Prefrontal Dopamine in Flexible Adaptation to Environmental Changes: A Game for Two Players.

Deficits in cognitive flexibility have been characterized in affective, anxiety, and neurodegenerative disorders. This paper reviews data, mainly from studies on animal models, that support the existence of a cortical-striatal brain circuit modulated by dopamine (DA), playing a major role in cognitive/behavioral flexibility. Moreover, we reviewed clinical findings supporting misfunctioning of this circuit in Parkinson's disease that could be responsible for some important non-motoric symptoms. The reviewed findings point to a role of catecholaminergic transmission in the medial prefrontal cortex (mpFC) in modulating DA's availability in the nucleus accumbens (NAc), as well as a role of NAc DA in modulating the motivational value of natural and conditioned stimuli. The review section is accompanied by a preliminary experiment aimed at testing weather the extinction of a simple Pavlovian association fosters increased DA transmission in the mpFC and inhibition of DA transmission in the NAc.

From skinner box to daily life: Sign-tracker phenotype co-segregates with impulsivity, compulsivity, and addiction tendencies in humans.

Pavlovian conditioning holds the potential to incentivize environmental cues, leading to approach behavior toward them, even outside our awareness. Animal models suggest that this is particularly true for the so-called sign-tracker (ST) phenotype, which is considered to reflect a predisposition toward developing addiction-related behaviours. Despite its potential clinical relevance, few studies have demonstrated the translational validity of this model, likely due to difficulties in studying Pavlovian processes in humans. To fill this gap, we combined an ecological momentary assessment with ambulatory peripheral autonomic monitoring to test the hypothesis that traits associated with ST in preclinical studies would be associated with attribution of high incentive salience to reward-related cues. Several times for 2 days, participants were asked to rate the attractiveness of several preselected ecological rewards (e.g., coffee) and the preceding cues (the smell of coffee) while their electrocardiogram was recorded. While no absolute difference in subjective and physiological measures of motivational approach to daily cues compared with rewards emerged, individuals with high levels of impulsivity, obsessive-compulsive, and addiction-prone behaviors rated as more attractive and showed a greater increase in sympathetic arousal to cues versus rewards. The opposite pattern emerged for those with low levels in those dispositional traits, who responded more (both subjectively and physiologically) to rewards compared with their preceding cues. This study represents an attempt to answer the call to parcel complex behaviors into smaller constructs, improving the early detection of those who are vulnerable to develop psychopathological disorders, particularly in the domain of impulse control such as addiction.

Role of Stress-Related Dopamine Transmission in Building and Maintaining a Protective Cognitive Reserve.

This short review presents the hypothesis that stress-dependent dopamine (DA) transmission contributes to developing and maintaining the brain network supporting a cognitive reserve. Research has shown that people with a greater cognitive reserve are better able to avoid symptoms of degenerative brain changes. The paper will review evidence that: (1) successful adaptation to stressors involves development and stabilization of effective but flexible coping strategies; (2) this process requires dynamic reorganization of functional networks in the adult brain; (3) DA transmission is amongst the principal mediators of this process; (4) age- and disease-dependent cognitive impairment is associated with dysfunctional connectivity both between and within these same networks as well as with reduced DA transmission.

Repetitive and Inflexible Active Coping and Addiction-like Neuroplasticity in Stressed Mice of a Helplessness-Resistant Inbred Strain.

Dysfunctional coping styles are involved in the development, persistence, and relapse of psychiatric diseases. Passive coping with stress challenges (helplessness) is most commonly used in animal models of dysfunctional coping, although active coping strategies are associated with generalized anxiety disorder, social anxiety disorder, panic, and phobias as well as obsessive-compulsive and post-traumatic stress disorder. This paper analyzes the development of dysfunctional active coping strategies of mice of the helplessness-resistant DBA/2J (D2) inbred strain, submitted to temporary reduction in food availability in an uncontrollable and unavoidable condition. The results indicate that food-restricted D2 mice developed a stereotyped form of food anticipatory activity and dysfunctional reactive coping in novel aversive contexts and acquired inflexible and perseverant escape strategies in novel stressful situations. The evaluation of FosB/DeltaFosB immunostaining in different brain areas of food-restricted D2 mice revealed a pattern of expression typically associated with behavioral sensitization to addictive drugs and compulsivity. These results support the conclusion that an active coping style represents an endophenotype of mental disturbances characterized by perseverant and inflexible behavior.

