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1 Any use of the contents of this presentation is authorized, on the condition of informing the author about it and quoting the source. Toute utilisation du contenu de cette présentation est autorisée, à condition d en aviser l auteur et de citer la source.
2 Sex Differences in Drug Addiction: A Translational Perspective W.J. Lynch, Ph.D. Associate Professor of Psychiatry and Neurobehavioral Sciences University of Virginia School of Medicine
3 Initiation of use Impulsive use Relapse Addiction Withdrawal Compulsive use
4 (12-17) Adults (18+) Males Females Adolescents Males Females Current Use Illicit Drugs * * Alcohol * Cigarette * Abuse Illicit Drugs Alcohol * 2.5* * 4.1* Dependence Illicit Drugs.8 0.6* Alcohol * Cigarette
5 (12-17) Adults (18+) Males Females Adolescents Males Females Current Use Illicit Drugs * * Alcohol * Cigarette * Abuse Illicit Drugs Alcohol * 2.5* * 4.1* Dependence Illicit Drugs.8 0.6* Alcohol * Cigarette
6 SOCIOCULTURAL/ BIOLOGICAL Initiation of use Women have accelerated course Women report shorter abstinence periods Relapse Impulsive use Addiction Binge use Withdrawal Compulsive use Women enter treatment sooner
7 Are women less vulnerable to addiction than men? Do women and men differ in the initiation of drug use? Does the progression to addiction differ between men and women? Do men and women differ in treatment outcome?
8 Are women less vulnerable to addiction than men? Do women and men differ in the initiation of drug use? Does the progression to addiction differ between men and women? Do men and women differ in vulnerability to relapse to drug use? In order to examine the biological basis of sex differences in addiction both clinical and preclinical findings will be discussed.
9 Are women less vulnerable to addiction than men? Women have historically had lower rates of drug abuse compared to men Sex differences disappear or reverse among adolescents.
10 Are differences between men and women during the initiation of drug use biologically based? PRECLINICAL STUDIES
11 Animal Models of Addiction: Drug Self-Administration Procedure
12 F > M on acquisition of drug selfadministration -Cocaine (Lynch et al. 1999; Jackson et al. 2006) -Heroin (Lynch et al. 1999) -Nicotine (Donny et al. 2000) -PCP (Carroll et al. 2000) -Methamphetamine (Roth and Carroll 2004) -Cannabinoid (Fattore et al. 2007) -Alcohol (Caihol and Mormede 2001; but see Vivian et al. 2001)
13 Mean Percent of Rats Meeting Acquisition Criterion Females > Males: Acquisition of Drug Self- Administration * Female Male 100 Cocaine 100 Heroin Days Lynch and Carroll 1999
14 Animal models to determine whether sex differences may be due to: Pharmacokinetics Hormonal Influences Neurotransmission
15 Hormonal Influences on Drug Use/Self- Administration In women, the subjective effects of cocaine and other psychostimulants varies with menstrual cycle phase (Terner and de Wit 2006). Estradiol enhances while progesterone reduces the positive subjective effects of cocaine and cigarettes (Evans 2007; Sofouglu et al. 2001; 2004; Lynch and Sofouglu 2010). Estrous cycle dependent changes in cocaine selfadministration in adult rats. Rats with estrogen acquire drug self-administration faster than animals without estrogen.
16 Percent of Group Meeting Acquisition Criterion 100 Cocaine Acquisition SH + VEH 80 Estrogen OVX + EB SH + Tam OVX + VEH * No Estrogen Days (Lynch et al. 2001)
17 Adolescence Hormone transition phase. Apparent vulnerability to initiate use. Adolescents seem to progress more rapidly to dependence after initial use than adults and show higher rates of dependence.
18 Rodent Model of Adolescence Adolescence in rats from postnatal day 28 to 42. Postnatal day 28--Surge in gonadal hormones (GnRH, testosterone and estrogen; Corpechot et al. 1981). In females, vaginal opening occurs on postnatal day 35, and by postnatal day 45, females are randomly cycling (Ojeda et al. 1983). In males, levels of testosterone continue to increase beginning at around postnatal day 35 with the first free sperm appearing around postnatal day 45 (Ojeda et al. 1980). Adult by day 60.
