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Background:Identifying neural substrates that are differentially affected by drugs of abuse and natural rewards is key to finding a target for an efficacious treatment for substance abuse. Melanin-concentrating hormone is a polypeptide with an inhibitory effect on the mesolimbic dopamine system. Here we test the hypothesis that melanin-concentrating hormone in the lateral hypothalamus and nucleus accumbens shell is differentially involved in the regulation of morphine and food-rewarded behaviors.Methods:Male Sprague–Dawley rats were trained with morphine (5.0 mg/kg, subcutaneously) or food pellets (standard chow, 10–14 g) to induce a conditioned place preference, immediately followed by extinction training. Melanin-concentrating hormone (1.0 µg/side) or saline was infused into the nucleus accumbens shell or lateral hypothalamus before the reinstatement primed by morphine or food, and locomotor activity was simultaneously monitored. As the comparison, melanin-concentrating hormone was also microinjected into the nucleus accumbens shell or lateral hypothalamus before the expression of food or morphine-induced conditioned place preference.Results:Microinfusion of melanin-concentrating hormone into the nucleus accumbens shell (but not into the lateral hypothalamus) prevented the reinstatement of morphine conditioned place preference but had no effect on the reinstatement of food conditioned place preference. In contrast, microinfusion of melanin-concentrating hormone into the lateral hypothalamus (but not in the nucleus accumbens shell) inhibited the reinstatement of food conditioned place preference but had no effect on the reinstatement of morphine conditioned place preference.Conclusions:These results suggest a clear double dissociation of melanin-concentrating hormone in morphine/food rewarding behaviors and melanin-concentrating hormone in the nucleus accumbens shell. Melanin-concentrating hormone could be a potential target for therapeutic intervention for morphine abuse without affecting natural rewards.

Negative affective states, e.g., anhedonia, may be linked to the long-lasting motivational processes associated with relapse. Here, this study investigated whether, and how, anhedonic states are influenced by stressful events that contribute to craving and relapse. All male rats were pretreated with a binge-like morphine paradigm for five days. After 12 to 16 days of withdrawal, rats were subjected to a one-hour free consumption test or three operant tasks with increasing cost/benefit ratio, i.e., fixed ratio 1 (FR1), progressive ratio (PR), and PR-punishment procedure of reinforcement, with sucrose solutions of three concentrations (4%, 15%, and 60%) as rewards. The consumption and operant responses under FR1 and PR procedures were measured following exposure to acute foot-shock stress (intermittent foot shock, 0.5 mA × 0.5 s × 10 min; mean intershock interval, 40 s), and the operant responses for 60% sucrose solution under PR-punishment procedure was measured following a forced-swim stress (5 minutes). Foot-shock stress increased water consumption in a subpopulation of rats and decreased consumption of sucrose solutions, while it did not influence the operant responses for sucrose solutions under either FR1 or PR procedure. The forced-swim stress reduced operant responses for 60% sucrose solution under PR-punishment procedure, but did not influence responding for 60% sucrose solution under PR procedure. In addition, the forced-swim stress also elevated anxiety level of rats in an open area test. Acute stress induced hedonic but not motivational deficit for sucrose reward in protracted drug-abstinent animals. Additional negative emotional states besides anhedonia were evoked by acute stress.

The return of fear is an important issue in anxiety disorder research. Each time a fear memory is reactivated, it may further strengthen overactivation of the fear circuit, which may contribute to long-term maintenance of the fear memory. Recent evidence indicates that glucocorticoids may help attenuate pathological fear, but its role in the return of fear is unclear. In the present study, systemic corticosterone (CORT; 25 mg/kg) administration 1 h after fear conditioning did not impair the consolidation process but significantly suppressed the return of fear evoked by a subthreshold conditioning (SC) procedure and elevated platform (EP) stress. Compared with the SC-induced return of fear, acute stress-induced return was state-dependent. In addition, post-training CORT treatment increased the adrenocorticotropic response after EP stress, which indicates that the drug-induced suppression of the return of fear may possibly derive from its regulation effect of the hypothalamic-pituitary-adrenal axis reactivity to stress. These results suggest that post-training CORT administration may help inhibit the return of fear evoked by EP or SC stress. The possible mechanisms involved in the high-dose CORT-induced suppression of the SC- and EP-induced return of fear are discussed. (C) 2015 Elsevier Inc. All rights reserved.

