The effects of oral micronized progesterone on smoked cocaine self-administration in women

There are currently no FDA-approved pharmacotherapies for cocaine abuse. Converging preclinical and clinical evidence indicates that progesterone may have potential as a treatment for cocaine-abusing women, who represent a growing portion of cocaine users. We have previously shown that oral progesterone reduced the positive subjective effects of cocaine in female cocaine users during the follicular phase of the menstrual cycle, when endogenous progesterone levels were low. To extend these findings, the present study assessed the effects of oral progesterone (150 mg BID) administered during the follicular phase on smoked cocaine self-administration in women relative to the normal follicular and luteal phases. Healthy, non-treatment seeking female cocaine smokers (N = 10) underwent three 4-day inpatient stays, during: 1) a normal follicular phase; 2) a normal luteal phase; and 3) a follicular phase when oral progesterone was administered. During each stay, participants completed 4 self-administration sessions in which they first smoked a “sample” dose of cocaine (0, 12, 25 or 50 mg) and then had 5 opportunities at 14-minute intervals to self-administer that dose at a cost of $5 per dose. Expected cocaine dose effects on self-administration, subjective effects, and cardiovascular effects were observed. However, there was no effect of oral progesterone administration or menstrual cycle phase on cocaine self-administration. Thus, oral progesterone was not effective in reducing cocaine use in women under the current conditions. However, based on previous literature, further research assessing the role of oral progesterone for the treatment of cocaine dependence in women is warranted.     

Does the response to cocaine differ as a function of sex or hormonal status in human and non-human primates?

Stimulant abuse continues to be a growing problem among women. Over the last 10-15 years, an increasing number of studies have focused on factors that may be implicated in stimulant abuse in women as compared to men, including the role of hormonal fluctuations across the menstrual cycle. Numerous preclinical studies have documented that female rodents are more sensitive than male rodents to the behavioral effects of stimulant administration and the hormone estradiol is involved in the enhanced response to stimulants observed in females. In contrast, fewer studies have been conducted in humans and non-human primates addressing the role of sex and gonadal hormones on the effects of cocaine. This review paper presents a recent update on data collected in our Human Cocaine Challenge Laboratory and our Non-human Primate Laboratory, including analysis of cocaine pharmacokinetics, sex differences, the menstrual cycle, and the role of progesterone in modulating the response to cocaine. Our studies indicate that there is minimal evidence that the response to intranasal cocaine varies across the menstrual cycle or between men and women. In contrast, the response to smoked cocaine is greater in the follicular phase than the luteal phase and differences between men and women generally only emerge when men are compared to women in the luteal phase. In terms of potential hormonal mechanisms for these differences, the hormone progesterone attenuates the subjective response to cocaine. With respect to cocaine self-administration, there are minimal changes across the menstrual cycle in both humans and non-human primates. Thus, there is converging evidence across a range of species that the behavioral effects of cocaine (1) differ between males and females, (2) differ in relation to hormonal fluctuations, (3) can be attenuated by progesterone (at least in females), and (4) do not appear to be related to differences in cocaine pharmacokinetics.     

Progesterone attenuates cocaine-induced responses

In this review, we summarize literature focused on how progesterone alters cocaine-induced psychomotor, reinforcement, and physiological responses. Clinical studies suggest that progesterone attenuates the subjective effects of cocaine. Similarly, preclinical studies have demonstrated that cocaine-induced reward and psychomotor responses are attenuated after progesterone administration. In rats progesterone also reduces the reinforcement effects of cocaine attenuates acquisition, escalation, reinstatement of cocaine self-administration, and cocaine-seeking behaviors. Progesterone also counteracts the facilitatory effects of estrogen on cocaine self-administration and psychomotor activation. These findings suggest that progesterone has a potential in clinical applications as a treatment for cocaine addiction. Constantly changing progesterone serum levels in female humans and rats affect the female's reinforcement responses to cocaine and may in part contribute to the known sex differences in cocaine responses.     

