Genetic Association of Recovery from Eating Disorders: The Role of GABA Receptor SNPs

Follow-up studies of eating disorders (EDs) suggest outcomes ranging from recovery to chronic illness or death, but predictors of outcome have not been consistently identified. We tested 5151 single-nucleotide polymorphisms (SNPs) in approximately 350 candidate genes for association with recovery from ED in 1878 women. Initial analyses focused on a strictly defined discovery cohort of women who were over age 25 years, carried a lifetime diagnosis of an ED, and for whom data were available regarding the presence (n=361 ongoing symptoms in the past year, ie, ‘ill'') or absence (n=115 no symptoms in the past year, ie, ‘recovered'') of ED symptoms. An intronic SNP (rs17536211) in GABRG1 showed the strongest statistical evidence of association (p=4.63 × 10⁻⁶, false discovery rate (FDR)=0.021, odds ratio (OR)=0.46). We replicated these findings in a more liberally defined cohort of women age 25 years or younger (n=464 ill, n=107 recovered; p=0.0336, OR=0.68; combined sample p=4.57 × 10⁻⁶, FDR=0.0049, OR=0.55). Enrichment analyses revealed that GABA (γ-aminobutyric acid) SNPs were over-represented among SNPs associated at p<0.05 in both the discovery (Z=3.64, p=0.0003) and combined cohorts (Z=2.07, p=0.0388). In follow-up phenomic association analyses with a third independent cohort (n=154 ED cases, n=677 controls), rs17536211 was associated with trait anxiety (p=0.049), suggesting a possible mechanism through which this variant may influence ED outcome. These findings could provide new insights into the development of more effective interventions for the most treatment-resistant patients.     

A Review of Integrated Care for Concurrent Disorders: Cost Effectiveness and Clinical Outcomes

Objective: The recognition of concurrent disorders (combined mental health and substance use disorders) has increased substantially over the last three decades, leading to greater numbers of people with these diagnoses and a subsequent greater financial burden on the health care system, yet establishing effective modes of management remains a challenge. Further, there is little evidence on which to base recommendations for a particular mode of health service delivery. This paper will further summarize the existing treatment models for a comprehensive overview. The objectives of this study are to determine whether existing service models are effective in treating combined mental health and substance use disorders and to examine whether an integrated model of service delivery should be recommended to policy makers. The following two research questions are the focus of this paper: (1) Are the existing service models effective at treating mental health and substance use disorders? (2) How are existing service models effective at treating mental health and substance use disorders? Methods: We used various databases to systematically review the effectiveness of service delivery models to treat concurrent disorders. Models were considered effective if they are found to be cost-effective and significantly improve clinical and social outcomes. Results: This systematic review revealed that integrated models of care are more effective than conventional, nonintegrated models. Integrated models demonstrated superiority to standard care models through reductions in substance use disorders and improvement of mental health in patients who had diagnoses of concurrent disorders. Our meta-analysis revealed similar findings, indicating that the integrated model is more cost-effective than standard care. Conclusions: Given the limited number of studies in relation to service delivery for concurrent disorders, it is too early to make a strong evidence-based recommendation to policy makers and service providers as to the superiority of one approach over the others. However, the available evidence suggests that integrated care models for concurrent disorders are the most effective models for patient care. More research is needed, especially around the translation of research findings to policy development and, vice versa, around the translation from the policy level to the patients’ level.     

GABAergic and glycinergic mechanisms within the substantia nigra: Pharmacological specificity of dopamine-independent contralateral turning behavior and interactions with other neurotransmitters

The pharmacological specificity of the GABA agonist muscimol-induced contralateral turning behavior after unilateral injection into substantia nigra pars reticulata (SNR) has been studied. Muscimol-induced turning was antagonized by intranigral bicuculline methochloride (BMC) and picrotoxin, whereas antagonists of glycine, morphine, dopamine, noradrenaline, and serotonin were ineffective. Glycine induced a qualitatively similar turning behavior which was strychnine-sensitive but relatively BMC and picrotoxin-insensitive. Other drugs, including substance P, kainic acid, clonidine, oxymetazoline, serotonin, and carbachol, induced turning that could be dissociated from the effect of muscimol. Muscimol-induced turning was dopamine-independent, indicated by resistance to haloperidol (1 mg/kg), to pretreatment with reserpine (7.5 mg/kg) plus -methyl-p-tyrosine (200 mg/kg), to haloperidol injections into the SNR, striatum and nucleus accumbens, and finally to kainic acid lesions of the striatum. 6-Hydroxydopamine lesions increased the efficacy of intranigral muscimol, while kainic acid lesions of the SNR antagonized muscimol. Muscimol-induced turning was inhibited by oxotremorine (0.25 mg/kg), by intranigral carbachol, and by apomorphine (0.1–0.5 mg/kg), but only moderately by intranigrally injected apomorphine. These data suggest specificity of GABA-agonist-induced contralateral turning and indicate an interaction between nigral GABA and other neurotransmitters, particularly dopamine and acetylcholine.     