Exposure therapy is widely used to treat anxiety disorders, including posttraumatic stress disorder (PTSD). However, preventing the return of fear is still a major challenge after this behavioral treatment. An increasing number of studies suggest that high-dose glucocorticoid treatment immediately after trauma can alleviate the symptoms of PTSD in humans. Unknown is whether high-dose glucocorticoid treatment following fear conditioning suppresses the return of fear. In the present study, a typical fear renewal paradigm (AAB) was used, in which the fear response to an auditory cue can be restored in a novel context (context B) when both training and extinction occur in the same context (context A). We trained rats for auditory fear conditioning and administered corticosterone (CORT; 5 and 25 mg/kg, i.p.) or vehicle with different delays (1 and 24 h). Forty-eight hours after drug injection, extinction was conducted with no drug in the training context, followed by a test of tone-induced freezing behavior in the same (AAA) or a shifted (AAB) context. Both immediate and delayed administration of high-dose CORT after fear conditioning reduced fear renewal. To examine the anxiolytic effect of CORT, independent rats were trained for cued or contextual fear conditioning, followed by an injection of CORT (5 and 25 mg/kg, i.p.) or vehicle at a 1 or 24 h delay. One week later, anxiety-like behavior was assessed in the elevated plus maze (EPM) before and after fear expression. We found that high-dose CORT decreased anxiety-like behavior without changing tone- or context-induced freezing. These findings indicate that a single high-dose CORT administration given after fear conditioning may selectively suppress fear renewal by reducing anxiety-like behavior and not by altering the consolidation, retrieval, or extinction of fear memory. (C) 2014 Elsevier Inc All rights reserved.

Accumulating evidence suggests that stress-dose corticosteroids impair fear memory in animals and humans. Corticosteroid treatment after critical illness is seen as a potential psychotropic medication by which to prevent posttraumatic stress disorder. However, individual difference in the responsiveness to stress (i.e., stress reactivity) is a factor that modulates the efficacy of corticosteroids. To understand the contribution of fear reactivity to the effect of post-stress corticosterone, male Sprague-Dawley rats were subjected to classical tone-cued fear conditioning and separated into high and low reactivity (HR and LR, respectively) responder groups based on their levels of freezing during conditioning. The HR rats showed significantly higher fear responses than the LR rats during conditioning as assessed by freezing behavior. At two intervals, 30 min and 48 hr later, the HR rats still displayed more pronounced conditioned responses to cued stimuli compared with the LR rats. Moreover, in contrast to the LR rats, the enhanced fear response in the HR rats was difficult to attenuate by post-training high-dose corticosterone. These results suggest that fear reactivity results in stronger fear memory, and that it is difficult to disrupt this strong fear memory in the HR phenotype using monotherapy. However, the strong fear memory in the HR rats was impaired by concurrent intramedial prefrontal cortex infusion of a high dose of the dopamine D1 receptor antagonist SCH 23390 and systemic administration of corticosterone. SCH 23390 and corticosterone alone did not decrease freezing levels in the HR rats. The fear impairment induced by SCH 23390 combined with corticosterone was not attributable to the effect of these drugs on locomotor activity. This effect was not found with administration of the D2 antagonist eticlopride combined with corticosterone. Our findings demonstrate that the conditioned fear memory in individuals with high stress reactivity is difficult to disrupt using monotherapy, but that combined pharmacotherapy may be useful for treating intervention-resistant fear.

