Kimber L. Price

Ovarian hormones and cognition in the aged female rat: I. Long-term, but not short-term, ovariectomy enhances spatial performance.

Although research suggests that ovariectomy (ovx) is detrimental to spatial cognition in young rats, little work has evaluated the cognitive effects of ovx in aged rats. The authors investigated the effects of ovx in aged rats using the water radial-arm maze. In Study 1, young rats and aged rats receiving ovx 1.5 months before testing outperformed aged rats receiving sham surgery or ovx 21 days before testing. In Study 2, young rats and aged rats receiving ovx 2.0 or 6.0 months before testing outperformed aged sham rats. Aged rats exhibited estradiol and elevated progesterone levels comparable to those of young rats. The findings suggest that 1.5-6.0 months, but not 21 days, of ovx improves spatial memory in aged rats. The hypothesis that long-term ovarian hormone loss is detrimental to spatial memory in aged rats was not supported. The authors hypothesize that removal of elevated progesterone levels is related to the ovx-induced cognitive enhancement.

D-cycloserine and Cocaine Cue Reactivity: Preliminary Findings

Background: D-cycloserine (DCS), a partial glutamate N-methyl-D-aspartic acid (NMDA) receptor agonist, enhances extinction of conditioned fear responding in rodents and facilitates exposure-based learning in humans with anxiety disorders. Objectives: This preliminary study investigates DCS pretreatment on response to cocaine cues in cocaine-dependent subjects. Methods: Ten cocaine-dependent subjects were randomly assigned to receive either 50 mg DCS or matching placebo two hours before each of two 1-hour cocaine cue exposure sessions one day apart. HR and craving ratings were obtained before and during cue exposure sessions. Results: There was a trend towards increased craving to cocaine cues in cocaine-dependent individuals after administration of DCS. Conclusions: The administration of DCS prior to cue exposure sessions may facilitate response activation. Scientific Significance: While facilitation of extinction-based learning by DCS may have therapeutic potential for cocaine dependence, this drug may exhibit a different profile in cocaine-dependent individuals as compared to those with anxiety disorders.

Unconditioned and conditioned factors contribute to the 'reinstatement' of cocaine place conditioning following extinction in C57BL/6 mice.

Relapse to drug use following prolonged periods of abstinence results, in part, from the ability of contextual cues paired previously with self-administered drug to elicit drug craving and -seeking behavior. Given the popularity of the mouse for the genetic analysis of drug-induced behaviors, a place conditioning model of drug-seeking behavior was used to examine the ability of cocaine (COC) to reinstate extinguished conditioned reward in mice. In a series of experiments, COC place conditioning was produced in male C57BL/6 (B6) mice by four pairings of COC (15 or 25 mg/kg, IP) with the non-preferred compartment of a two-compartment place conditioning apparatus. Following a post-conditioning test (Post-Test), place conditioning was extinguished by repeated testing. The mice were then challenged with one of five COC doses (0, 5, 10, 15 or 25 mg/kg, IP) and allowed free access to both environments. Following extinction, COC injections reinstated place conditioning to 100% or greater, relative to the Post-Test. In a control experiment, mice received either COC or SAL paired with non-preferred compartment and were then challenged with either COC (15 mg/kg, IP) or SAL on the Post-Test. COC-conditioned, but not SAL-conditioned, mice exhibited place conditioning when tested in a COC-free state. Interestingly, COC injection on the Post-Test elicited an increase in approach behavior in both SAL- and COC-conditioned mice and this increase was equivalent to that produced by COC conditioning alone. No direct relationships were observed between the magnitude of place conditioning and either COC-induced or -conditioned locomotor hyperactivity in the non-preferred compartment. Thus, at least two independent processes appear to underlie the ability of a COC injection to elicit approach behavior towards the non-preferred compartment of a biased place conditioning apparatus in mice-reactivation of the conditioned incentive motivational properties of COC-paired cues and elicitation of unconditioned behavioral disinhibition. One or both of these processes sensitizes with the passage of time, increasing the propensity of B6 mice to approach non-preferred environments upon COC re-administration.

