas involved in blood pressure control and their physiological outcomes. Our aim for the present study was to analyze the possible role for AT 1 -R in these events using a two-injection protocol and to further characterize the proposed AT 1 -R antagonism protocol. Central effect of orally administered AT 1 -R blocker (Candesartan, 3 mg/kg p.o. × 5 days) in male Wistar rats was analyzed by spontaneous activity of neurons within locus coeruleus. In another group of animals pretreated with the AT 1 -R blocker or vehicle, sensitization was achieved by a single administration of amphetamine (5 mg/kg i.p. – day 6) followed by a 3-week period off drug. On day 27, after receiving an amphetamine challenge (0.5 mg/kg i.p.), we evaluated: (1) the sensitized c-Fos expression in locus coeruleus (LC), nucleus of the solitary tract (NTS), caudal ventrolateral medulla (A1) and central amygdala (CeAmy); and (2) the blood pressure response. AT 1 -R blockade decreased LC neurons’ spontaneous firing rate. Moreover, sensitized c-Fos immunoreactivity in TH + neurons was found in LC and NTS; and both responses were blunted by the AT 1 -R blocker pretreatment. Meanwhile, no differences were found neither in CeAmy nor A1. Sensitized blood pressure response was observed as sustained changes in mean arterial pressure and was effectively prevented by AT 1 -R blockade. Our results extend AT 1 -R role in amphetamine-induced sensitization over noradrenergic nuclei and their cardiovascular output. [ABSTRACT FROM AUTHOR]

Summary Previous studies demonstrate that schizophrenia symptomatology in women is dependent upon estrogen levels. Estrogen has beneficial properties when administered in conjunction with antipsychotics, and estrogen also alters, in rats, dopamine neurotransmission, which is a common target of all antipsychotic medications, suggesting a possible interaction between the two. The aim of the current study was to investigate this possible interaction using functional magnetic resonance imaging in awake, female rats. Amphetamine-sensitized, ovariectomized rats receiving no, chronic low, or phasic high levels of estradiol replacement were used, and changes in blood-oxygen-level-dependent (BOLD) signal were recorded over time in response to an acute amphetamine injection. Increasing levels of estradiol enhanced BOLD activation in pathways previously known to be implicated in schizophrenia symptomatology, such as the mesocorticolimbic, habenular and olfactory pathways, as well as more widespread areas. We propose here the first comprehensive “amphetamine activation map” integrating brain regions where amphetamine-related BOLD activity is influenced by estrogen levels in sensitized female rats. [ABSTRACT FROM AUTHOR]

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]

The neural substrates of the unconditioned and conditioned components of amphetamine (AMPH)-induced behavioral sensitization remain unknown. The present study examines the brain activation of rats in response to an AMPH challenge with augmented locomotion in groups receiving chronic AMPH under chloral hydrate anesthetization (i.e., the 'zero context') or when tested in the 'same context' as a chronic treatment, or when tested in a 'different context'. The neural activations of the three groups reveal fairly consistent patterns: (a) The substantia nigra is activated in the same context condition and the pure AMPH effect (i.e., the zero context with the unconditioned component), but not in the switch context condition, (b) The ventral pallidum showed Fos expression in the switch context and the same context, but not in the zero context condition, (c) The other nuclei, including the medial prefrontal cortex, nucleus accumbens, caudate putamen, medial thalamus, hippocampus, amygdala, and ventral tegmental area, are activated in all contextual conditions and the pure AMPH effect (the zero context). The context exerts definable effects on the mesocorticolimbic dopamine system on AMPH-induced behavioral sensitization, (d) The ventral pallidum and the substantia nigra activations dissociate the unconditioned component from the conditioned component in behavioral sensitization. Further studies are needed to determine how these two nuclei mediate the effect in terms of primary and conditioned rewards. [ABSTRACT FROM AUTHOR]

