Interactions among ovarian hormones and time of testing on behavioral sensitization and cocaine self-administration

Abstract

Ovarian hormones play a role in the use of drugs of abuse in women. In female rats estradiol has been shown to enhance acquisition of cocaine self-administration and behavioral sensitization induced by repeated cocaine treatment. Experiments were conducted to determine the effects of estradiol and/or progesterone on cocaine self-administration and behavioral sensitization to cocaine (10mg/kg; in animals with unilateral 6-hydroxydopamine lesions). Five groups of ovariectomized females were tested: (1) oil vehicle; (2) estradiol (E); (3) progesterone (P); (4) estradiol and progesterone given concurrently (EPC); (5) estradiol and progesterone given sequentially (EPS: 3 days of estradiol, 1 day progesterone, 1 day oil). All animals were tested during the dark phase of the light:dark cycle at ZT1600 and ZT2000-2100. Behavioral sensitization results: there was substantial conditioned turning throughout the habituation periods, and all animals exhibited behavioral sensitization with repeated cocaine treatment. Multivariate analysis indicated a significant effect of hormone treatment, time of day and day of testing. When individual groups were compared, however, only at ZT1600 did the E-treated and the EPS-treated animals show a trend (p<0.06) for greater behavioral sensitization to cocaine relative to the oil-treated animals. Self-administration results: all groups showed rapid acquisition of cocaine self-administration at 0.3 mg/kg/infusion, so we did not see an effect of ovarian hormones on acquisition, or a difference between groups tested at ZT1600 versus ZT2100 (p<0.05). There was, however, enhanced total intake of cocaine at 0.75 mg/kg/infusion in the E and the EPS groups. Concurrent administration of progesterone with estradiol counteracted the effect of estradiol on cocaine intake at 0.75 mg/kg/infusion, while progesterone alone did not enhance cocaine self-administration.

Increasing Progesterone Levels Are Associated With Smoking Abstinence Among Free-Cycling Women Smokers Who Receive Brief Pharmacotherapy

“…The results of the present study were not consistent with the tentatively hypothesized negative relationship between estradiol level and abstinence, which was based primarily on preclinical research suggesting estradiol may have a facilitative effect on cocaine related sensitization, self-administration and relapse/reinstatement. [51][52][53][54][55][56][57] Since there is no preclinical research examining the effects of estradiol in nicotinereinforced behavior (e.g., self-administration), the lack of association between estradiol and abstinence observed here is consistent with the possibility that estradiol may not have uniform effects across different substances of abuse.…”

Sex differences in drug abuse

“…We have recently confirmed this finding, and shown that progesterone alone does not affect cocaine self-administration, but that progesterone enhances cocaine intake in EB primed OVX rats [141]. Taken together, a wealth of data now indicate that ovarian hormones contribute to sex differences in cocaine self-administration and that estradiol in particular is a key factor influencing the reinforcing effects of cocaine in female rats.…”

Protracted time-dependent increases in cocaine-seeking behavior during cocaine withdrawal in female relative to male rats

“…However, when cocaine dose per infusion is under subject control, estrus females exhibit increased selection of higher dose and decreased selection of lower dose relative to males and females in other estrous cycle phases . Similarly, chronic estrogen treatments increase operant responding and intake of cocaine during self-administration under a variety of conditions (Hu et al 2004;Jackson et al 2006;Yang et al 2007; see however, Grimm and See 1997). It is interesting to note that when ovariectomized female rats are withdrawn from extended access to cocaine, there is a transient decline in progressive ratio responding that can be blocked by chronic estrogen treatments .…”