Gonadal hormones provide the biological basis for sex differences in behavioral responses to cocaine

Both clinical and rodent studies show sexually dimorphic patterns in the behavioral response to cocaine in all phases of the addiction process (induction, maintenance, and relapse). Clinical and rodent studies also indicate that hormonal fluctuations during the menstrual/estrous cycle modulate cocaine-induced subjective effects in women and locomotor activity in female rats. Evidence suggests that gonadal hormones underlie these observed differences and could be the biological basis of sex-specific differences in cocaine addiction. To study the effects of gonadal hormones on cocaine-induced activity, two approaches have been used. First, studies have examined the role of endogenous hormones through gonadectomy (GDX) and side-by-side comparisons with intact rats. Second, the individual contributions of testosterone, progesterone, and estrogen have been determined by hormone replacement in GDX rats. In this review, we discuss gonadal hormones as the biological basis for the behavioral responses to cocaine, and the clinical implications of these findings.     

Hormones, nicotine, and cocaine: Clinical studies

Nicotine and cocaine each stimulate hypothalamic-pituitary-adrenal and -gonadal axis hormones, and there is increasing evidence that the hormonal milieu may modulate the abuse-related effects of these drugs. This review summarizes some clinical studies of the acute effects of cigarette smoking or IV cocaine on plasma drug and hormone levels and subjective effects ratings. The temporal covariance between these dependent measures was assessed with a rapid (2 min) sampling procedure in nicotine-dependent volunteers or current cocaine users. Cigarette smoking and IV cocaine each stimulated a rapid increase in LH and ACTH, followed by gradual increases in cortisol and DHEA. Positive subjective effects ratings increased immediately after initiation of cigarette smoking or IV cocaine administration. However, in contrast to cocaine's sustained positive effects (< 20 min), ratings of “high” and “rush” began to decrease within one or two puffs of a high-nicotine cigarette while nicotine levels were increasing. Peak nicotine levels increased progressively after each of three successive cigarettes smoked at 60 min intervals, but the magnitude of the subjective effects ratings and peak ACTH and cortisol levels diminished. Only DHEA increased consistently after successive cigarettes. The possible influence of neuroactive hormones on nicotine dependence and cocaine abuse and the implications for treatment of these addictive disorders are discussed.     

Impulsivity as a determinant and consequence of drug use: a review of underlying processes

Impulsive behaviors are closely linked to drug use and abuse, both as contributors to use and as consequences of use. Trait impulsivity is an important determinant of drug use during development, and in adults momentary 'state' increases in impulsive behavior may increase the likelihood of drug use, especially in individuals attempting to abstain. Conversely, acute and chronic effects of drug use may increase impulsive behaviors, which may in turn facilitate further drug use. However, these effects depend on the behavioral measure used to assess impulsivity. This article reviews data from controlled studies investigating different measures of impulsive behaviors, including delay discounting, behavioral inhibition and a newly proposed measure of inattention. Our findings support the hypothesis that drugs of abuse alter performance across independent behavioral measures of impulsivity. The findings lay the groundwork for studying the cognitive and neurobiological substrates of impulsivity, and for future studies on the role of impulsive behavior as both facilitator and a result of drug use.     

Heritable variation in locomotion,reward sensitivity and impulsive behaviors in a genetically diverse inbred mouse panel

Drugs of abuse, including alcohol and stimulants like cocaine, produce effects that are subject to individual variability, and genetic variation accounts for at least a portion of those differences. Notably, research in both animal models and human subjects point toward reward sensitivity and impulsivity as being trait characteristics that predict relatively greater positive subjective responses to stimulant drugs. Here we describe use of the eight collaborative cross (CC) founder strains and 38 (reversal learning) or 10 (all other tests) CC strains to examine the heritability of reward sensitivity and impulsivity traits, as well as genetic correlations between these measures and existing addiction-related phenotypes. Strains were all tested for activity in an open field and reward sensitivity (intake of chocolate BOOST®). Mice were then divided into two counterbalanced groups and underwent reversal learning (impulsive action and waiting impulsivity) or delay discounting (impulsive choice). CC and founder mice show significant heritability for impulsive action, impulsive choice, waiting impulsivity, locomotor activity, and reward sensitivity, with each impulsive phenotype determined to be non-correlating, independent traits. This research was conducted within the broader, inter-laboratory effort of the Center for Systems Neurogenetics of Addiction (CSNA) to characterize CC and DO mice for multiple, cocaine abuse related traits. These data will facilitate the discovery of genetic correlations between predictive traits, which will then guide discovery of genes and genetic variants that contribute to addictive behaviors.     