Opposite genotype-specific effects of serotoninergic treatments on Pavlovian Conditioned Approach in mice of two inbred strains C57 BL/6J and DBA/2J.

Individual variability in the response to pharmacological therapies is a major problem in the treatment of psychiatric disorders. Comparative studies of phenotypes expressed by mice of the C57BL/6J (C57) and DBA/2J (DBA) inbred strains can help identify neurobiological determinants of this variability at preclinical levels. We have recently demonstrated that whereas young adult mice of both strains develop sign-tracking in a Pavlovian Conditioned Approach (PCA), a trait associated with dysfunctional behavior in rat models, in full adult C57 mice acquisition of this phenotype is inhibited by pre-frontal cortical (PFC) serotonin (5HT) transmission. These findings suggest a different role of 5HT transmission on sign-tracking development in mice of the two genotypes. In the present experiments, we tested the effects of the 5-HT synthesis booster 5-hydroxytryptophan (5-HTP) and of the selective 5HT reuptake inhibitor (SSRI) fluoxetine on the development and expression of sign-tracking in young adult mice from both inbred strains. In mice of the C57 strain, administration of 5-HTP before each training session blocked the training-induced shift to positive PCA scores which indicates the development of sign-tracking, whereas the same treatment was ineffective in mice of DBA strain. On the other hand, a single administration of fluoxetine was ineffective in unhandled saline- and 5-HTP-treated C57 mice, whereas it enhanced the expression of positive PCA scores by mice of DBA strain treated with 5-HTP during training. These findings confirm the strain-specific inhibitory role of PFC 5-HT transmission on sign-tracking development by mice of the C57 strain and support the hypothesis that different genotype-specific neurobiological substrates of dysfunctional phenotypes contribute to variable effects of pharmacotherapies.

Interactions Between Experience, Genotype and Sex in the Development of Individual Coping Strategies.

Coping strategies, the first line of defense against adversities, develop through experience. There is consistent evidence that both genotype and sex contribute to the development of dysfunctional coping, leading to maladaptive outcomes of adverse experiences or to adaptive coping that fosters rapid recovery even from severe stress. However, how these factors interact to influence the development of individual coping strategies is just starting to be investigated. In the following review, we will consider evidence that experience, sex, and genotype influence the brain circuits and neurobiological processes involved in coping with adversities and discuss recent results pointing to the specific effects of the interaction between early experiences, genotype, and stress in the development of functional and dysfunctional coping styles.

Functional and Dysfunctional Neuroplasticity in Learning to Cope with Stress.

In this brief review, we present evidence of the primary role of learning-associated plasticity in the development of either adaptive or maladaptive coping strategies. Successful interactions with novel stressors foster plasticity within the neural circuits supporting acquisition, consolidation, retrieval, and extinction of instrumental learning leading to development of a rich repertoire of flexible and context-specific adaptive coping responses, whereas prolonged or repeated exposure to inescapable/uncontrollable stressors fosters dysfunctional plasticity within the learning circuits leading to perseverant and inflexible maladaptive coping strategies. Finally, the results collected using an animal model of genotype-specific coping styles indicate the engagement of different molecular networks and the opposite direction of stress effects (reduced vs. enhanced gene expression) in stressed animals, as well as different behavioral alterations, in line with differences in the symptoms profile associated with post-traumatic stress disorder.

The endocannabinoid system is affected by cholesterol dyshomeostasis: Insights from a murine model of Niemann Pick type C disease.

