The role of stress in drug addiction is well established. The negative affective states of withdrawal most probably involve recruitment of brain stress neurocircuitry [e.g., induction of hypothalamo-pituitary-adrenocortical (HPA) axis, noradrenergic activity, and corticotropin-releasing factor (CRF) activity]. The present study investigated t$he role of CRF receptor-1 subtype (CRF1R) on the response of brain stress system to morphine withdrawal. The effects of naloxone-precipitated morphine withdrawal on noradrenaline (NA) turnover in the paraventricular nucleus (PVN), HPA axis activity, signs of withdrawal, and c-Fos expression were measured in rats pretreated with vehicle, CP-154526 [N-butyl-N-ethyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidin-4-amine], or antalarmin (selective CRF1R antagonists). Tyrosine hydroxylase-positive neurons expressing CRF1R were seen at the level of the nucleus tractus solitarius-A 2 cell group in both control and morphine-withdrawn rats. CP-154526 and antalarmin attenuated the increases in body weight loss and irritability that were seen during naloxone-induced morphine withdrawal. Pretreatment with CRF1R antagonists resulted in no significant modification of the increased NA turnover at PVN, plasma corticosterone levels, or c-Fos expression that was seen during naloxone-induced morphine withdrawal. However, blockade of CRF1R significantly reduced morphine withdrawal-induced increases in plasma adrenocorticotropin levels. These results suggest that the CRF1R subtype may be involved in the behavioral and somatic signs and in adrenocorticotropin release (partially) during morphine withdrawal. However, CRF1R activation may not contribute to the functional interaction between NA and CRF systems in mediating morphine withdrawalactivation of brain stress neurocircuitry.

Our findings suggest that dopaminergic pathways and proBDNF signaling and TrkB receptors play different roles in social defeat-stressed mice exposed to cocaine.

BACKGROUND AND PURPOSE Recent evidence suggests that corticotropin‐releasing factor (CRF) receptor signalling is involved in modulating the negative symptoms of opiate withdrawal. In this study, a series of experiments were performed to further characterize the role of CRF‐type 2 receptor (CRF2) signalling in opiate withdrawal‐induced physical signs of dependence, hypothalamus‐pituitary‐adrenal (HPA) axis activation, enhanced noradrenaline (NA) turnover in the hypothalamic paraventricular nucleus (PVN) and tyrosine hydroxylase (TH) phosphorylation (activation), as well as CRF2 expression in the nucleus of the solitary tract‐A2 noradrenergic cell group (NTS‐A2). EXPERIMENTAL APPROACH The contribution of CRF2 signalling in opiate withdrawal was assessed by i.c.v. infusion of the selective CRF2 antagonist, antisauvagine‐30 (AS‐30). Rats were implanted with two morphine (or placebo) pellets. Six days later, rats were pretreated with AS‐30 or saline 10 min before naloxone and the physical signs of abstinence, the HPA axis activity, NA turnover, TH activation and CRF2 expression were measured using immunoblotting, RIA, HPLC and immunohistochemistry. KEY RESULTS Rats pretreated with AS‐30 showed decreased levels of somatic signs of naloxone‐induced opiate withdrawal, but the corticosterone response was not modified. AS‐30 attenuated the increased production of the NA metabolite, 3‐methoxy‐4‐hydroxyphenylglycol, as well as the enhanced NA turnover observed in morphine‐withdrawn rats. Finally, AS‐30 antagonized the TH phosphorylation at Serine40 induced by morphine withdrawal. CONCLUSIONS AND IMPLICATIONS These results suggest that physical signs of opiate withdrawal, TH activation and stimulation of noradrenergic pathways innervating the PVN are modulated by CRF2 signalling. Furthermore, they indicate a marginal role for the HPA axis in CRF2‐mediation of opiate withdrawal.

BackgroundTraditional bullying victimization and the growing number of cyber-teasing victims during the last decade is a major public health concern. The objective of this study was to examine the relationship between students’ experiences of traditional bullying victimization and cyber-teasing and the sociodemographic characteristics of a sample composed of college students in Spain.MethodsIn the fall of 2014, 543 sixth-grade students from southeast Spain completed an anonymous survey on their experience of both kinds of to ascertain any relationship with sociodemographic characteristics, including gender, nationality, economic problems, family conflicts and alcohol and cannabis use.ResultsA total of 62.2 % of the students reported to having suffered traditional bullying victimization and 52.7 % reported that they had been subject to cyber-teasing. 40.7 % of participants had been victims of traditional bullying victimization and cyber-teasing in the past 12 months. Most (65.7 %) of the victims were at the same time cyber-teasing victims; 77.6 % of cyber-teasing victims were also victimized in a different manner. Traditional bullying victimization was higher among boys than among girls, while female students were more likely to have been subjected to cyber-teasing than male students. The characteristics that most heavily influenced suffering traditional bullying victimization were economic problems, family conflicts and cannabis use.ConclusionsOur findings confirm overlapping results in the risk factors that influence suffering both traditional bullying victimization and cyber-teasing: there was a strong influence of certain sociodemographic and individual characteristics of the college population, suggesting that specific policies are necessary to improve college students’ environment in Spain.