Progesterone's effects on the psychology of disease avoidance: support for the compensatory behavioral prophylaxis hypothesis

In the human menstrual cycle, luteal phase immunomodulation prevents the maternal immune system from attacking the half-foreign blastocyst should conception occur, thereby facilitating implantation and development. However, tolerance of the conceptus comes at the cost of increased vulnerability to infection. The compensatory behavioral prophylaxis hypothesis (Fessler, 2001; Fessler & Navarrete, 2003) holds that evolved psychological mechanisms enhance avoidance of potential contaminants during periods of reproductive immunomodulation so as to decrease the likelihood of infection. Because such immunomodulation is triggered by progesterone, this hormone is predicted to correspondingly enhance behavioral prophylaxis and the motivational states underlying it. We investigated specific domains of disease avoidance psychology in a nonclinical sample of women (n = 120) by measuring salivary progesterone in naturally cycling women. We find that progesterone correlates directly with the degree to which women report emotions, thoughts, and behaviors consonant with enhanced prophylaxis.     

Interaction of the tachykinin NK3 receptor agonist senktide with behavioral effects of cocaine in marmosets (Callithrix penicillata)

Brain neuropeptide transmitters of the tachykinin family are involved in the organization of many behaviors. However, little is known about their contribution to the behavioral effects of drugs of abuse. Recently, antagonism of the tachykinin NK3-receptor (NK3-R), one of the three tachykinin receptors in the brain, was shown to attenuate the acute and chronic behavioral effects of cocaine in rats and the acute effects in non-human primates. In order to expand these findings we investigated the effects of the NK3-R agonist, succinyl-[Asp6, Me-Phe8]SP(6-11) (senktide), on the acute behavioral effects of cocaine in marmoset monkeys (Callithrix penicillata) using a figure-eight maze procedure. Animals were pretreated with senktide (0, 0.1, 0.2, 0.4 mg/kg, s.c.), and received either a treatment with cocaine (10 mg/kg) or saline (i.p.). Cocaine increased locomotor activity and the duration of aerial scanning behavior, but reduced exploratory activity, bodycare activity, the frequency of aerial scanning, and terrestrial glance behavior. Senktide blocked the effects of cocaine on locomotor activity, but enhanced the cocaine effects on exploratory activity, aerial scanning frequency, and terrestrial glance behavior. Senktide alone did not significantly influence monkey behavior in this study. These data expand previous findings suggesting a complex role of the NK3-R in the acute behavioral effects of cocaine in non-human primates.     

Activity and impulsive action are controlled by different genetic and environmental factors

Both impulsivity in operant tasks and locomotor activity in a novel open field are known to predict the development of addiction-related behavior in rodents. In this study, we investigated to what extent impulsivity in the five-choice serial reaction time task and various measures of novelty exploration are controlled by shared genetic and environmental factors in 12 different inbred mouse strains. No genetic correlation was observed between the level of impulsivity and levels of activity, a low correlation was observed with traditional measures of anxiety-like behavior (impulsive strains tend to be less anxious) and a highly significant correlation was found between impulsivity and specific aspects of movement. Furthermore, we found that impulsivity and all measures of novelty exploration were under control of different environmental factors. Interestingly, in the dorsal medial prefrontal cortex, a brain region involved in impulsivity and activity in novelty exploration tests; these behavioral measures correlated with the expression of different genes (respectively, Frzb , Snx5, BC056474 and the previously identified Glo1 ). Taken together, our study shows that impulsivity and activity in novelty exploration tests are genetically and environmentally distinct, suggesting that mouse models of these behaviors provide complementary insights into the development of substance abuse disorder.     

Estradiol and mental rotation: Relation to dimensionality,difficulty, or angular disparity?