The dyshomeostasis of intracellular cholesterol trafficking is typical of the Niemann-Pick type C (NPC) disease, a fatal inherited lysosomal storage disorder presenting with progressive neurodegeneration and visceral organ involvement. In light of the well-established relevance of cholesterol in regulating the endocannabinoid (eCB) system expression and activity, this study was aimed at elucidating whether NPC disease-related cholesterol dyshomeostasis affects the functional status of the brain eCB system. To this end, we exploited a murine model of NPC deficiency for determining changes in the expression and activity of the major molecular components of the eCB signaling, including cannabinoid type-1 and type-2 (CB1 and CB2) receptors, their ligands, N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), along with their main synthesizing/inactivating enzymes. We found a robust alteration of distinct components of the eCB system in various brain regions, including the cortex, hippocampus, striatum and cerebellum, of Npc1-deficient compared to wild-type pre-symptomatic mice. Changes of the eCB component expression and activity differ from one brain structure to another, although 2-AG and AEA are consistently found to decrease and increase in each structure, respectively. The thorough biochemical characterization of the eCB system was accompanied by a behavioral characterization of Npc1-deficient mice using a number of paradigms evaluating anxiety, locomotor activity, spatial learning/memory abilities, and coping response to stressful experience. Our findings provide the first description of an early and region-specific alteration of the brain eCB system in NPC and suggest that defective eCB signaling could contribute at producing and/or worsening the neurological symptoms of this disorder.

Animal models of liability to post-traumatic stress disorder: going beyond fear memory.

In this review, we advocate a dimensional approach on the basis of candidate endophenotypes to the development of animal models of post-traumatic stress disorder (PTSD) capable of including genetic liability factors, variations in symptoms profile and underlying neurobiological mechanisms, and specific comorbidities. Results from the clinical literature pointed to two candidate endophenotypes of PTSD: low sensory gating and high waiting impulsivity. Findings of comparative studies in mice of two inbred strains characterized by different expressions of the two candidate endophenotypes showed different strain-specific neural and behavioral effects of stress experiences. Thus, mice of the standard C57BL/6J strain show stress-induced helplessness, stress-learned helplessness, and stress-extinction-resistant conditioned freezing. Instead, mice of the genetically unrelated DBA/2J strain, expressing both candidate endophenotypes, show stress-induced extinction-resistant avoidance and neural and behavioral phenotypes promoted by prolonged exposure to addictive drugs. These strain differences are in line with evidence of associations between genetic variants and specific stress-promoted pathological profiles in PTSD, support a role of genotype in determining different PTSD comorbidities, and offer the means to investigate specific pathogenic processes.

Epidemiological, demographic and clinical data on chronic viral hepatitis C in Tuscany.

BACKGROUND: Recent introduction of direct antiviral agents (DAAs) has completely changed the scenario regarding hepatitis C virus (HCV) treatment. Certain countries' economic health programs prioritize DAAs according to specific clinical features of HCV-infected patients. The aim of this study was to define epidemiological, demographic and clinical characteristics of HCV-infected patients in the Tuscany region of central Italy. METHODS: We enrolled HCV patients with chronic viral hepatitis who were referred to the outpatient services of 16 hospitals in Tuscany from 1 January 2015 to 31 December 2015. Case report forms contained patient information including main demographic data, blood chemistry data, viral hepatitis markers, instrumental evaluations (liver biopsy or transient elastometry, liver ultrasound), eligibility for DAAs, and liver transplantation or therapy already in progress. RESULTS: Of all patients considered, 2919 HCV patients were enrolled (mean age: 57.44 ± 15.15; 54% males, 46% females). All routes of transmission were well represented (intravenous drug use in 20.7%; nosocomial/dental care in 20.6%; and coagulation factors/blood transfusions in 13.3%). Diabetes was the highest represented comorbidity (20.8%), followed by metabolic syndrome (15.5%) and ischemic heart disease (6.2%). The most prevalent HCV genotypes were 1b (47.4%) and 2 (16.5%). In the whole cohort of patients, 32.8% were cirrhotic (40 patients were listed for liver transplantation). Signs of portal hypertension were present mostly in the group older than 45 years (92.3%). Extrahepatic HCV-related diseases were present in 13.3% of cases (cryoglobulinemic syndrome in 58.3% and B-cell non-Hodgkin's lymphoma in 10.5%). CONCLUSIONS: Our study provides evidence of a high prevalence of epidemiological changes in HCV infection with a major prevalence of advanced liver disease, such as portal hypertension, in this elderly cohort of patients.