Phytocannabinoids: General Aspects and Pharmacological Potential in Neurodegenerative Diseases

In the last few years research into Cannabis and its constituent phytocannabinoids has burgeoned, particularly in the potential application of novel cannabis phytochemicals for the treatment of diverse illnesses related to neurodegeneration and dementia, including Alzheimer’s (AD), Parkinson’s (PD) and Huntington’s disease (HD). To date, these neurological diseases have mostly relied on symptomatological management. However, with an aging population globally, the search for more efficient and disease-modifying treatments that could delay or mitigate disease progression is imperative. In this context, this review aims to present state of the art in the research with cannabinoids and novel cannabinoid-based drug candidates that have been emerged as novel promising alternatives for drug development and innovation in the therapeutics of a number of diseases, especially those related to CNS-disturbance and impairment.     

Gender of Physicians with Substance Use Disorders: Clinical Characteristics,Treatment Utilization,and Post-treatment Functioning

Gender has emerged as an important variable in both the course and treatment of substance-use disorders. This study examines the role of gender in a sample of physicians (n = 73) treated for substance-use disorders. Pilot data gathered on physicians treated during 1995 to 1997, included initial pretreatment characteristics, service utilization, and posttreatment functioning. Although there were many similarities, important differences emerged among the groups. These differences have implications for physician education and training and warrant more systematic clinical research.     

The dopaminergic system in peripheral blood lymphocytes: from physiology to pharmacology and potential applications to neuropsychiatric disorders

Besides its action on the nervous system, dopamine (DA) plays a role on neural-immune interactions. Here we review the current evidence on the dopaminergic system in human peripheral blood lymphocytes (PBL). PBL synthesize DA through the tyrosine-hydroxylase/DOPA-decarboxylase pathway, and express DA receptors and DA transporter (DAT) on their plasma membrane. Stimulation of DA receptors on PBL membrane contributes to modulate the development and initiation of immune responses under physiological conditions and in immune system pathologies such as autoimmunity or immunodeficiency.The characterization of DA system in PBL gave rise to a further line of research investigating the feasibility of PBL as a cellular model for studying DA derangement in neuropsychiatric disorders. Several reports showed changes of the expression of DAT and/or DA receptors in PBL from patients suffering from several neuropsychiatric disorders, in particular parkinsonian syndromes, schizophrenia and drug- or alcohol-abuse. Despite some methodological and theoretical limitations, these findings suggest that PBL may prove a cellular tool with which to identify the derangement of DA transmission in neuropsychiatric diseases, as well as to monitor the effects of pharmacological treatments.     

Pharmacological Effects of Saffron and its Constituents in Ocular Disorders from in vitro Studies to Clinical Trials: A Systematic Review

Introduction: Some medicinal plants have shown promising therapeutic potential for the management of the diseases. We aimed to systematically review the literature wherein the therapeutic effects of saffron have been studied on eye disorders.Methods A systematic literature search was performed in PubMed, Scopus, Web of Science, Google scholar and other databases using eye disorders and saffron as key terms. No strict inclusion criteria were defined, and almost all clinical studies, as well as in vivo and in vitro studies were included. The reported data in each study were extracted and then qualitatively described.Results Finally, 78 articles were found but only 29 relevant articles were included. Nine articles were clinical trials and 20 articles were studies conducted on cellular and molecular aspects of saffron on eye disorders. According to the included studies, crocin prevented the pro-inflammatory response in retinal cells and decreased glucose levels in diabetic mice. Also, crocetin prevented retinal degeneration and saffron protected photoreceptors from light-induced damage in retinal cells. Saffron also improved visual function in age-related macular edema and decreased intraocular pressure in patients with glaucoma. In addition, it was shown that crocin can improve best corrected visual acuity and decrease central macular thickness in patients with diabetic maculopathy.Conclusion The results of this review indicated that saffron and its main ingredients such as crocin could be a potential candidate for the treatment of ocular disease especially eye inflammation; however, further clinical studies are needed to confirm such efficiency.     

