TL neuro

April 24, 2012

ASPET 2012: Affective Disorder

Filed under: Uncategorized — mtaffe @ 9:55 am

Chuck O’Brien-

-individual differences, power of a SNP
-1983: IND for naltrexone for human, based on suppression of alcohol seeking in rats
-naltrexone did not significantly change abstinence but measures of alcohol quantity reduced
-vivitrol (depot formulation) $800 per injection, monthly schedule…compliance is good though
-naltrexone effect driven by groups w/ high craving, highest family history “dose”…because they respond poorly to regular therapy (placebo groups high drinking compared w/ lower craving, less family history)
-OPRM1: 118 A>;G exon associated w/ increased beta-endorphin affinity
-enriched in Swedish populations Bart et al 2005
-G allele associated w/ increased alcoholism and opiate addiction
-o’Brien showed increased naltrexone response in the G allele subpopulation, Anton replicated in alcoholics (both retrospective analyses of banked blood samples)
-Heilig study- alcohol induced dopamine release (PET) highest in G allele carriers

Mark Geyer
-predicting treatment response in schizophrenia
-NIMH-MATRICS, spurred BigPharma to go after non psychotic, cognitive deficit therapy
MG: rush to clinical trials led to some disappointments, need more work at preclinical level
-overview of pre-pulse inhibition as model of sensory gating
-Braff Geyer and Swerdlow 2001 reviews populations tested for PPI deficits
-not present in ADHD for example
-PPI in rats predicts antipsychotic efficacy in clinical
-NIMH-MAtRICS 2002-2004- pathway for approving cog enhancers
-no treatments found yet…..
-Clozapine seems to have some positive effect on cognition, typical antipsychotics (D2 antagonists) don’t
-low PPI in C57Bl/6j vs 129/SvEv mice
-C57Bl/6j mouse as good model to test antipsychotics or other compounds w/o receptor tautology
-MG rightfully cautions about a popular preclinical approach of examining reversal of an effect caused by another drug. (Think scopolamine model if memory deficits)
-Median split on PPI in humans- clozapine only increases PpI in the low-PPI group, just like mouse strain comparison
-pregabalin study: humans and C57Bl/6j : same median split on baseline PPI, drug works in low but not high PPI subgroups
-low PPI “normal” humans may be a model for testing pro-cognitive drugs?

Kathy Cunningham
-serotonin receptor 2A and 2C homeostasis
-context: treatment for drug relapse
-impulsivity and cue reactivity as mediators of relapse liability
-these two phenotypes are “interlocked”
-KC focus is on cocaine users
-Ersche et al 2910, Moeller at al 2001 for background
-5HT2A antagonists and 5HT2C agonists improve impulsive action and cocaine cue reactivity
-target: “reprogram” the 2A/2C rheostat
-1-choice serial RT task to phenotype rats as high and low quartile for impulsive responding (premature responding, low accuracy)
-cocaine reinstatement uses forced abstinence rather than extinction
-NAcc receptor protein: 2A receptor protein higher in high impulsives, 2C protein levels lower.
-cue reactivity also associated- high reactivity >;;;; high 2A, low 2C in mPF
-Moeller work in cocaine using humans, 5HT2C SNP (loss of function) homozygous have elevated cocaine cue reactivity
-genetic knockdown of 2C in rat- shRNA
-premature responding in 1choice serial RT task higher in knockdown animals
-2A antagonist reversal of this deficit is produced at subthreshold dose for normals.

Rich de la Garza
-individual differences in human stimulant dependence
-he lives in the Phase Ib, Phase II zone
-developing new compounds and repurposing approved meds
-still no approved meds for cocaine or methamphetamine dependence
-large number of cocaine dependent have 20 yr histories, lifetime traumas and/or co-abuse other substances. 50% marijuana, for example
-therefore difficult to find a single medication
-modafinil decreased cocaine use only in non-alcohol comorbid patients
-Dackis et al 2012 showed sex split in efficacy for cocaine dependence
-N-acytl-cisteine for subjective high response to smoked methamphetamine
-NAC reduces high in males but not females
-meth users tend to be white, cocaine users tend to be black
-study (n=8) showed lower desire for methamphetamine primed by IV dose (unpublished)
-HR change is identical, other physiological responses similar
-Race and ethnicity may also contribute to medication response
-disulfiram (Antabuse) also works for cocaine, but effect stronger in high body weight cocaine abusers
-typically don’t do mg/kg dosing in human studies
-Modafinil improves working memory (n-back) in meth-dependent individuals, but only in low-performing part of the sample.
-even after 15-20 yr abuse patterns only some stimulant users exhibit impairment on (a given?) cognitive task
-“craving” is similarly variable, some w/ long history show very little craving
-there will be no magic bullet for addiction
-one size doesn’t fit all

Mike Nader
-leads with Anthony 1994 observation that conditional probability of cocaine dependence only 16%, this would kill any animal model
-advantages of Old World monkeys as the model
-d2-like receptor occupancy correlates with cocaine response rates, declines after a year of cocaine (similar to methylphenidate data shown by Porrino on Sun?)
-12 yr olds w/ in utero cocaine exposure
-similar on D2 measures on PET
-quinpirole-induced yawning higher in the prenatal exposed, correlated with maternal dose
-faster acquisition of cocaine self-admin, but similar intakes during maintenance
-Coc-exposed are more impulsive on delay-discounting
-cocaine-food choice procedure also reveals group differences, perhaps driven by a sub-group within the in utero cocaine exposure group
-reviews their dominant/subordinate story….


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