Clinical epidemiology of chronic viral hepatitis B: A Tuscany real-word large-scale cohort study.

AIM: To build a regional database of chronic patients to define the clinical epidemiology of hepatitis B virus (HBV)-infected patients in the Tuscan public health care system. METHODS: This study used a cross-sectional cohort design. We evaluated chronic viral hepatitis patients with HBV referred to the outpatient services of 16 hospital units. Information in the case report forms included main demographic data, blood chemistry data, viral hepatitis markers, instrumental evaluations, and eligibility for treatment or ongoing therapy and liver transplantation. RESULTS: Of 4015 chronic viral hepatitis patients, 1096 (27.3%) were HBV infected. The case report form was correctly completed for only 833 patients (64% males, 36% females; mean age 50.1 ± 15.4). Of these HBV-infected patients, 73% were Caucasian, 21% Asian, 4% Central African, 1% North African and 1% American. Stratifying patients by age and nationality, we found that 21.7% of HBV-infected patients were aged < 34 years (only 2.8% were Italian). The most represented routes of transmission were nosocomial/dental procedures (23%), mother-to-child (17%) and sexual transmission (12%). The most represented HBV genotypes were D (72%) and A (14%). Of the patients, 24.7% of patients were HBeAg positive, and 75.3% were HBeAg negative. Of the HBV patients 7% were anti-HDV positive. In the whole cohort, 26.9% were cirrhotic (35.8% aged < 45 years), and 47% were eligible for or currently undergoing treatment, of whom 41.9 % were cirrhotic. CONCLUSION: Only 27.3% of chronic viral hepatitis patients were HBV infected. Our results provide evidence of HBV infection in people aged < 34 years, especially in the foreign population not protected by vaccination. In our cohort of patients, liver cirrhosis was also found in young adults.

Stress-Induced Reduction of Dorsal Striatal D2 Dopamine Receptors Prevents Retention of a Newly Acquired Adaptive Coping Strategy.

The inability to learn an adaptive coping strategy in a novel stressful condition leads to dysfunctional stress coping, a marker of mental disturbances. This study tested the involvement of dorsal striatal dopamine receptors in the dysfunctional coping with the Forced Swim test fostered by a previous experience of reduced food availability. Adult male mice were submitted to a temporary (12 days) reduction of food availability [food-restricted (FR)] or continuously free-fed (FF). Different groups of FF and FR mice were used to evaluate: (1) dorsal striatal mRNA levels of the two isoforms of the dopamine D2 receptor (D2S, D2L). (2) Forced Swim-induced c-fos expression in the dorsal striatum; (3) acquisition and 24 h retention of passive coping with Forced Swim. Additional groups of FF mice were tested for 24 h retention of passive coping acquired during a first experience with Forced Swim immediately followed by intra-striatal infusion of vehicle or two doses of the dopamine D2/D3 receptors antagonist sulpiride or the D1/D5 receptors antagonist SCH23390. Previous restricted feeding selectively reduced mRNA levels of both D2 isoforms and abolished Forced Swim-induced c-fos expression in the left Dorsolateral Striatum and selectively prevented 24 h retention of the coping strategy acquired in a first experience of Forced Swim. Finally, temporary blockade of left Dorsolateral Striatum D2/D3 receptors immediately following the first Forced Swim experience selectively reproduced the behavioral effect of restricted feeding in FF mice. In conclusion, the present results demonstrate that mice previously exposed to a temporary reduction of food availability show low striatal D2 receptors, a known marker of addiction-associated aberrant neuroplasticity, as well as liability to relapse into maladaptive stress coping strategies. Moreover, they offer strong support to a causal relationship between reduction of D2 receptors in the left Dorsolateral Striatum and impaired consolidation of newly acquired adaptive coping.