Several studies have reported that performance on spatial rotation tests is better at menses than at high estradiol phases of the menstrual cycle in women. These effects are debated because nearly all reports of menstrual cycle variability have relied on a single test, the Mental Rotations Test (MRT, Vandenberg and Kuse, 1978). In the present study, we investigated key features of the MRT that might be responsible for its association with estradiol levels. We hypothesized that associations could be demonstrated for other tasks that share the same characteristics. Forty-four women ages 20–38 years, matched on education and general ability, were assessed at low (n = 24) or high (n = 20) estradiol stages of the menstrual cycle on a set of spatial tests that varied in dimensionality, plane of rotation, angular disparity, and effortfulness. Saliva was used to quantify estradiol and progesterone. Low estradiol was found to be associated with significantly better accuracy on the MRT and also on a mental rotation task that required large angles of rotation but employed only two-dimensional object representations and rotations limited to the picture plane. In contrast, a task using identical stimuli that required only small angles of rotation did not show an estradiol effect. A group difference also was seen on a test of perceptual closure. The results confirm that the estradiol effect is not limited to the MRT, and identify the rotational element, but also aspects of figural perception, as possible processes that may be responsive to estrogens. These findings advance our understanding by showing an association between estradiol and discrete spatial processes. Implications for understanding the origins of the robust sex difference commonly observed on the MRT are discussed.     

Temporal effects of estrogen and progesterone on behavioral and endocrinological responses to acute cocaine administration.

Estrogen and progesterone have been postulated to play a key role modulating cocaine-induced behavioral and neurochemical activation in female rats. This study investigated the temporal relationship between estrogen and progesterone in the modulation of cocaine-induced behavioral alterations. Ovariectomized Fischer rats received s.c. injections of estradiol benzoate 48 hr prior to cocaine or saline treatment and one s.c. injection of progesterone concurrently or 1, 4, 20, 24, 30, 44 or 48 hr after estrogen treatment. Forty-eight hours after estrogen treatment rats received either a single i.p. injection of 15 mg/kg of cocaine or 0.9% saline. Overall, cocaine induced increases in locomotor behaviors (ambulatory and rearing activity). A bimodal interaction between estrogen and progesterone was observed in the modulation of all locomotor activities. A gradual increase in behaviors, which peaked when progesterone was administered 24 hr after estrogen was followed by an inhibition of both ambulatory and rearing activity when progesterone was administered for a shorter period of time. This estrogen and progesterone interaction was not observed in the modulation of cocaine-induced stereotypic activity. However, shorter administration of progesterone in relation to estrogen administration resulted in lowered benzoylecgonine plasma levels when compared to longer progesterone administration times. On the other hand, longer administration of progesterone (48 hr of estrogen and progesterone) caused increases in corticosterone levels in cocaine-treated rats. Thus, the temporal interaction between estrogen and progesterone in the regulation of cocaine metabolism and hypothalamic-pituitary-axis (HPA) activation do not completely correlate with that observed for locomotor behavioral activation. Taken together, these results suggest that temporal interactions between estrogen and progesterone may underlie some of the previously reported estrous cycle and sex effects on cocaine-induced behavioral and endocrinological alteration.     

Chronic amphetamine alters D-2 but not D-1 agonist-induced behavioral responses in rats

In two experiments, using different drug doses and periods of drug administration, rats were given amphetamine (AMPH) either continuously (via slow-release pellets), or intermittently (via injections). In both experiments, only the rats pretreated with intermittent AMPH subsequently showed heightened responsivity to the selective D-2 dopamine agonist LY171555 but not to SKF38393 (a D-1 agonist). This altered response to LY171555 was still present 30 days after the AMPH withdrawal, implying that D-2 dopamine receptors at least partially mediate AMPH inverse tolerance effects. The behavioral response to the D-2 agonist was clearly different in animals receiving high versus low doses of AMPH, suggesting that different drug-state learning may have occurred during pretreatment. In a third experiment, in which rats were given repeated daily injections of either the D-1 or the D-2 agonist, only rats pretreated with the D-2 agonist and subsequently injected with the D-2 agonist clearly showed heightened responsivity. These data imply an important role of D-2 receptors in the AMPH inverse tolerance effect.     

