BACKGROUND AND PURPOSEThe enduring propensity for alcoholics to relapse even following years of abstinence presents a major hurdle for treatment.Here we report a model of relapse following protracted abstinence and investigate the pattern of neuronal activation following cue-induced reinstatement and administration of the orexin1 receptor antagonist SB-334867 in inbred alcohol-preferring rats. EXPERIMENTAL APPROACHRats were trained to self-administer alcohol under operant conditions and divided into two groups: immediate (reinstated immediately following extinction) and delayed (extinguished and then housed for 5 months before reinstatement). Prior to reinstatement, animals were treated with vehicle (immediate n = 11, delayed n = 11) or SB-334867 (20 mg·kg -1 i.p.; immediate n = 6, delayed n = 11). Fos expression was compared between each group and to animals that underwent extinction only. KEY RESULTSSB-334867 significantly attenuated cue-induced reinstatement in both groups. Immediate reinstatement increased Fos expression in the nucleus accumbens (NAc), infra-limbic (IL), pre-limbic (PrL), orbitofrontal (OFC) and piriform cortices, the lateral and dorsomedial hypothalamus, central amygdala and basolateral amygdala (BLA), and the bed nucleus of the stria terminalis. Following delayed reinstatement, Fos expression was further elevated in cortical structures. Concurrent with preventing reinstatement, SB-334867 decreased Fos in NAc core, PrL and OFC following immediate reinstatement. Following protracted abstinence, SB-334867 treatment decreased reinstatement-induced Fos in the PrL, OFC and piriform cortices. CONCLUSIONS AND IMPLICATIONSCue-induced alcohol seeking can be triggered following protracted abstinence in rats. The effects of SB-334867 on both behaviour and Fos expression suggest that the orexin system is implicated in cue-induced reinstatement, although some loci may shift following protracted abstinence. AbbreviationsBLA, basolateral amygdala; BNST, bed nucleus of the stria
L-glutamate is the principal excitatory neurotransmitter at fast synapses in the mammalian central nervous system, and signals though a number of ionotropic and metabotropic receptors. Among the latter are the group I metabotropic glutamate (mGlu1 and mGlu5) receptors that upon activation elevate intracellular calcium levels through activation of the phospholipase C pathway. The role of glutamatergic transmission in both the development of addiction and the phenomenon of relapse that may occur after prolonged abstinence, has come under intense scrutiny in recent times. While both mGlu1 and mGlu5 receptors have been implicated in certain aspects of the addictive state, the exact roles these receptors play in this process is, as yet, unclear. This review will introduce contemporary theories on drug addiction, including neural circuitry, before critically assessing the current body of knowledge on group I metabotropic glutamate receptors in this regard. This will involve an in-depth discussion of the distribution of these receptors in the brain, their presence in neural pathways known or postulated to be involved in addiction and their involvement in drug-related behavioral paradigms. The effect of acute and chronic drug administration on the activity and expression of group I metabotropic glutamate receptors will be investigated, as will the effect these receptors have on behavioral and biochemical responses to drugs of abuse. Finally, there will be a brief discussion on current and future therapeutic applications using our knowledge of these receptors, and the direction that future studies will need to take to close the gaps in our understanding.
Cancer is a major cause of mortality around the world, representing about 13% of deaths on the planet. Among the available cancer treatments, chemotherapy is most frequently utilized compared to other treatments such as surgery and radiotherapy. Many dietary antioxidants have proven to effectively prevent oxidative stress, which has been noted in many disease pathogeneses, including cancer. However, during chemotherapy or radiotherapy treatment of cancer patients, antioxidants are used as an adjuvant treatment. The use of a proof-based technique is advised in determining the supplements most suited to cancer patients. Though there are numerous opinions about the dangers and advantages of antioxidants, it is reasonable to conclude that side effects caused by antioxidants, for now, remain unclear for patients during cancer treatment, aside from smokers during radiotherapy. In this report, details of the effectiveness of antioxidants on cancer treatment aiding in the reduction of cancer therapy side effects are discussed.
Neurodegenerative diseases (NDs) like Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, and Huntington’s disease predominantly pose a significant socioeconomic burden. Characterized by progressive neural dysfunction coupled with motor or intellectual impairment, the pathogenesis of ND may result from contributions of certain environmental and molecular factors. One such condition is hypoxia, characterized by reduced organ/tissue exposure to oxygen. Reduced oxygen supply often occurs during the pathogenesis of ND and the aging process. Despite the well-established relationship between these two conditions (i.e., hypoxia and ND), the underlying molecular events or mechanisms connecting hypoxia to ND remain ill-defined. However, the relatedness may stem from the protective or deleterious effects of the transcription factor, hypoxia-inducible factor 1-alpha (HIF-1α). The upregulation of HIF-1α occurs in the pathogenesis of most NDs. The dual function of HIF-1α in acting as a “killer factor” or a “protective factor” depends on the prevailing local cellular condition. The kynurenine pathway is a metabolic pathway involved in the oxidative breakdown of tryptophan. It is essential in neurotransmission and immune function and, like hypoxia, associated with ND. Thus, a good understanding of factors, including hypoxia (i.e., the biochemical implication of HIF-1α) and kynurenine pathway activation in NDs, focusing on Alzheimer’s disease could prove beneficial to new therapeutic approaches for this disease, thus the aim of this review.
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