The transition to addiction often involves a gradual process of escalated drug intake. The purpose of the present study was to characterize neuronal activation in the ventral tegmental area (VTA) and substantia nigra (SN) following chronic escalating-dose morphine exposure (days 1-7, 2 mg/kg/d; days 8-21, beginning at 10 mg/kg/d, increasing by 2 mg/kg/d), with steady-dose morphine (2 mg/kg/d, i.p., for 21 days) as the comparison. Using immunohistochemical double-staining for tyrosine hydroxylase (TH) and Fos, we found that the number of Fos(+)TH(+) neurons in the rostral VTA and number of Fos(+)TH(-) neurons in the lateral SNr were significantly increased in escalating-dose morphine-treated rats compared with steady-dose morphine-treated rats and acute morphine-treated rats. Meanwhile, this increase was associated with robust expression of behavioral sensitization after a challenge with 10 mg/kg morphine. The number of Fos(+)TH(+) neurons was significantly increased by acute morphine in the caudal VTA and SNc, but this number did not increase further with morphine pretreatment. These results demonstrate that behavioral sensitization was associated with elevated activation of dopaminergic neurons in the rostral VTA and nondopaminergic neurons in the lateral SNr, which could only be induced by chronic escalating-dose morphine rather than chronic steady-dose morphine pretreatment. (C) 2012 Elsevier B.V. All rights reserved.

Orexins are neuropeptides involved in multiple neurophysiological functions such as reward and motivation. However, it is not clear whether orexins are implicated in sexual motivation. This study aims to evaluate the effects of orexin A and the OX(1)R antagonist SB334867 on unconditioned sexual motivation. Forty-five male Wistar rats are divided into four groups. The four groups are respectively administered intracerebroventricularly with saline, orexin A (1, 10 mu g), 10% DMSO (cyclodextrin) and SB334867 (5, 15 mu g) 10- 15 min before sexual motivation tests. The preference for a receptive female to a male in in open arena with two tethered animals is designated as unconditioned sexual motivation. The results show that orexin A reduces the female preference (reducing time in the female zone and/or increasing time in the male zone). the number of visits for the female zone and the total distance traveled in sexually high-motivated males. SB334867 has no effect on the female preference, the number of visits and the distance traveled in either sexually high-motivated or low-motivated males. Our experiments reveal that centrally administered orexin A attenuates sexual motivation in high-motivated males although endogenous orexin A might not play an important role in the expression of unconditioned sexual motivation. (c) 2008 Elsevier Inc. All rights reserved.

Fil: Garcia, Ana P. University of Cambridge. Department of Pharmacology; Reino Unido Fil: García, Ana P. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Neurobiología Molecular; Argentina Fil: García, Ana P. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Aitta-aho, Teemu. University of Cambridge. Department of Pharmacology; Reino Unido Fil: Schaaf, Laura. University of Cambridge. Department of Pharmacology; Reino Unido Fil: Heeley, Nicholas. University of Cambridge. Institute of Metabolic Science; Reino Unido Fil: Heuschmid, Lena. University of Cambridge. Department of Pharmacology; Reino Unido Fil: Bai, Yunjing. Chinese Academy of Sciences. Key Laboratory of Mental Health, Institute of Psychology; China Fil: Barrantes, Francisco José. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Neurobiología Molecular; Argentina Fil: Barrantes, Francisco José. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Apergis-Schoute, John. University of Cambridge. Department of Pharmacology; Reino Unido Fil: Apergis-Schoute, John. University of Cambridge. Institute of Metabolic Science; Reino Unido Abstract: Nicotinic acetylcholine receptors (nAChRs) play an important role in regulating appetite and have been shown to do so by influencing neural activity in the hypothalamus. To shed light on the hypothalamic circuits governing acetylcholine's (ACh) regulation of appetite this study investigated the influence of hypothalamic nAChRs expressing the α4 subunit. We found that antagonizing the α4β2 nAChR locally in the lateral hypothalamus with di-hydro-ß-erythroidine (DHβE), an α4 nAChR antagonist with moderate affinity, caused an increase in food intake following free access to food after a 12 hour fast, compared to saline-infused animals. Immunocytochemical analysis revealed that orexin/hypocretin (HO), oxytocin, and tyrosine hydroxylase (TH)-containing neurons in the A13 and A12 of the hypothalamus expressed the nAChR α4 subunit in varying amounts (34%, 42%, 50%, and 51%, respectively) whereas melanin concentrating hormone (MCH) neurons did not, suggesting that DHβE-mediated increases in food intake may be due to a direct activation of specific hypothalamic circuits. Systemic DHβE (2 mg/kg) administration similarly increased food intake following a 12 hour fast. In these animals a subpopulation of orexin/hypocretin neurons showed elevated activity compared to control animals and MCH neuronal activity was overall lower as measured by expression of the immediate early gene marker for neuronal activity cFos. However, oxytocin neurons in the paraventricular hypothalamus and TH-containing neurons in the A13 and A12 did not show differential activity patterns. These results indicate that various neurochemically distinct hypothalamic populations are under the influence of α4β2 nAChRs and that cholinergic inputs to the lateral hypothalamus can affect satiety signals through activation of local α4β2 nAChR-mediated transmission.