BACKGROUND AND PURPOSE Recent evidence suggests that glucocorticoid receptor (GR) is a major molecular substrate of addictive properties of drugs of abuse. Hence, we performed a series of experiments to further characterize the role of GR signalling in opiate withdrawal‐induced physical signs of dependence, enhanced noradrenaline (NA) turnover in the hypothalamic paraventricular nucleus (PVN) and tyrosine hydroxylase (TH) phosphorylation (activation) as well as GR expression in the nucleus of the solitary tract noradrenergic cell group (NTS‐A2). EXPERIMENTAL APPROACH The role of GR signalling was assessed by i.p. pretreatment of the selective GR antagonist, mifepristone. Rats were implanted with two morphine (or placebo) pellets. Six days later, rats were pretreated with mifepristone or vehicle 30 min before naloxone and physical signs of abstinence, NA turnover, TH activation, GR expression and the hypothalamus–pituitary–adrenocortical axis activity were measured using HPLC, immunoblotting and RIA. KEY RESULTS Mifepristone alleviated the somatic signs of naloxone‐induced opiate withdrawal. Mifepristone attenuated the increase in the NA metabolite, 3‐methoxy‐4‐hydroxyphenylethylen glycol (MHPG), in the PVN, and the enhanced NA turnover observed in morphine‐withdrawn rats. Mifepristone antagonized the TH phosphorylation at Ser31 and the expression of c‐Fos expression induced by morphine withdrawal. Finally, naloxone‐precipitated morphine withdrawal induced up‐regulation of GR in the NTS. CONCLUSIONS AND IMPLICATIONS These results suggest that the physical signs of opiate withdrawal, TH activation and stimulation of noradrenergic pathways innervating the PVN are modulated by GR signalling. Overall, the present data suggest that drugs targeting the GR may ameliorate stress and aversive effects associated with opiate withdrawal.

Stress induces the release of the peptide corticotropin-releasing factor (CRF) into the ventral tegmental area (VTA), and also increases dopamine (DA) levels in brain regions receiving dense VTA input. Since the role of stress in drug addiction is well established, the present study examined the possible involvement of CRF1 receptor in the interaction between morphine withdrawal and catecholaminergic pathways in the reward system. The effects of naloxone-precipitated morphine withdrawal on signs of withdrawal, hypothalamo-pituitary-adrenocortical (HPA) axis activity, dopamine (DA) and noradrenaline (NA) turnover in the nucleus accumbens (NAc) and activation of VTA dopaminergic neurons, were investigated in rats pretreated with vehicle or CP-154,526 (selective CRF1R antagonist). CP-154,526 attenuated the increases in body weight loss and suppressed some of withdrawal signs. Pretreatment with CRF1 receptor antagonist resulted in no significant modification of the increased NA turnover at NAc or plasma corticosterone levels that were seen during morphine withdrawal. However, blockade of CRF1 receptor significantly reduced morphine withdrawal-induced increases in plasma adrenocorticotropin (ACTH) levels, DA turnover and TH phosphorylation at Ser40 in the NAc. In addition, CP-154,526 reduced the number of TH containing neurons expressing c-Fos in the VTA after naloxone-precipitated morphine withdrawal. Altogether, these results support the idea that VTA dopaminergic neurons are activated in response to naloxone-precipitated morphine withdrawal and suggest that CRF1 receptors are involved in the activation of dopaminergic pathways which project to NAc.

Dysautonomia is a common non-motor symptom in Parkinson’s disease (PD). Most dysautonomic symptoms appear due to alterations in the peripheral nerves of the autonomic nervous system, including both the sympathetic and parasympathetic nervous systems. The degeneration of sympathetic nerve fibers and neurons leads to cardiovascular dysfunction, which is highly prevalent in PD patients. Cardiac alterations such as orthostatic hypotension, heart rate variability, modifications in cardiogram parameters and baroreflex dysfunction can appear in both the early and late stages of PD, worsening as the disease progresses. In PD patients it is generally found that parasympathetic activity is decreased, while sympathetic activity is increased. This situation gives rise to an imbalance of both tonicities which might, in turn, promote a higher risk of cardiac damage through tachycardia and vasoconstriction. Cardiovascular abnormalities can also appear as a side effect of PD treatment: L-DOPA can decrease blood pressure and aggravate orthostatic hypotension as a result of a negative inotropic effect on the heart. This unwanted side effect limits the therapeutic use of L-DOPA in geriatric patients with PD and can contribute to the number of hospital admissions. Therefore, it is essential to define the cardiac features related to PD for the monitorization of the heart condition in parkinsonian individuals. This information can allow the application of intervention strategies to improve the course of the disease and the proposition of new alternatives for its treatment to eliminate or reverse the motor and non-motor symptoms, especially in geriatric patients.

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