Stress- and cue-elicited craving and reactivity in marijuana-dependent individuals

RationaleCue-elicited craving and stress responses have been identified as predictors of relapse in drug dependence, but little research exists on the contribution of these factors to marijuana use specifically.ObjectivesThe aims of the present study were to evaluate (1) responses to a psychological stressor, (2) responses to marijuana-related cues, and (3) if an exposure to a psychological stressor augmented craving subsequently elicited by marijuana-related cue exposure in marijuana-dependent individuals.MethodsSubjective (craving, stress), neuroendocrine (adrenocorticotropic hormone (ACTH), cortisol), and physiologic responses to the presentation of neutral and marijuana cues were assessed after randomization to a stress (Trier Social Stress Task (TSST)) or non-stress control condition in marijuana-dependent individuals. Outcome measures were assessed at baseline, post-stressor/pre-neutral cue, post-neutral cue, and post-marijuana cue.ResultsEighty-seven participants completed procedures (stress group, n = 45; non-stress group, n = 42). The stress group had a significant increase over the non-stress group in stress rating (p < 0.001), craving (p = 0.028), cortisol (p < 0.001), and ACTH (p < 0.001) after the completion of the TSST. An increased craving response for all participants was seen following the presentation of the marijuana cues (p = 0.005). Following the TSST or non-stress condition, the non-stress group had an increase in craving to marijuana cues as compared to neutral cues (p = 0.002); an increase in craving was not observed in the stress group (p = 0.404).ConclusionsMarijuana cue exposure and a social stressor increased craving in marijuana-dependent individuals. Completion of the TSST did not increase craving response to subsequent marijuana cue exposure.

Community-Dwelling Cocaine-Dependent Men and Women Respond Differently to Social Stressors versus Cocaine Cues

UNLABELLED There are likely to be gender differences in determinants of relapse to drug use following abstinence in cocaine-dependent individuals. Cocaine-dependent women are more likely to attribute relapse to negative emotional states and interpersonal conflict. Cocaine dependence has also been linked to dysregulation of stress response and the hypothalamic pituitary adrenal (HPA) axis which may differ between genders. Subjective and HPA-axis responses to a social evaluative stressor, the Trier Social Stress Test (TRIER), and in vivo cocaine-related cues were examined in the present study. RESULTS There were no gender differences in magnitude of craving responses to the TRIER or the CUE. Both genders had a greater craving response to the CUE than to the TRIER, but the magnitude of the difference was greater for men than women (p=0.04). Cocaine-dependent subjects, compared to the control group, had significantly higher response throughout the TRIER (p<0.0001) and CUE (p<0.0001) testing sessions. There were no gender differences and no gender by cocaine interaction for ACTH responses to the TRIER, although women had lower baseline ACTH (p=0.049). On the CUE task, in contrast, female cocaine-dependent subjects had a more blunted ACTH response than did the other three groups (p=0.02). Female cocaine-dependent subjects also had a lower odds of a positive cortisol response to the TRIER as compared to the other three groups (OR=0.84, 95% CI=[0.02, 1.01]). During the CUE task, cocaine-dependent subjects had overall higher mean cortisol levels (p=0.0001), and higher odds of demonstrating a positive cortisol response to the CUE (OR=2.61, 95% CI=[1.11, 6.11]). No gender differences were found in ACTH responses to the CUE. The results are reviewed in the context of the existing literature on gender differences in cocaine dependence and potential implications for treatment are discussed.

Determinants of Cue-Elicited Craving and Physiologic Reactivity in Methamphetamine-Dependent Subjects in the Laboratory

Objective: Craving for methamphetamine is commonly reported by heavy users of the drug and may increase the risk of relapse in newly abstinent individuals. Exposure to methamphetamine-associated cues in the laboratory can elicit measureable craving and autonomic reactivity in some individuals with methamphetamine dependence. In this study, clinical and demographic correlates of methamphetamine craving and the optimal conditions for its measurement in the laboratory are explored. Methods: Subjective (craving) and physiologic (heart rate and skin conductance) reactivity to presentation of methamphetamine-associated photo, video, and paraphernalia cues were evaluated in 43 subjects with methamphetamine dependence. Association of cue reactivity with demographic and clinical characteristics including duration, frequency, amount, and recency of methamphetamine use were assessed. Results: Craving was reported by fewer than half of subjects at baseline and by approximately 70% of subjects after methamphetamine cue exposure. Relative to baseline, subjective craving was increased by all three cue modalities to a similar extent. In general, physiological cue reactivity correlated poorly with cue-induced craving. Craving at baseline was strongly predictive of cue-induced craving. Differences in cue-induced craving were not associated with age, sex, education, employment, treatment status, or number of days using methamphetamine in the 60 days prior to study entry. In contrast, the degree of baseline craving was strongly associated with employment status and the number of days using methamphetamine in the past 60 days. Conclusions: Cue-induced craving for methamphetamine may be reliably measured in methamphetamine-dependent individuals in the laboratory. Further studies employing the cue reactivity paradigm in methamphetamine dependence are warranted.