The anhedonia-like behaviors following about 1-week withdrawal from morphine were examined in the present study. Male rats were pretreated with either a binge-like morphine paradigm or daily saline injection for 5 days. Three types of natural reward were used, food reward (2.5, 4, 15, 30, 40, and 60% sucrose solutions), social reward (male rat) and sexual reward (estrous female rat). For each type of natural stimulus, consummatory behavior and motivational behaviors under varied testing conditions were investigated. The results showed that the morphine-treated rats significantly reduced their consumption of 2.5% sucrose solution during the 1-h consumption testing and their operant responding for 15, 30, and 40% sucrose solutions under a fixed ratio 1 (FR1) schedule. However, performance under a progressive ratio (PR) schedule increased in morphine-treated rats reinforced with 60% sucrose solution, but not in those reinforced with sucrose concentrations lower than 60%. Pretreatment with morphine significantly decreased the male rats' ejaculation frequency (EF) during the 1-h copulation testing, and impaired the maintenance of appetitive motivations to sexual and social stimuli under a free-approach condition. Moreover, the morphine-treated rats demonstrated a diminished motivation to approach social stimulus in the effort-based appetitive behavior test but showed a remarkable increase in motivation to approach sexual stimulus in the risky appetitive behavior test. These results demonstrated some complex motivated behaviors following about 1 week of morphine withdrawal: (1) The anhedonia-like behavior was consistently found in animals withdrawn from morphine. However, for a given reward, there was often a dissociation of the consummatory behaviors from the motivational behaviors, and whether the consummatory or the motivational anhedonia-like behaviors could be discovered heavily depended on the type and magnitude of the reward and the type of testing task; (2) These anhedonia-like behaviors coexisted with a craving for the high-incentive reward which was evidenced by the increased PR performance for the 60% sucrose solution and the heightened risky appetitive behavior for the sexual stimulus. The craving for the high-incentive reward alongside with the impaired inhibitory control in drug-withdrawn subjects might form one of psychological mechanisms underlying drug relapse after withdrawal.

Drug seeking, craving, and relapse can be triggered by environmental stimuli that acquire motivational salience through repeated associations with the drug's effects. Previous studies indicated that the dopamine D-3 receptor (Drd3) might be involved in the expression of drug-conditioned responses in rats, and brain-derived neurotrophic factor (BDNF) could modulate Drd3 expression in the nucleus accumbens (NAc). However, the involvement of neural regions with Drd3 activation and the underlying interaction between BDNF and Drd3 in the expression of behavioral responses controlled by a drug-associated environment have remained poorly understood. The present study used a conditioning procedure to assess the roles of BDNF, Drd3, and their interactions in the NAc in the expression of morphine-induced context-specific locomotor sensitization. We showed that the expression of locomotor sensitization in the morphine-paired environment was accompanied by significantly increased expression of Drd3 mRNA and BDNF mRNA and protein levels. Both sensitized locomotion in morphine-paired rats and enhanced Drd3 mRNA were suppressed by intra-NAc infusion of anti-tyrosine kinase receptor B (TrkB) IgG. Furthermore, intra-NAc infusion of the Drd3-selective antagonist SB-277011A significantly decreased the expression of context-specific locomotor sensitization and upregulated BDNF mRNA. Altogether, these results suggest that BDNF/TrkB signaling and activation of Drd3 in the NAc are required for the expression of morphine-induced context-specific locomotor sensitization. (C) 2011 Elsevier B.V. and ECNP. All rights reserved.