Women's genital sexual arousal to oral versus penetrative heterosexual sex varies with menstrual cycle phase at first exposure

Reproductive-aged women show increased interest in sexual activity during the fertile phase of the menstrual cycle that can motivate sexual behavior and thereby increase the likelihood of conception. We examined whether women demonstrated greater sexual responses (subjective and genital sexual arousal) to penetrative versus oral sexual activities during the fertile versus non-fertile phases of their cycles, and whether women's arousal responses were influenced by the phase during which they were first exposed to these sexual stimuli (e.g., Slob et al., 1991; Wallen and Rupp, 2010). Twenty-two androphilic women completed two identical sexual arousal assessments in which genital responses were measured with a vaginal photoplethysmograph and their feelings of sexual arousal were recorded. Women viewed an array of 90 s films varying by couple type (female–female, male–male, female–male) and sexual activity type (oral or penetrative), during the fertile (follicular) and non-fertile (luteal) phases of their menstrual cycle, with the order of cycle phase at the first testing session counter-balanced. Women tested first in the fertile phase showed significantly greater genital arousal to female–male penetrative versus oral sex in both testing sessions, whereas self-reports of sexual arousal were not affected by cycle phase or testing order. These results contribute to a growing body of research suggesting that fertility status at first exposure to sexual stimuli has a significant effect on subsequent sexual responses to sexual stimuli, and that this effect may differ for subjective versus genital sexual arousal.     

Strong genetic influences on measures of behavioral‐regulation among inbred rat strains

A fundamental challenge for any complex nervous system is to regulate behavior in response to environmental challenges. Three measures of behavioral‐regulation were tested in a panel of eight inbred rat strains. These measures were: (1) sensation seeking as assessed by locomotor response to novelty and the sensory reinforcing effects of light onset, (2) attention and impulsivity, as measured by a choice reaction time task and (3) impulsivity as measured by a delay discounting task. Deficient behavioral‐regulation has been linked to a number of psychopathologies, including ADHD, Schizophrenia, Autism, drug abuse and eating disorders. Eight inbred rat strains (August Copenhagen Irish, Brown Norway, Buffalo, Fischer 344, Wistar Kyoto, Spontaneous Hypertensive Rat, Lewis, Dahl Salt Sensitive) were tested. With n = 9 for each strain, we observed robust strain differences for all tasks; heritability was estimated between 0.43 and 0.66. Performance of the eight inbred rat strains on the choice reaction time task was compared to the performance of outbred Sprague Dawley (n = 28) and Heterogeneous strain rats (n = 48). The results indicate a strong genetic influence on complex tasks related to behavioral‐regulation and indicate that some of the measures tap common genetically driven processes. Furthermore, our results establish the potential for future studies aimed at identifying specific alleles that influence variability for these traits. Identification of such alleles could contribute to our understanding of the molecular genetic basis of behavioral‐regulation, which is of fundamental importance and likely contributes to multiple psychiatric disorders .     

Effects of menstrual cycle phase and oral contraceptive use on verbal memory

Surgical or pharmacological suppression of ovarian hormones leads to declines in verbal memory, and estrogen treatment reverses these deficits. In the current study, we investigated the effects of menstrual cycle phase and oral contraceptives on verbal memory, as measured by the California Verbal Learning Test, in two groups of premenopausal women — 16 naturally cycling women and 20 current users of estrogen-based oral contraceptives (OCs). Naturally cycling women were assessed twice — once during the early follicular phase (Days 2-4) and once during the midluteal phase (Days 20-22) of the menstrual cycle. OC users were tested on the same cycle days, corresponding to inactive and active pill phases, respectively. We predicted that naturally cycling women would show improved verbal memory during the midluteal phase, when estradiol levels are high, compared with the follicular phase, when estradiol levels are low. We also predicted that OC users, who show no change in endogenous estradiol across the cycle, would show no change in verbal memory. Contrary to predictions, naturally cycling women showed no changes in verbal memory across the cycle, whereas OC users showed enhanced memory during the active pill phase (p < .05). None of the secondary cognitive outcome measures varied with cycle phase or OC use including measures of visuospatial memory, verbal fluency, visuospatial abilities, and attention. Overall, these results suggest that verbal memory performance in premenopausal women varies across the cycle with OC use, but does not vary systematically with changes in endogenous estradiol.     

