Rescue of Infralimbic mGluR2 Deficit Restores Control Over Drug-Seeking Behavior in Alcohol Dependence.

Rescue of Infralimbic mGluR2 Deficit Restores Control Over Drug-Seeking Behavior in Alcohol Dependence.

Filed under: Addiction Rehab

J Neurosci. 2013 Feb 13; 33(7): 2794-806
Meinhardt MW, Hansson AC, Perreau-Lenz S, Bauder-Wenz C, Stählin O, Heilig M, Harper C, Drescher KU, Spanagel R, Sommer WH

A key deficit in alcohol dependence is disrupted prefrontal function leading to excessive alcohol seeking, but the molecular events underlying the emergence of addictive responses remain unknown. Here we show by convergent transcriptome analysis that the pyramidal neurons of the infralimbic cortex are particularly vulnerable for the long-term effects of chronic intermittent ethanol intoxication. These neurons exhibit a pronounced deficit in metabotropic glutamate receptor subtype 2 (mGluR(2)). Also, alcohol-dependent rats do not respond to mGluR(2/3) agonist treatment with reducing extracellular glutamate levels in the nucleus accumbens. Together these data imply a loss of autoreceptor feedback control. Alcohol-dependent rats show escalation of ethanol seeking, which was abolished by restoring mGluR(2) expression in the infralimbic cortex via viral-mediated gene transfer. Human anterior cingulate cortex from alcoholic patients shows a significant reduction in mGluR(2) transcripts compared to control subjects, suggesting that mGluR(2) loss in the rodent and human corticoaccumbal neurocircuitry may be a major consequence of alcohol dependence and a key pathophysiological mechanism mediating increased propensity to relapse. Normalization of mGluR(2) function within this brain circuit may be of therapeutic value.
HubMed – addiction

Role of metabotropic glutamate receptor 5 signaling and homer in oxygen glucose deprivation-mediated astrocyte apoptosis.

Filed under: Addiction Rehab

Mol Brain. 2013 Feb 14; 6(1): 9
Paquet M, Ribeiro FM, Guadagno J, Esseltine JL, Ferguson SS, Cregan SP

ABSTRACT: BACKGROUND: Group I metabotropic glutamate receptors (mGluR) are coupled via Galphaq/11 to the activation of phospholipase Cbeta, which hydrolyzes membrane phospholipids to form inositol 1,4,5 trisphosphate and diacylglycerol. In addition to functioning as neurotransmitter receptors to modulate synaptic activity, pathological mGluR5 signaling has been implicated in a number of disease processes including Fragile X, amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, epilepsy, and drug addiction. The expression of mGluR5 in astrocytes has been shown to be increased in several acute and chronic neurodegenerative conditions, but little is known about the functional relevance of mGluR5 up-regulation in astrocytes following injury. RESULTS: In the current study, we investigated primary mouse cortical astrocyte cell death in response to oxygen glucose deprivation (OGD) and found that OGD induced both necrotic and apoptotic cell death of astrocytes. OGD resulted in an increase in astrocytic mGluR5 protein expression, inositol phosphate formation and extracellular regulated kinase (ERK1/2) phosphorylation, but only inositol phosphate formation was blocked with the mGluR5 selective antagonist MPEP. Cortical astrocytes derived from mGluR5 knockout mice exhibited resistance to OGD-stimulated apoptosis, but a lack of mGluR5 expression did not confer protection against necrotic cell death. The antagonism of the inositol 1,4,5 trisphosphate receptor also reduced apoptotic cell death in wild-type astrocytes, but did not provide any additional protection to astrocytes derived from mGluR5 null mice. Moreover, the disruption of Homer protein interactions with mGluR5 also reduced astrocyte apoptosis. CONCLUSION: Taken together these observations indicated that mGluR5 up-regulation contributed selectively to the apoptosis of astrocytes via the activation of phospholipase C and the release of calcium from intracellular stores as well as via the association with Homer proteins.
HubMed – addiction

Atrial Natriuretic Peptide, Arginine Vasopressin Peptide and Cortisol Serum Levels in Opiate-Dependent Patients.

Filed under: Addiction Rehab

Neuropsychobiology. 2013 Feb 9; 67(2): 111-115
Glahn A, Heberlein A, Dürsteler-Macfarland KM, Lenz B, Frieling H, Gröschl M, Wiesbeck GA, Kornhuber J, Bönsch D, Bleich S, Hillemacher T

Preclinical studies suggest that chronic drug abuse profoundly alters stress-responsive systems. The best studied of the stress-responsive systems in humans is the hypothalamic-pituitary-adrenal (HPA) axis. Apart from cortisol, arginine vasopressin peptide (AVP), and atrial natriuretic peptide (ANP) are known to directly impact upon the HPA axis in addictive behavior. We investigated alterations in ANP, AVP and cortisol serum levels in opiate-dependent patients who received diacetylmorphine treatment within a structured opiate maintenance program. ANP serum levels were significantly increased in opiate-dependent patients as compared to healthy controls, whereas AVP and cortisol serum levels were reduced. The ANP, AVP and cortisol serum levels were not significantly associated with the psychometric dimensions of heroin craving. In conclusion, chronic drug abuse profoundly alters stress-responsive systems like the HPA axis. Alterations of AVP, ANP and cortisol appear to constitute an important component in the neurobiology of opiate-dependent patients.
HubMed – addiction

Reductions in non-medical prescription opioid use among adults in Ontario, Canada: are recent policy interventions working?

Filed under: Addiction Rehab

Subst Abuse Treat Prev Policy. 2013 Feb 14; 8(1): 7
Fischer B, Ialomiteanu A, Kurdyak P, Mann RE, Rehm J

ABSTRACT: BACKGROUND: Non-medical prescription opioid use (NMPOU) and prescription opioid (PO) related harms have become major substance use and public health problems in North America, the region with the world’s highest PO use levels. In Ontario, Canada’s most populous province, NMPOU rates, PO-related treatment admissions and accidental mortality have risen sharply in recent years. A series of recent policy interventions from governmental and non-governmental entities to stem PO-related problems have been implemented since 2010. FINDINGS: We compared the prevalence of NMPOU in the Ontario general adult population (18 years+) in 2010 and 2011 based on data from the ‘Centre for Addiction and Mental Health (CAMH) Monitor’ (CM), a long-standing annual telephone interview-based representative population survey of substance use and health indicators. While ‘any PO use’ (in past year) changed non-significantly from 26.6% to 23.9% (Chi2 =2.511; df = 1; p = 0.113), NMPOU decreased significantly from 7.7% to 4.0% (Chi2 =14.786; df = 1; p < 0.001) between 2010 and 2011. Over-time changes varied by age group but not by sex. CONCLUSIONS: The observed substantial decrease in NMPOU in the Ontario adult population could be related to recent policy interventions, alongside extensive media reporting, focusing on NMPOU and PO-related harms, and may mean that these interventions have shown initial effects. However, other factors could have been involved. Thus, it is necessary to systematically examine whether the observed changes will be sustained, and whether other key PO-related harm indicators (e.g., treatment admissions, accidental mortality) change correspondingly in order to more systematically assess the impact of the policy measures. HubMed – addiction

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