19 Sex Differences in Acquisition of Cocaine Self-Administration Percent group acquisition Females Males * Postnatal day Lynch 2008
20 Number of infusions Final ratio completed Mean Pearson Coefficient Sex Differences in PR Responding for Cocaine 20 Females 20 * * Males Prog Estr Ratio Testo Postnatal day Lynch 2008
21 Percent group acquisition Sex Difference in the Acquisition of Nicotine Self-Administration Percent group acquisition 10 g/kg 5 g/kg Males Females Males Females * Postnatal day Postnatal day Lynch 2009
22 Infusions Sex Differences in PR Responding for Nicotine Infusions Breakpoint g/kg 5 g/kg Males Females * * Postnatal day Postnatal day Lynch 2009
23 Gonadal Hormones and PR Responding for Nicotine Pearson Correlation E P E/P Test Lynch 2009
24 Number of pellets Final ratio completed No Sex Difference in PR responding for Food Females Males Postnatal day 00 Lynch 2008
25 Animal models to determine whether sex differences may be due to: Pharmacokinetics Hormonal Influences Neurotransmission
26 The Reward Pathway prefrontal cortex nucleus accumbens ventral tegmental area
27 Biological or Sociocultural Differences? Biological differences: Pharmacokinetic Hormonal Neurotransmission Sociocultural differences: Drug use opportunity Social constraints Women experience more social disapproval of drug use Women often have sole responsibility of children
28 Do women and men differ in the initiation of drug use? Females are at least equally, if not more, vulnerable during initiation of drug use: Preclinical studies suggest they are at a greater biological vulnerability Estrogen may underlie increased vulnerability Progesterone may protect Sociocultural factors may protect
29 Does the progression to addiction differ between women and men? HUMAN DATA
30 Telescoping effect Females use drugs and alcohol for a shorter period of time before becoming dependent for: - Alcohol (Randall et al. 1999) - Cocaine (Griffin et al. 1989) - Heroin (Hser 1990) - Marijuana (Mezzich et al. 1994)
31 Telescoping effect Females use drugs and alcohol for a shorter period of time before becoming dependent for: - Alcohol (Randall et al. 1999) - Cocaine (Griffin et al. 1989) - Heroin (Hser 1990) - Marijuana (Mezzich et al. 1994) - Gambling (Tavares et al. 2001)
32 Are differences between men and women during the progression to addiction biologically based? PRECLINICAL STUDIES
33 How do you model the transition to addiction in animals? Focus on features central to addiction: Escalation of drug use over time Transition from controlled to uncontrolled use Increased motivation as a result of drug use Increased drug seeking/susceptibility to relapse
34 F>M on escalation of drug use Under extended access conditions female self-administer more: Cocaine (Roth and Carroll 2004; Lynch and Taylor 2004) PCP (Carroll et al. 2005)
35 Discrete Trials Procedure NON- REINFORCED Lever Extension 10 min 5 min Trial REINFORCE D Lever Extension 5 min 10 min Trial Infusion 1 HR 24 HR * 7 days
36 NON- REINFORCED Discrete Trials Procedure Lever Extension 10 min 5 min REINFORCED Trial Lever Extension 5 min 10 min Trial Infusion 1 HR 24 HR * 7 days
37 Diurnal Intake 2 Trials/Hr Dark Phase Light Phase Lynch and Roberts 2004
38 Loss of Diurnal Control, Dysregulation 4 Trials/Hr Dark Phase Light Phase Lynch and Roberts 2004
39 Cocaine Intake (mg/kg) Initial Binge (hr) Females >> Males: Daily Cocaine and Initial Binge Length * * Females Males Lynch and Taylor 2004
40 Infusions Final Ratio Females>>Males: Motivation to Cocaine * * * Baseline Re-test Lynch and Taylor 2004; Sex by Time p<0.05
41 Females>Males: Motivation for Cocaine Following Extended Access Number of infusions Number of infusions Final ratio reached Final ratio reached 20 ExA Females (n=8) ShA Females (n=9) ExA Males (n=6) ShA Males (n=14) * * * Session Session Preliminary findings
42 Biologically Based Differences? Biological differences: Pharmacokinetic--Higher BALs Hormonal Estrogen/Progesterone Neurotransmission--Enhanced DA + Estrogen interactions
43 OVX + Estradiol > OVX + Vehicle: Cocaine Intake Under Extended Access Conditions Number of infusions 100 * OVX + EB OVX + Veh Day Preliminary findings