The neural substrates of the unconditioned and conditioned components of amphetamine (AMPH)-induced behavioral sensitization remain unknown. The present study examines the brain activation of rats in response to an AMPH challenge with augmented locomotion in groups receiving chronic AMPH under chloral hydrate anesthetization (i.e., the 'zero context') or when tested in the 'same context' as a chronic treatment, or when tested in a 'different context'. The neural activations of the three groups reveal fairly consistent patterns: (a) The substantia nigra is activated in the same context condition and the pure AMPH effect (i.e., the zero context with the unconditioned component), but not in the switch context condition. (b) The ventral pallidum showed Fos expression in the switch context and the same context, but not in the zero context condition. (c) The other nuclei, including the medial prefrontal cortex, nucleus accumbens, caudate putamen, medial thalamus, hippocampus, amygdala, and ventral tegmental area, are activated in all contextual conditions and the pure AMPH effect (the zero context). The context exerts definable effects on the mesocorticolimbic dopamine system on AMPH-induced behavioral sensitization. (d) The ventral pallidum and the substantia nigra activations dissociate the unconditioned component from the conditioned component in behavioral sensitization. Further studies are needed to determine how these two nuclei mediate the effect in terms of primary and conditioned rewards. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Rationale: Psychosis susceptibility is mediated in part by the dopaminergic neurotransmitter system. In humans, individual differences in vulnerability for psychosis are reflected in differential sensitivity for psychostimulants such as amphetamine. We hypothesize that the same genes and pathways underlying behavioral sensitization in mice are also involved in the vulnerability to psychosis. Objectives: The aim of the current study was to investigate which genes and pathways may contribute to behavioral sensitization in different dopaminergic output areas in the mouse brain. Methods: We took advantage of the naturally occurring difference in psychostimulant sensitivity in DBA/2 mice and selected animals displaying extremes in behavioral sensitization to amphetamine. Subsequently, the dopamine output areas, prefrontal cortex, nucleus accumbens, and cornu ammonis 1 (CA1) area of the hippocampus, were isolated by laser microdissection and subjected to DNA microarray analysis 1 h after a challenge dose of amphetamine. Results: A large number of genes with differential expression between high and low responders were identified, with no overlap between brain regions. Validation of these gene expression changes with real-time quantitative polymerase chain reaction demonstrated that the most robust and reproducible effects on gene expression were in the CA1 region of the hippocampus. Interestingly, many of the validated genes in CA1 are members of the cAMP response element (CRE) family and targets of the glucocorticoid receptor (GR) and myocyte enhancer factor 2 (Mef2) transcription factors. Conclusion: We hypothesize that CRE, Mef2, and GR signaling form a transcription regulating network, which underlies differential amphetamine sensitivity, and therefore, may play an important role in susceptibility to psychosis. [ABSTRACT FROM AUTHOR]

Abstract: Dysbindin-1 (dystrobrevin binding protein-1) has been reported as a candidate gene associated with schizophrenia. Dysbindin-1 mRNA and protein levels are significantly reduced in the prefrontal cortex and hippocampus of schizophrenia subjects. To understand the in-vivo functions of dysbindin-1, we studied schizophrenia relevant behaviors in adult male Sandy homozygous (sdy/sdy) and heterozygous (sdy/+) mice that have a natural mutation in dysbindin-1 gene (on a DBA/2J background) resulting in loss of protein expression. Spontaneous locomotor activity of sdy/sdy and sdy/+ mice in novel environment was not significantly different from DBA/2J controls. However, on repeated testing in the same environment for 7 days, sdy/sdy mice, in contrast to DBA/2J controls showed a lack of locomotor habituation. Locomotor activating effect of a low dose of d-amphetamine (2.5mg/kg ip), a behavioral measure of mesolimbic dopamine activity, was significantly reduced in the mutant mice. Interestingly, sdy/sdy mice showed enhanced locomotor sensitization to repeated five daily injection of amphetamine. Possible cognitive impairment in Sandy mutants was revealed in novel object recognition test as sdy/sdy and sdy/+ mice spent significantly less time exploring novel objects compared to DBA/2J. Sdy/sdy mice also showed deficits in emotionally motivated learning and memory showing greater freezing response to auditory conditioned stimulus (CS) in fear conditioning paradigm. In thermal nociceptive test, the latency of paw withdrawal in sdy/sdy and sdy/+ animals was significantly higher compared to DBA/2J indicating hypoalgesia in the mutants. Taken together, these data suggest that dysbindin-1 gene deficiency leads to significant changes in cognition and altered responses to psychostimulants. [Copyright &y& Elsevier]

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]

Abstract: Individual differences in novelty-related behavior are associated with sensitivity to various neurochemical manipulations. In the present study the amphetamine-induced locomotor activity and behavioral sensitization to amphetamine (0.5 mg/kg) was investigated in rats with high or low spontaneous exploratory activity (HE- and LE-rats, respectively) after partial denervation of the locus coeruleus (LC) projections with a low dose of the selective neurotoxin DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine; 10 mg/kg). DSP-4 produced a partial depletion (about 30%) of noradrenaline in the frontal cortex of both HE- and LE-rats; additionally the levels of metabolites of dopamine and 5-HT were reduced in the frontal cortex and nucleus accumbens of the LE-rats. Amphetamine-stimulated locomotor activity was attenuated by the DSP-4 pretreatment only in the HE-rats and this effect persisted over repeated testing. Behavioral sensitization to repeated amphetamine was evident only in the LE-rats with intact LC projections. Repeated amphetamine treatment reduced D2 receptor mediated stimulation of [35S]GTPγS-binding and dopamine-dependent change in GDP-binding affinity in the striatum, but only in HE-rats. The absence of amphetamine sensitization in HE-rats could thus be related to the downregulation by amphetamine of the G protein stimulation through D2 receptors. Conclusively, acute and sensitized effects of amphetamine depend on the integrity of LC projections but are differently regulated in animals with high or low trait of exploratory activity. These findings have implications to the neurobiology of depression, drug addiction, and attention deficit hyperactivity disorder. [Copyright &y& Elsevier]