Behavioral and neurochemical characterization of new mouse model of hyperphenylalaninemia.

Hyperphenylalaninemia (HPA) refers to all clinical conditions characterized by increased amounts of phenylalanine (PHE) in blood and other tissues. According to their blood PHE concentrations under a free diet, hyperphenylalaninemic patients are commonly classified into phenotypic subtypes: classical phenylketonuria (PKU) (PHE > 1200 µM/L), mild PKU (PHE 600-1200 µM/L) and persistent HPA (PHE 120-600 µM/L) (normal blood PHE < 120 µM/L). The current treatment for hyperphenylalaninemic patients is aimed to keep blood PHE levels within the safe range of 120-360 µM/L through a PHE-restricted diet, difficult to achieve. If untreated, classical PKU presents variable neurological and mental impairment. However, even mildly elevated blood PHE levels, due to a bad compliance to dietary treatment, produce cognitive deficits involving the prefrontal cortical areas, extremely sensible to PHE-induced disturbances. The development of animal models of different degrees of HPA is a useful tool for identifying the metabolic mechanisms underlying cognitive deficits induced by PHE. In this paper we analyzed the behavioral and biochemical phenotypes of different forms of HPA (control, mild-HPA, mild-PKU and classic-PKU), developed on the base of plasma PHE concentrations. Our results demonstrated that mice with different forms of HPA present different phenotypes, characterized by increasing severity of behavioral symptoms and brain aminergic deficits moving from mild HPA to classical PKU forms. In addition, our data identify preFrontal cortex and amygdala as the most affected brain areas and confirm the highest susceptibility of brain serotonin metabolism to mildly elevated blood PHE.

[The health conditions of prison inmates in Tuscany]. / Lo stato di salute della popolazione detenuta all'interno delle strutture penitenziarie della Regione Toscana.

OBJECTIVE: Investigation of health conditions of prison inmates in Tuscany (Italy) compared with non-institutionalized population and literature data. DESIGN: Cross-sectional descriptive study of a sample recruited for a prospective cohort study. SETTING E PARTICIPANTS: Prison inmates detained in Tuscany on June 15th 2009. Istat data concerning the survey "Aspects of daily life" 2006-2009 has been used for comparison. MAIN OUTCOME MEASURES: The measures used for the analysis are prevalence data by age classes and odds ratios obtained through a logistic regression model. Outcome variables are: broad disease groups, in particular infectious and parasitic diseases and psychic disorders. RESULTS: Prison inmates from Northern Africa and Eastern Europe are 40% of the population studied. A high consumption of tobacco is observed, with 70.6% of regular smokers among prisoners vs 33.2% among free citizens. Digestive system diseases are the most frequent diseases (25.1%), followed by infectious and parasitic diseases (15.7%). Among digestive disease,more than half are teeth and oral cavity pathologies that affect 13.7% of prisoners.Other frequently reported disease groups were diseases of the bone-muscular and connective systems (11.0%), of the circulatory system (10.8%), endocrine and metabolic systems (9.2%), traumatisms and poisonings (6.8%), respiratory system diseases (5.9%), and nervous system diseases (4.9%). The prevalence of ischemic heart diseases, diabetes, obesity and esophagitis, gastritis and gastro-duodenal ulcers is significantly higher among prisoners than in the general population. The most frequent infectious and parasitic diseases are Hepatitis C Virus (HCV) infection with a prevalence of 9.0%, Hepatitis B Virus (HBV) infection (2.2%), and Human Immunodeficiency Virus (HIV) infection (1.4%). Hepatitis C, HIV and hepatitis A have a higher prevalence among inmates of Italian nationality, while syphilis is more common among prisoners from Eastern Europe (1.2%). The prevalence of psychic disorders among prison inmates is 33.3% (vs 11.6% in the general population), while it decreases to 29.3% if we exclude the population detained in the Psychiatric Prison. CONCLUSIONS: According to previous national and international studies, the cohort is more affected than the general population by physical and psychic disorders, partly associated to the prison inmate's country of origin.

