Gender effects following repeated administration of cocaine and alcohol in humans.
ABSTRACT Use of cocaine, alcohol, and the two drugs simultaneously is common and the risk of morbidity and mortality associated with these drugs is widely reported. This double-blind, placebo-controlled, randomized study examined gender differences in response to administration of these drugs alone and in combination.
Current users of cocaine and alcohol (n = 17) who met diagnostic criteria (DSM-IV) for cocaine dependence and alcohol abuse or dependence (not physiologically dependent on alcohol) and who were not seeking treatment for substance use disorders gave voluntary, written, informed consent to participate in three drug administration sessions:1) four doses of intranasal cocaine (1 mg/kg every 30 min) with oral alcohol (1 g/kg following the initial cocaine dose and a second drink at +60 min (120 mg/kg) calculated to maintain a plasma alcohol concentration of approximately 100 mg/dL; 2)four doses of cocaine and alcohol placebo; 3) cocaine placebo and alcohol. Pharmacokinetics were obtained by serial blood sampling, physiological measurements (heart rate and blood pressure) were obtained with automated equipment, and subjective effects were assessed using visual analog scales over 480 min.
Responses to cocaine, alcohol, and cocaine-alcohol were equivalent by gender for most measurements. Women had higher heart rates following alcohol administration (p = .02). Women consistently reported higher ratings for "Feel Good:' a measure of overall mental/physical well-being, for all study conditions, reaching statistical significance for cocaine (p = .05) and approaching significance for alcohol administration (p = .1).
Women showed equivalent responses to drug administration with the exception of perception of well-being, which was significantly increased for women. These findings may have implications for differential risk for acute and chronic toxicity in women.
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ABSTRACT: The patterns of cocaine use differ between men and women. Women are more likely and take shorter time to become cocaine dependent after initial use of cocaine. Behavioral sensitization is an animal model that allows us to explore plastic changes with repeated cocaine use and to understand factors influencing this process, which may be involved in addition. This dissertation is trying to further characterize cocaine sensitization in females and to examine the role of ascending midbrain dopaminergic system in sex differences in cocaine sensitization. This dissertation first reports that cocaine sensitization promotes the acquisition of cocaine self-administration in females, suggesting the reinforcing effect is enhanced as a result of sensitization in females as in males. In addition, cocaine sensitization is suggested to be associated with enhanced midbrain dopamine neuron reactivity in males, which has not yet been tested in nucleus accumbens in vitro. This dissertation for the first time show that enhanced stimulated dopamine release in vitro from nucleus accumbens as well as striatum after cocaine experience in females, suggesting the same hypothesis is applicable in females as in males. Furthermore, estradiol treatment enhances behavioral sensitization in females when it is given with repeated cocaine treatment as predicted. More importantly, by comparing the cocaine-induced behavioral activation post sensitization on challenge day with or without additional estradiol treatment, acute estradiol treatment is first found to enhance cocaine-induced behavioral activation on cocaine-sensitized rats, suggesting estradiol produces an independent activating effect on sensitized neural circuits to affect behavioral sensitization. Lastly, cocaine sensitization and associated changes of dopamine neuron reactivity in the striatum are first compared between males and females in one experiment. Repeated cocaine treatment results in sexually dimorphic patterns of both cocaine sensitization and cross-sensitization to amphetamine. Accordingly, neuroadaptive changes of amphetamine-induced dopamine efflux in the striatum associated with sensitization also exhibit a sexually dimorphic pattern. It suggests sex differences in behavioral sensitization might be associated with sex differences in DA neuron reactivity in the striatum. This work improves our understanding of gender differences in patterns of cocaine abuse and has important implications for the development of gender-specific therapies in cocaine addiction. Ph.D. Psychology University of Michigan, Horace H. Rackham School of Graduate Studies http://deepblue.lib.umich.edu/bitstream/2027.42/61686/1/zhaowei_1.pdf
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ABSTRACT: Aims: Gender-related differences in the pharmacological effects of addictive drug are an emerging issue. This review examines gender differences in both pharmacokinetic and pharmacodynamic aspects of alcohol and cocaine intake since they cause complex pharmacological interactions, not least the formation of the active metabolite cocaethylene. Methods: The MEDLINE database was searched from 1990 to 2014 in order to find articles related to gender differences in alcohol, cocaine and cocaethylene pharmacokinetics and pharmacodynamics. Results: Besides the well known gender differences in alcohol pharmacokinetics, women appear more susceptible to alcohol-mediated brain damage and seem to suffer more than men the acute effects of alcohol on hepatic and gonadal hormones. No significant gender differences have been found in the pharmacokinetics of cocaine taken alone; yet, in women pharmacological sensitivity to the drug seems to vary in relation to menstrual cycle; moreover, progesterone attenuates subjective effects of cocaine in women. Higher ratings at a subjective measure of mental/physical well-being have been observed in women when given cocaine and alcohol, alone or in combination. Finally, among subjects dependent on both alcohol and cocaine, men only benefit from naltrexone, whereas women used more cocaine during the trial and were less compliant to therapy than men. Conclusions: The observed subtle gender differences in the pharmacokinetics and pharmacodynamics of both alcohol and cocaine may have no subtle influence on the natural history of the co-abuse of the two drugs by women.Pharmacological Research 09/2014; 87. DOI:10.1016/j.phrs.2014.06.009 · 3.98 Impact Factor
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ABSTRACT: This study explores the hypotheses that: (1) ethanol will interact with dl-Methylphenidate (MPH) to enantioselectively elevate plasma d-MPH, and primarily yield l-ethylphenidate as a transesterification metabolite; (2) women will exhibit lower relative bioavailability of MPH than men; and (3) sex-dependent differences in subjective effects will exist. dl-MPH HCl (0.3 mg/kg) was administered orally 30 min before ethanol, 30 min after ethanol (0.6 gm/kg), or without ethanol, in a randomized, normal subject three-way crossover study of 10 men and 10 women. Pharmacokinetic parameters were compared. Subjective effects were recorded using visual analog scales. One subject was a novel poor MPH metabolizer whose data were analyzed separately. Ethanol after or before MPH significantly (P<0.0001) elevated the geometric mean for the maximum d-MPH plasma concentration (C(max) (+/-SD)) from 15.3 (3.37) ng/ml to 21.5 (6.81) and 21.4 (4.86), respectively, and raised the corresponding geometric mean for the area under the concentration-time curve values from 82.9 (21.7) ng ml/h to 105.2 (23.5) and 102.9 (19.2). l-MPH was present in plasma only at 1-3% of the concentration of d-MPH, except in the poor metabolizer where l-MPH exceeded that of d-MPH. The metabolite l-ethylphenidate frequently exceeded 1 ng/ml in plasma, whereas d-ethylphenidate was detected only in low pg/ml concentrations. Women reported a significantly greater stimulant effect than men when questioned "Do you feel any drug effect?" (P<0.05), in spite of lower mean plasma d-MPH area under the response-time curves in women. Ethanol elevates plasma d-MPH C(max) and area under the concentration-time curve by approximately 40% and 25%, respectively. If the poor metabolizer of MPH proves to be a distinct phenotype, determining the genetic mechanism may be of value for individualizing drug therapy. The more pronounced stimulant effects experienced by women have sex-based abuse liability implications.Clinical Pharmacology & Therapeutics 04/2007; 81(3):346-53. DOI:10.1038/sj.clpt.6100082 · 7.39 Impact Factor