Pyruvate Dehydrogenase Kinases in the Nervous System: Their Principal Functions in Neuronal-glial Metabolic Interaction and Neuro-metabolic Disorders

Metabolism is involved directly or indirectly in all processes conducted in living cells. The brain, popularly viewed as a neuronal–glial complex, gets most of its energy from the oxygen-dependent metabolism of glucose, and the mitochondrial pyruvate dehydrogenase complex (PDC) plays a key regulatory role during the oxidation of glucose. Pyruvate dehydrogenase kinase (also called PDC kinase or PDK) is a kinase that regulates glucose metabolism by switching off PDC. Four isoforms of PDKs with tissue specific activities have been identified. The metabolisms of neurons and glial cells, especially, those of astroglial cells, are interrelated, and these cells function in an integrated fashion. The energetic coupling between neuronal and astroglial cells is essential to meet the energy requirements of the brain in an efficient way. Accumulating evidence suggests that alterations in the PDKs and/or neuron-astroglia metabolic interactions are associated with the development of several neurological disorders. Here, the authors review the results of recent research efforts that have shed light on the functions of PDKs in the nervous system, particularly on neuron-glia metabolic interactions and neuro-metabolic disorders.     

Neurotrophins Role in Depression Neurobiology: A Review of Basic and Clinical Evidence

Depression is a neuropsychiatric disorder affecting a huge percentage of the active population especially in developed countries. Research has devoted much of its attention to this problematic and many drugs have been developed and are currently prescribed to treat this pathology. Yet, many patients are refractory to the available therapeutic drugs, which mainly act by increasing the levels of the monoamines serotonin and noradrenaline in the synaptic cleft. Even in the cases antidepressants are effective, it is usually observed a delay of a few weeks between the onset of treatment and remission of the clinical symptoms. Additionally, many of these patients who show remission with antidepressant therapy present a relapse of depression upon treatment cessation. Thus research has focused on other possible molecular targets, besides monoamines, underlying depression. Both basic and clinical evidence indicates that depression is associated with several structural and neurochemical changes where the levels of neurotrophins, particularly of brain-derived neurotrophic factor (BDNF), are altered. Antidepressants, as well as other therapeutic strategies, seem to restore these levels. Neuronal atrophy, mostly detected in limbic structures that regulate mood and cognition, like the hippocampus, is observed in depressed patients and in animal behavioural paradigms for depression. Moreover, chronic antidepressant treatment enhances adult hippocampal neurogenesis, supporting the notion that this event underlies antidepressants effects. Here we review some of the preclinical and clinical studies, aimed at disclosing the role of neurotrophins in the pathophysiological mechanisms of depression and the mode of action of antidepressants, which favour the neurotrophic/neurogenic hypothesis.     

Effect of apomorphine and Gabaergic drugs in monkeys pretreated with haloperidol

The behavioural effects of apomorphine and GABAergic drugs alone and in combination were studied in eight monkeys (Cercopithecus aethiops) showing behavioural supersensitivity to dopamine agonists after long-term haloperidol treatment. Apomorphine (0.1–0.5 mg/kg SC) produced an increase in locomotion, repetitive movements of head, limbs and trunk, oral hyperkinesia (licking and chewing) and reactivity. Gamma-acetylenic GABA (GAG, a GABA transaminase inhibitor, 50–100 mg/kg SC) reduced spontaneous activity in two monkeys, but otherwise had no behavioural effect when given alone. Muscimol (a direct GABA receptor agonist, 0.25–1.0 mg/kg SC) caused decreased locomotion, slight ataxia (lack of coordinated movements), and myoclonic jerks at the highest doses, whereas 4,5,6,7-tetrahydroisoazolo-(5,4-c)-pyridin-3-ol (THIP, another GABA receptor agonist, 1.0–10.0 mg/kg SC) produced dose-dependent bradykinesia, dystonia, ataxia, and myoclonic jerks. All three GABA agonists reduced apomorphine-induced locomotion, repetitive movements and reactivity, whereas oral hyperkinesia was unchanged during THIP and slightly decreased by GAG and muscimol. Picrotoxin (a GABA antagonist, 0.4 mg/kg SC) also decreased apomorphine-induced responses, but at the same time produced signs of toxicity, especially vomiting and convulsions. These findings suggest that apomorphine and GABA agonists induce distinct types of behaviour, possibly related to a differential influence on separate dopamine/GABA receptors, and that GABA agonists in relatively high doses counteract apomorphine-induced behaviour with the exception that THIP does not influence oral hyperkinesia. This is consistent with the reported limited therapeutic effect of GABA agonists in tardive dyskinesia.