We previously demonstrated that morphine withdrawal induced hyperactivity of noradrenergic pathways innervating the hypothalamic paraventricular nucleus (PVN) in rats, in parallel with an increase in the neurosecretory activity of the hypothalamus-pituitary-adrenocortical (HPA) axis, as evaluated by corticosterone release. These neuroendocrine effects were dependent on stimulation of a-adrenoceptors. In the present study, Fos immunostaining was used as a reflection of neuronal activity and combined with immunostaining for tyrosine hydroxylase (TH) for immunohistochemical identification of active neurones during morphine withdrawal. Dependence on morphine was induced by 7-day chronic subcutaneous implantation of six morphine pellets (75 mg). Morphine withdrawal was precipitated by administration of naloxone (5 mg/kg subcutaneously) on day 8. Fos immunoreactivity in the PVN and also in the nucleus tractus solitarius (NTS)-A 2 and ventrolateral medulla (VLM)-A 1 cell groups, which project to the PVN, increased during morphine withdrawal. Following withdrawal, Fos immunoreactivity was present in most of the TH-positive neurones of the A 2 and A 1 neurones. In a second study, the effects of administration of adrenoceptor antagonists on withdrawal-induced Fos expression in the PVN were studied. Pre-treatment with a 1 -or a 2 -adrenoceptor antagonists, prazosin (1 mg/kg intraperitoneally) and yohimbine (1 mg/kg intraperitoneally), respectively, 20 min before naloxone administration to morphine-dependent rats markedly reduced Fos expression in the PVN. Similarly, pre-treatment with the b antagonist, propranolol (3 mg/kg intraperitoneally), significantly prevented withdrawal-induced Fos expression. Collectively, these results suggest the hypothesis that noradrenergic neurones in the brainstem innervating the PVN are active during morphine withdrawal, and that activation of transcriptional responses mediated by Fos in the HPA axis following withdrawal are dependent upon hypothalamic a-and b-adrenoceptors. The physiological response to morphine dependence and withdrawal invokes a number of complex neural and hormonal processes. Several lines of evidence provide support for the participation of noradrenergic pathways in the expression of morphine dependence (Maldonado 1997; Nestler and Aghajanian 1997), most of which have been derived from studies of the locus coeruleus. One of the prominent components of the morphine-withdrawal response is the central activation of the hypothalamus-pituitaryadrenocortical (HPA) axis (Pechnick 1993;Vargas et al. 1997;Fuertes et al. 2000a). Parvocellular neuroendocrine cells in the hypothalamic paraventricular nucleus (PVN) project to the median eminence and release corticotropinreleasing factor (CRF) and vasopressin (AVP) into the portal circulation when activated by a variety of stressors, resulting in the release of adrenocorticotropic hormone (ACTH) from anterior pituitary and the subsequent secretion of glucocorticoids from the adrenals. Previous anatomical and physiological dat...
This study examined the actions of pregabalin and topiramate on behavioural and gene transcription alterations induced by spontaneous cannabinoid withdrawal in mice. Tolerance was induced in mice by administration of CP-55,940 (0.5 mg/kg/12 hours; i.p.; 7 days). Behavioural assessment of spontaneous cannabinoid withdrawal was performed by measuring motor activity, somatic signs and anxiety-like behaviour on days 1 and 3 after cessation of treatment with CP-55,940. On days 1-3 of cannabinoid withdrawal, mice received pregabalin (40 mg/kg/12 hours; p.o.) or topiramate (50 mg/kg/12 hours; p.o.) and their actions on signs of withdrawal and anxiety-like behaviour were evaluated. The administration of CP-55,940 decreased rectal temperature and motor activity on day 1. On day 1 after interruption of cannabinoid administration, motor activity and the number of rearings increased compared with control group. Anxiety-like behaviour induced by cessation of cannabinoid treatment increased significantly on days 1 and 3 of withdrawal. The administration of pregabalin or topiramate blocked the motor signs and reduced significantly anxiety-like behaviour. Cannabinoid withdrawal decreased tyrosine hydroxylase (TH) gene expression in the ventral tegmental area and µ-opioid receptor gene expression in the nucleus accumbens (NAcc) and increased CB1 receptor gene expression in the NAcc. Treatment with topiramate or pregabalin blocked the decrease of TH and the increase of CB1 gene expressions induced by cannabinoid withdrawal. Both drugs failed to alter µ-opioid receptor gene expression. These results suggest that pregabalin and topiramate may result useful for the treatment of anxiety-like behaviour and motor symptoms associated with spontaneous cannabinoid withdrawal.
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: Our previous studies have shown that morphine withdrawal induced hyperactivity of cardiac noradrenergic pathways. The purpose of the present study was to evaluate the effects of morphine withdrawal on site-specific phosphorylation of TH in the heart. Experimental approach: Dependence on morphine was induced by a 7-day s.c. implantation of morphine pellets in rats. Morphine withdrawal was precipitated on day 8 by an injection of naloxone (2 mg kg À1 ). TH phosphorylation was determined by quantitative blot immunolabelling using phosphorylation state-specific antibodies. Key results: Naloxone-induced morphine withdrawal induced phosphorylation of TH at serine (Ser)40 and Ser31 in the right ventricle, associated with both an increase in total TH levels and an enhancement of TH activity. When HA-1004 (PK A inhibitor) was infused, concomitantly with morphine, it diminished the increase in noradrenaline turnover, total TH levels and TH phosphorylation at Ser40 in morphine-withdrawn rats. In contrast, the infusion of calphostin C (PKC inhibitor), did not modify the morphine withdrawal-induced increase in noradrenaline turnover and total TH levels. In addition, we show that the ability of morphine withdrawal to stimulate phosphorylation at Ser31 was reduced by SL327, an inhibitor of ERK 1/2 activation. Conclusions and implications:The present findings demonstrate that the enhancement of total TH levels and the increased phosphorylation state of TH during morphine withdrawal were dependent on PKA and ERK activities and suggest that these transduction pathways might contribute to the activation of the cardiac catecholaminergic neurons in response to morphine withdrawal.
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