[New users of mental health services for adults in Tuscany (Italy). Characteristics of cases and pathways of care]. / Nuova utenza dei Servizi di Salute Mentale per adulti della Toscana. Caratteristiche dei casi e percorsi della presa in carico.

The aim of this cross-sectional study was to describe the characteristics and pathways of care for users ("first visits") of adult mental health services in Tuscany. A questionnaire was mailed to healthcare workers of mental health services in Tuscany. Overall 184 psychiatrists and psychologists replied (136 psychiatrists and 48 psychologists) Sixty three percent of new users of mental health services were female, 32.6% were aged 18 to 34 years (32.6%) and 4.4% were foreign-born. Waiting times were lower for seeing a psychiatrist with respect to a psychologist (9.0 days ± 8.5 versus 19.2 days ± 18.7; p < 0.001). Severity of disease was the main reason for accepting persons presenting to the mental health services as patients; this occurred in 87% of cases. Persons accepted as patients were younger (42.2 years ± 14.9 versus 51.0 years ± 20.9; p < 0.05) and had an earlier onset of symptoms with respect to those not accepted as patients (32.1 years ± 15.2 vs 39.7 years ± 19.7; p < 0.05). The average duration of the mental disorder at the time of contact with the mental health service was 10.1 years and only 1/3 contacted the health service within one year of onset of the mental disorder. In conclusion, the duration of the mental disorder of adult patients contacting mental health services is high. This highlights the need for the various community agencies (e.g social services, health agencies, etc.) to facilitate access to care for people with a mental disorder.

Genetic liability increases propensity to prime-induced reinstatement of conditioned place preference in mice exposed to low cocaine.

RATIONALE: Relapse to drug use after periods of forced or self-imposed abstinence is a central problem in the treatment of addiction; therefore, identification of factors modulating the risk to relapse is a relevant goal of preclinical research. OBJECTIVES: These experiments evaluated the influence of the amount of drug experienced, the duration of drug withdrawal, and individual liability on the propensity to cocaine-induced reinstatement of conditioned place preference (CPP). MATERIALS AND METHODS: Mice from the inbred strains C57BL/6J and DBA/2J were trained for CPP with a high (20 mg/kg) or low (5 mg/kg) effective dose of cocaine. After CPP testing, all groups underwent extinction. Twenty-four hours after the extinction test, mice were challenged with saline, a cocaine dose unable to induce CPP (2.5 mg/kg) or an intermediate effective dose (10 mg/kg), and tested for CPP reinstatement. Additional groups of mice trained with the low cocaine dose were left undisturbed for 8 days after extinction test (long withdrawal), retested for extinction, and evaluated for prime-induced reinstatement (0, 2.5, 10 mg/kg of cocaine). RESULTS: Mice trained with the high cocaine dose, but not with the low one, showed prime-induced reinstatement 24 h after the extinction test; DBA/2J mice trained with the low dose showed reinstatement after long withdrawal. CONCLUSIONS: These results indicate that reinstatement of CPP by cocaine prime depends on the amount of drug experienced and on an interaction between individual liability and duration of drug abstinence and suggest that the risk to relapse into drug seeking is not prevented by moderated drug consumption.

Selective improvement of strain-dependent performances of cognitive tasks by food restriction.

Temporary food restriction affects strain differences for behavioral phenotypes in the inbred strains of mice C57BL/6 (C57) and DBA/2 (DBA). Since food restriction is a routine procedure to motivate learning, we evaluated its influence on differences for spatial and non-spatial discrimination between these strains of mice by using two non-associative tasks: the Spatial Novelty Test (SNT) and the Spontaneous Object Recognition Test (SORT). The results confirmed the poor performance of the DBA mice in SNT. Nonetheless, DBA mice were perfectly able to recognize the novel object in SORT. By contrast, C57 mice were good performers in SNT but failed to recognize a novel object in SORT. Finally, food restriction selectively improved C57 performance in SNT and DBA performance in SORT. These results support the view that a food restricting procedure enhances strain differences for discrimination of configurational information.

Susceptibility to amphetamine-induced place preference is predicted by locomotor response to novelty and amphetamine in the mouse.

