Regulation of cocaine self-administration in humans: Lack of evidence for loading and maintenance phases

Background

In rodents, cocaine self-administration under a fixed-ratio schedule and with timeout intervals limited to the duration of the infusions is characterized by an initial burst of drug intake (loading) followed by more stable infusion rates (maintenance). We sought to examine whether similar phases might characterize self-regulated cocaine use in humans.

Methods

31 Non-treatment seeking, cocaine dependent subjects participated in three (8, 16, and 32 mg/70 kg/infusion), self-regulated, 2-h cocaine self-administration sessions under a fixed-ratio 1, 5-min timeout schedule. Data were assessed for visual (e.g., by graphs of cumulative numbers of infusions) and statistical evidence of change in phase (by step-function analyses of individual infusion rates).

Results

Graphs of cumulative infusions over time suggested a single, linear rate of self-administration over 2 h at each cocaine dose. Statistical analyses of infusion data by generalized estimating equation (GEE) models also failed to support a loading/maintenance pattern (suggesting, if anything, the possibility of increasing infusion rates over time).

Conclusions

Our findings fail to support the existence of distinct loading and maintenance phases of self-regulated cocaine administration in humans at behaviorally relevant doses. Several factors may account for these observations including differences between humans and rodents in self-regulated drug intake.     

Risk factors for cocaine-induced paranoia in cocaine-dependent sibling pairs

OBJECTIVE: Cocaine-induced paranoia (CIP), an irrational intense suspicion of others, is a common manifestation of cocaine dependence. Both environmental and genetic factors are thought to play a role, but the specific nature of such contributions is poorly understood. METHODS: Demographic, diagnostic, and cocaine-use data were obtained from 420 cocaine-dependent, genetically confirmed, full-sibling pairs (N=840 subjects) interviewed with the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA). Probands with and without CIP were compared; then, factors associated with sibling CIP status were analyzed by logistic regression. Alcohol dependence, a known heritable phenotype, was analyzed as a positive control. RESULTS: Of 420 probands, 273 (65%) experienced CIP. Probands with CIP were more severely dependent upon cocaine, had an earlier age of onset, were more likely to smoke cocaine, and used cocaine less frequently during the preceding year. Independent analyses of siblings replicated two of the former (i.e., dependence severity and age of onset). Probands with CIP also had a non-significantly higher proportion of siblings with the trait (66% versus 59%). Probands with concurrent alcohol dependence were confirmed to have significantly higher rates of alcoholism among their siblings. CONCLUSIONS: Severity of cocaine dependence and age of onset appear to be important risk factors for CIP. Concordance for CIP between siblings did not emerge as significant in our analyses.     

Genome-wide meta-analysis of alcohol use disorder in East Asians

Alcohol use disorder (AUD) is a leading cause of death and disability worldwide. Genome-wide association studies (GWAS) have identified ~30 AUD risk genes in European populations, but many fewer in East Asians. We conducted GWAS and genome-wide meta-analysis of AUD in 13,551 subjects with East Asian ancestry, using published summary data and newly genotyped data from five cohorts: (1) electronic health record (EHR)-diagnosed AUD in the Million Veteran Program (MVP) sample; (2) DSM-IV diagnosed alcohol dependence (AD) in a Han Chinese–GSA (array) cohort; (3) AD in a Han Chinese–Cyto (array) cohort; and (4) two AD Thai cohorts. The MVP and Thai samples included newly genotyped subjects from ongoing recruitment. In total, 2254 cases and 11,297 controls were analyzed. An AUD polygenic risk score was analyzed in an independent sample with 4464 East Asians (Genetic Epidemiology Research in Adult Health and Aging (GERA)). Phenotypes from survey data and ICD-9-CM diagnoses were tested for association with the AUD PRS. Two risk loci were detected: the well-known functional variant rs1229984 in ADH1B and rs3782886 in BRAP (near the ALDH2 gene locus) are the lead variants. AUD PRS was significantly associated with days per week of alcohol consumption (beta = 0.43, SE = 0.067, p = 2.47 × 10⁻¹⁰) and nominally associated with pack years of smoking (beta = 0.09, SE = 0.05, p = 4.52 × 10⁻²) and ever vs. never smoking (beta = 0.06, SE = 0.02, p = 1.14 × 10⁻²). This is the largest GWAS of AUD in East Asians to date. Building on previous findings, we were able to analyze pleiotropy, but did not identify any new risk regions, underscoring the importance of recruiting additional East Asian subjects for alcohol GWAS.Subject terms: Addiction, Genetics     

Dopamine beta-hydroxylase gene (DbetaH) -1021C-->T influences self-reported paranoia during cocaine self-administration.

BACKGROUND: Variation in the gene for dopamine beta-hydroxylase (DbetaH) has been reported to associate with cocaine-induced paranoia as assessed by retrospective self-report. This association has yet to be tested prospectively. METHODS: Visual analog scale (VAS) ratings of paranoia were obtained in 31 cocaine users during three cocaine self-administration sessions (8, 16, and 32 mg/70 kg). Pharmacogenetic interactions between cocaine and a putative functional polymorphism in DbetaH (-1021C-->T) were assessed. RESULTS: VAS self-ratings showed significant or trend-level interactions of genotype and time during each session (p = .004, .09 and .003, respectively) with TT homozygotes endorsing greater paranoia over time than either CT or CC individuals. Interactions were significant at all doses in African Americans (n = 19; p = .02, .04 and .05). No other demographic or experimental variable distinguished genotypic groups. CONCLUSIONS: Results indicate that individuals homozygous for the 'very low-activity' T allele at DbetaH -1021C-->T show an increased propensity to paranoia over time during cocaine self-administration.