Extinction of Drug Cue Reactivity in Methamphetamine-Dependent Individuals

Conditioned responses to drug-related environmental cues (such as craving) play a critical role in relapse to drug use. Animal models demonstrate that repeated exposure to drug-associated cues in the absence of drug administration leads to the extinction of conditioned responses, but the few existing clinical trials focused on extinction of conditioned responses to drug-related cues in drug-dependent individuals show equivocal results. The current study examined drug-related cue reactivity and response extinction in a laboratory setting in methamphetamine-dependent individuals. Methamphetamine cue-elicited craving was extinguished during two sessions of repeated (3) within-session exposures to multi-modal (picture, video, and in-vivo) cues, with no evidence of spontaneous recovery between sessions. A trend was noted for a greater attenuation of response in participants with longer (4-7 day) inter-session intervals. These results indicate that extinction of drug cue conditioned responding occurs in methamphetamine-dependent individuals, offering promise for the development of extinction- based treatment strategies.

Relationship between child abuse and adult smoking.

Objective: A strong association between a history of child abuse and subsequent psychiatric disorders including substance use has been demonstrated. However, few studies have examined the relationship between child abuse and cigarette smoking in individuals without co-occurring psychiatric disorders. In this study, the relationship between severe childhood abuse and smoking were examined in a group of adults without significant psychopathology. Methods: Participants (N = 57) represent the control group of a larger study of substance dependence. Participants were without major DSM-IV psychopathology, including substance use disorders, major depression, or posttraumatic stress disorder. The Early Trauma Inventory [20] assessed history of exposure to traumatic events prior to age 18. Results: The majority of individuals with, as compared to without, a history of severe child abuse (79% vs. 47%, p = .02) were current cigarette smokers. The odds of smoking was four times as high in participants with versus without a severe childhood abuse history (OR = 4.0, p = 0.04). Conclusions: Although preliminary, the findings demonstrate a strong link between early childhood trauma and later adult cigarette smoking among individuals without significant substance use or other psychopathology.

The dopamine D1 antagonist reduces ethanol reward for C57BL/6 mice.

BACKGROUND Dopamine D1 antagonist effects on behaviors related to obtaining and consuming ethanol remain unclear. The highly selective D1 antagonist ecopipam (SCH 39166), which has no effect on the serotonin system, was used to evaluate the role of D1 receptors in ethanol reward and its potential for treating alcohol abuse by determining its effect on several measures of ethanol reward in C57BL/6 (B6) mice. METHODS Ecopipam (0.025-0.2 mg/kg) effects on instrumental and contingent consummatory responses and on noncontingent consummatory responses for ethanol and water reward were determined in food-restricted male mice trained to lever-respond for 12% ethanol delivered on a fixed ratio-4 reinforcement schedule. The mice were tested for 15-min sessions under preprandial (high-hunger and low-thirst) and postprandial (low-hunger and high-thirst) test conditions. RESULTS Ecopipam dose-dependently reduced instrumental and consummatory responses for ethanol and ethanol intake when tested under hunger- or thirst-motivated conditions with free access to water. Under thirst motivation with no access to an alternate fluid source, lever responses for ethanol and water were similar; however, ecopipam reduced responding for ethanol more than responding for water reward. When given concurrent free access to the same fluid delivered for lever pressing, animals made more contacts for ethanol than for water; ecopipam reduced free ethanol but not water contacts. CONCLUSIONS Ecopipam attenuated ethanol reward at doses that did not affect water reward, indicating an effect independent of reductions in motor system function or general motivation and arousal. Ecopipam also reduced ethanol reward to the same degree under hunger, thirst, or sated conditions, again indicating that it affected ethanol reward at doses that did not grossly affect general motivational states. These data suggest that ecopipam may reduce ethanol reward with few side effects and that it warrants further investigation as a pharmacological tool for treating alcohol abuse.

The impact of clinical and demographic variables on cognitive performance in methamphetamine-dependent individuals in rural South Carolina

Inconsistencies in reports on methamphetamine (METH) associated cognitive dysfunction may be attributed, at least in part, to the diversity of study sample features (eg, clinical and demographic characteristics). The current study assessed cognitive function in a METH-dependent population from rural South Carolina, and the impact of demographic and clinical characteristics on performance. Seventy-one male (28.2%) and female (71.8%) METH-dependent subjects were administered a battery of neurocognitive tests including the Test of Memory Malingering (TOMM), Shipley Institute of Living Scale, Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), Grooved Pegboard Test, California Verbal Learning Test (CVLT), and Wisconsin Card Sorting Test (WCST). Demographic and clinical characteristics (eg, gender, frequency of METH use) were examined as predictors of performance. Subjects scored significantly lower than expected on one test of attention and one of fine motor function, but performed adequately on all other tests. There were no predictors of performance on attention; however, more frequent METH use was associated with better performance for males and worse for females on fine motor skills. The METH-dependent individuals in this population exhibit very limited cognitive impairment. The marked differences in education, Intellectual Quotient (IQ), and gender in our sample when compared to the published literature may contribute to these findings. Characterization of the impact of clinical and/or demographic features on cognitive deficits could be important in guiding the development of treatment interventions.