RATIONALE: It has been demonstrated that major differences between mice of the C57BL/6J and DBA/2J inbred strains for amphetamine-induced place conditioning (preference and avoidance, respectively) are evident in standard housing conditions but abolished by temporary restricted feeding. This gene-experience model may be usefully exploited to dissect behavioral phenotypes related to place conditioning induced by addictive drugs. OBJECTIVES: This study evaluated a number of behavioral phenotypes related to amphetamine-induced place preference for strain differences (C57BL/6J vs DBA/2J) susceptible to be abolished by temporary food restriction. METHODS: Mice of the two inbred strains were tested for: (1) conditioned taste aversion and place preference induced by amphetamine within the same dose-range; (2) preference for a novel compartment 24 h after a single exposure to only one of two compartments; (3) amphetamine-induced behavioral sensitization and conditioned hyperactivity; and (4) locomotor activity during exploration of a novel environment. RESULTS: The two strains showed consistent taste aversion at doses of amphetamine that promoted opposite strain-dependent place conditioning. Both strains spent more time exploring the novel rather than the known compartment of the place conditioning apparatus. Instead, only mice of the C57 strain showed amphetamine-induced behavioral sensitization and conditioned hyperactivity. However, temporary food restriction did not affect strain differences for these phenotypes. Finally, C57 mice were more active than DBA in a novel environment and restricted feeding abolished this strain-dependent difference. CONCLUSIONS: These results relate individual differences for amphetamine-induced place conditioning with locomotor response to amphetamine and novelty.

Norepinephrine in the prefrontal cortex is critical for amphetamine-induced reward and mesoaccumbens dopamine release.

Increasing evidence points to a major involvement of cortical areas in addictive mechanisms. Noradrenergic transmission in the medial prefrontal cortex (mpFC) has been shown to affect the motor effects of amphetamine, although there is no evidence of its involvement in the rewarding effects of this psychostimulant. The present experiments were aimed at investigating the possibility of a selective involvement of prefrontal cortical norepinephrine (NE) in the rewarding-reinforcing effects of amphetamine. To do so, we evaluated the effects of mpFC NE selective depletion in mice of C57BL/6J inbred strain, a background commonly used in molecular approaches that is known to be highly susceptible to the rewarding effects of the psychostimulant. In a first set of experiments, we demonstrated the absence of amphetamine-induced conditioned place preference in mice bearing prefrontal NE depletion. In a second series of experiments, we demonstrated that the same lesion dramatically reduced amphetamine-induced mesoaccumbens dopamine release as measured by intracerebral microdialysis. These results indicate that noradrenergic prefrontal transmission, by allowing increased dopamine release in the nucleus accumbens induced by amphetamine, is a critical factor for the rewarding-reinforcing effects of this drug.

Predictable stress promotes place preference and low mesoaccumbens dopamine response.

Aversive stimuli that are signaled, and therefore predictable, are preferred to unsignaled ones and promote less severe stress-related disturbances. Since stressful events are known to activate mesoaccumbens dopamine (DA) transmission, in the present experiments, we evaluated possible differences in mesoaccumbens DA response to predictable and unpredictable footshocks. Mice of the inbred strain DBA/2 were trained for conditioned place preference (CPP) in shuttle boxes. The procedure promoted significant preference for the compartment previously paired with predictable shocks (PR) to that paired with unpredictable shocks (NP). Mesoaccumbens levels of DA and its metabolites were therefore evaluated either after the first or the last (third) training session. A significant increase of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels were observed in animals exposed for the first time to the apparatus without shock delivery (SHAM) or to the PR and NP conditions compared with unhandled mice. There was no difference between PR and NP values, and DOPAC and HVA levels in both groups differed from those observable in the SHAM-exposed group. However, trained mice exposed to NP showed a significant elevation of DOPAC and HVA levels in comparison with those exposed to PR. These results show that information about predictability of aversive stimuli reduces central stress responses and suggest a possible relationship between reduced stressfulness and preference for predictable aversive experiences.