44 Number of infusions OVX + Estradiol > OVX + Vehicle: Motivation for Cocaine Following Extended Access Final ratio completed OVX + Vehicle OVX + Estradiol 20 ShA: OVX + Vehicle ExA: OVX + Vehicle 20 ShA: OVX + EB * ExA: OVX + EB Session Session 5 Preliminary findings
45 Biologically Based Differences? Biological differences: Pharmacokinetic--Higher BALs Hormonal Estrogen/Progesterone Neurotransmission--Enhanced DA + Estrogen interactions
46 Sex differences in cocaine abusers: SPECT imaging Men Women Cocaine-dependent men: Decreased perfusion in the precentral gyrus, superior and medial frontal gyri, and the anterior cingulate cortex, areas implicated in drug withdrawal and response inhibition. Cocaine-dependent women: Increased perfusion within the posterior cingulate, an area associated with heightened stress responsivity and worse treatment outcome. Tucker et al. 2004
47 Glutamatergic signaling is critical vpfc dopamine dpfc glutamate core NAc shell ventral tegmental area
48 Change from baseline (%) Roles of Dopamine and Glutamate Vary with Stage of Addiction Dopamine > Following ShA Glutamate > Following ExA 50 ShA ExA Dose of SCH Dose of CNQX Preliminary findings
49 Change from baseline (%) 50 Female ShA Male ShA 50 Female ExA Male ExA * * * Dose of SCH Dose of SCH22390
50 Change from baseline (%) 50 Female ShA Male ShA 50 Female ExA Male ExA Dose of CNQX Dose of CNQX
51 Biological or Sociocultural Differences? Biological differences: Pharmacokinetic Hormonal Neurotransmission Sociocultural differences: Difference in seeking medical attention
52 Do women and men differ during the transition to addiction? Females appear to have an increased biological vulnerability during transition to addiction: May result from DA/estrogen interactions, but not the only factor Sociocultural factors may also contribute
53 Do men and women differ in treatment outcome? HUMAN DATA
54 Treatment Behavioral therapies Pharmacotherapies
55 Behavioral Therapies F=M on treatment seeking Despite observations that women have more problems, they do just as well, if not better, than men in treatment. Exception: Nicotine dependence
56 Are differences between men and women during treatment biologically based?
57 How do you model cognitive/behavioral therapy in animals? You can t, but you can examine environmental manipulations: Presence of an alternative non-drug reward Enriched environment Exercise
58 Effect of Aerobic Exercise on Cocaine Seeking in a Rat Model of Relapse Acquisition Binge Self-Administration // 10 days Forced Abstinence 14 days Wheel (2 hrs/day)/no wheel Extinction/Reinstatement 1 day Tissue collection
59 Number of responses Exercise < Sedentary: Cocaine Seeking Behavior Lynch et al Number of responses Sedentary Exercise Last Extinction Reinstatement Last Extinction Reinstatement Extinction session
60 Total ERK (A.U.) Lynch et al perk (A.U) Exercise May Block Neuroadaptations in PFC ERK1 ERK2 tubulin Sedentary ERK1 ERK2 tubulin 80 Exercise Sedentary Sedentary Exercise 3 Exercise perk1 perk2 tubulin 2 Sedentary perk1 perk2 tubulin Exercise Sedentary Exercise * Last Extinction Reinstatement * 0 ERK1 ERK2 0 perk1 perk2
61 Number of responses Effect of Exercise on Cocaine Seeking in Female Rats Sedentary Exercise Extinction session 0 Last Extinction Reinstatement
62 Do women and men differ on treatment outcome? Males and females appear to differ during treatment: Environmental strategies Hormonal influences
63 Gender Differences: Menstrual Cycle NICOTINE CESSATION Greater abstinence when cessation is initiated in the follicular phase. Abstinence rates at 9 weeks post-quit date: All women: 46% Follicular phase quit date: 69% Luteal phase quit date: 29% Franklin et al. 2009
64 Women are not less vulnerable than men SOCIOCULTURAL/ BIOLOGICAL Initiation of use Women have accelerated course Women men Relapse Impulsive use Addiction Binge use Withdrawal Compulsive use Women enter treatment sooner
65 Lab support: Susie Doyle, Ph.D. Richard Morgan, Ph.D. Carolina Ramôa Alexis Peterson Victoria Sanchez Vivian Hofler Courtney King Colin Bond Taylor Powell Kaitlyn Watson Kristen Piehl Florence Breslin, M.S. Acknowledgments: This work was supported: NIDA (R01 DA024716) NIDA (R01 DA supplement) Virginia Youth Tobacco Project Collaborators: Scott Hemby, Ph.D. Marilyn Carroll, Ph.D. Darlene Brunzell, Ph.D.
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