The relationship between impulsive choice and impulsive action: a cross-species translational study

Maladaptive impulsivity is a core symptom in various psychiatric disorders. However, there is only limited evidence available on whether different measures of impulsivity represent largely unrelated aspects or a unitary construct. In a cross-species translational study, thirty rats were trained in impulsive choice (delayed reward task) and impulsive action (five-choice serial reaction time task) paradigms. The correlation between those measures was assessed during baseline performance and after pharmacological manipulations with the psychostimulant amphetamine and the norepinephrine reuptake inhibitor atomoxetine. In parallel, to validate the animal data, 101 human subjects performed analogous measures of impulsive choice (delay discounting task, DDT) and impulsive action (immediate and delayed memory task, IMT/DMT). Moreover, all subjects completed the Stop Signal Task (SST, as an additional measure of impulsive action) and filled out the Barratt impulsiveness scale (BIS-11). Correlations between DDT and IMT/DMT were determined and a principal component analysis was performed on all human measures of impulsivity. In both rats and humans measures of impulsive choice and impulsive action did not correlate. In rats the within-subject pharmacological effects of amphetamine and atomoxetine did not correlate between tasks, suggesting distinct underlying neural correlates. Furthermore, in humans, principal component analysis identified three independent factors: (1) self-reported impulsivity (BIS-11); (2) impulsive action (IMT/DMT and SST); (3) impulsive choice (DDT). This is the first study directly comparing aspects of impulsivity using a cross-species translational approach. The present data reveal the non-unitary nature of impulsivity on a behavioral and pharmacological level. Collectively, this warrants a stronger focus on the relative contribution of distinct forms of impulsivity in psychopathology.     

Workshop 3: 2

For over 20 years, the focus of studies examining the neurochemical and behavioral effects of cocaine and other psychostimulants has been on dopamine. Many behavioral studies have shown that dopamine plays an important role in the reinforcing and behavioral effects of cocaine. Cocaine binds to the dopamine transporter and inhibits dopamine uptake. While there are some effects of cocaine on dopamine receptors, dopamine levels, and the dopamine transporter, these neurochemical studies have not been able to account fully for the altered behavioral effects of cocaine following chronic cocaine administration. Recent studies by Kantak et al. have shown that the reinforcing effects of psychostimulants depend upon activation of brain nitric oxide synthase. In addition, Rocha et al. have reported that cocaine is self‐administered in animals lack dopamine transporters. This finding suggests that other neurochemical components are necessary for the reinforcing effects (and hence the abuse) of cocaine. Since cocaine binds to dopamine, norepinephrine and serotonin transporters, it is likely that a combination of effects on these systems may be responsible for the behavioral effects of cocaine. Mu‐ and kappa‐opioids regulate dopamine and serotonin and this regulation plays a role in the effects of cocaine (Izenwasser et al.). Unterwald and colleagues have shown that there are large effects of cocaine on opioid receptors and second messenger regulation. These studies show that there are interactions between multiple systems and that these interactions are important factors in the effects of abused drugs, perhaps more important than activation of dopaminergic systems alone. These findings will be discussed in terms of the implications for the development of treatments for cocaine abuse.     

Synaptic Cytoskeletal Plasticity in the Prefrontal Cortex Following Psychostimulant Exposure

Addiction is characterized by maladaptive decision‐making, a loss of control over drug consumption and habit‐like drug seeking despite adverse consequences. These cognitive changes may reflect the effects of drugs of abuse on prefrontal cortical neurobiology. Here, we review evidence that amphetamine and cocaine fundamentally remodel the structure of excitatory neurons in the prefrontal cortex. We summarize evidence in particular that these psychostimulants have opposing effects in the medial and orbital prefrontal cortices (‘mPFC’ and ‘oPFC’, respectively). For example, amphetamine and cocaine increase dendrite length and spine density in the mPFC, while dendrites are impoverished and dendritic spines are eliminated in the oPFC. We will discuss evidence that certain cytoskeletal regulatory proteins expressed in the oPFC and implicated in postnatal (adolescent) neural development also regulate behavioral sensitivity to cocaine. These findings potentially open a window of opportunity for the identification of novel pharmacotherapeutic targets in the treatment of drug abuse disorders in adults, as well as in drug‐vulnerable adolescent populations. Finally, we will discuss the behavioral implications of drug‐related dendritic spine elimination in the oPFC, with regard to reversal learning tasks and tasks that assess the development of reward‐seeking habits, both used to model aspects of addiction in rodents.