Neurons in ventral pallidum fire to reward and its predictive cues. We tested mesolimbic activation effects on neural reward coding. Rats learned that a Pavlovian conditioned stimulus (CS+1 tone) predicted a second conditioned stimulus (CS+2 feeder click) followed by an unconditioned stimulus (UCS sucrose reward). Some rats were sensitized to amphetamine after training. Electrophysiological activity of ventral pallidal neurons to stimuli was later recorded under the influence of vehicle or acute amphetamine injection. Both sensitization and acute amphetamine increased ventral pallidum firing at CS+2 (population code and rate code). There were no changes at CS+1 and minimal changes to UCS. With a new ‘ Profile Analysis’, we show that mesolimbic activation by sensitization/amphetamine incrementally shifted neuronal firing profiles away from prediction signal coding (maximal at CS+1) and toward incentive coding (maximal at CS+2), without changing hedonic impact coding (maximal at UCS). This pattern suggests mesolimbic activation specifically amplifies a motivational transform of CS+ predictive information into incentive salience coded by ventral pallidal neurons. Our results support incentive-sensitization predictions and suggest why cues temporally proximal to drug presentation may precipitate cue-triggered relapse in human addicts. [ABSTRACT FROM AUTHOR]

Background: There is growing interest in detecting and treating schizophrenia during the “prodrome,” before the symptoms are fully manifested. The objective of this study was to develop a putative model of the prodrome and study the effects of medications on it. Methods: Rats were treated with different regimens of amphetamine to produce full sensitization (full syndrome) and partial sensitization (to model the prodromal state) and were then treated with typical and atypical antipsychotics and a D1 antagonist to mimic early intervention. After several weeks of withdrawal, locomotor activity in response to amphetamine and behavioral deficits (prepulse inhibition [PPI] and latent inhibition [LI]) were examined. Results: Animals that received the full sensitization showed significant increase in locomotor activity and a disruption in both PPI and LI. Animals treated with a partial regimen showed only a muted phenotype. The animals that received “early intervention” did not show progression from the prodromal to the full-blown phenotype. Conclusions: The partial regimen of amphetamine injections provided a modified phenotype that could be regarded as a representative of the “prodromal” state. Early intervention, instituted once the prodromal state was already developed, prevented further progression into the full phenotype analogous to schizophrenia. [Copyright &y& Elsevier]

Slot-machine gambling incorporates numerous audiovisual cues prior to and during reward delivery (e.g. spinning wheels, flashing lights, celebratory sounds). Over time, these cues may motivate playing and even elicit cravings and relapse in those affected by gambling disorder. Animal studies suggest a heightened attraction to these cues despite diminished predictive ability under reward uncertainty, as evidenced by sign-tracking behavior in rats. Repeated amphetamine administration may also enhance the incentive value attributed to cues. Here, we explored the impact of reward uncertainty and prior amphetamine sensitization on the relative attractiveness and conditioned reinforcing properties of serial Pavlovian cues with different degrees of predictive and incentive value in rats. Animals were sensitized through repeated injections of amphetamine (1–4 mg/kg) or saline and then trained in a Pavlovian autoshaping task involving two sequential lever-auditory cue combinations (CS1, CS2) under Certain (100%-1) or Uncertain (50%-1-2-3) reward conditions. Subsequently, we evaluated the impact of acute amphetamine exposure on cue attraction. Our results suggest that Uncertainty alone enhanced attraction towards the reward-proximal CS2. However, combined sensitization and Uncertainty reversed cue preference relative to Uncertainty alone, enhancing attraction towards the more predictive reward-distal CS1. Both cues acquired conditioned reinforcing properties, despite the CS2 being otherwise ignored in all groups besides Uncertainty. However, combined sensitization and Uncertainty increased the reinforcing value of both cues and doubled the amount of interaction with the CS1 lever per presentation. Our results imply competitive mechanisms for attributing incentive value to gambling-related cues between reward uncertainty, prior amphetamine sensitization, and acute amphetamine administration. • Reward uncertainty increases attraction to otherwise ignored reward-proximal cues. • Prior sensitization counters this effect and shifts attraction to reward-distal cues. • Prior sensitization makes uncertain gambling-like cues become more rewarding. • It also enhances responding on reward-distal cues during conditioned reinforcement. • Acute amphetamine promotes goal-tracking under Certain but not Uncertain conditions. [ABSTRACT FROM AUTHOR]