Chicora F. Oliver

The effects of acute nicotine on contextual safety discrimination

Anxiety disorders, such as post-traumatic stress disorder (PTSD), may be related to an inability to distinguish safe versus threatening environments and to extinguish fear memories. Given the high rate of cigarette smoking in patients with PTSD, as well as the recent finding that an acute dose of nicotine impairs extinction of contextual fear memory, we conducted a series of experiments to investigate the effect of acute nicotine in an animal model of contextual safety discrimination. Following saline or nicotine (at 0.0275, 0.045, 0.09 and 0.18 mg/kg) administration, C57BL/6J mice were trained in a contextual discrimination paradigm, in which the subjects received presentations of conditioned stimuli (CS) that co-terminated with a foot-shock in one context (context A (CXA)) and only CS presentations without foot-shock in a different context (context B (CXB)). Therefore, CXA was designated as the ‘dangerous context’, whereas CXB was designated as the ‘safe context’. Our results suggested that saline-treated animals showed a strong discrimination between dangerous and safe contexts, while acute nicotine dose-dependently impaired contextual safety discrimination (Experiment 1). Furthermore, our results demonstrate that nicotine-induced impairment of contextual safety discrimination learning was not a result of increased generalized freezing (Experiment 2) or contingent on the common CS presentations in both contexts (Experiment 3). Finally, our results show that increasing the temporal gap between CXA and CXB during training abolished the impairing effects of nicotine (Experiment 4). The findings of this study may help link nicotine exposure to the safety learning deficits seen in anxiety disorder and PTSD patients.

Long-term effects of chronic nicotine on emotional and cognitive behaviors and hippocampus cell morphology in mice: comparisons of adult and adolescent nicotine exposure

Nicotine dependence is associated with increased risk for emotional, cognitive and neurological impairments later in life. This study investigated the long‐term effects of nicotine exposure during adolescence and adulthood on measures of depression, anxiety, learning and hippocampal pyramidal cell morphology. Mice (C57BL/6J) received saline or nicotine for 12 days via pumps implanted on postnatal day 32 (adolescent) or 54 (adults). Thirty days after cessation of nicotine/saline, mice were tested for learning using contextual fear conditioning, depression‐like behaviors using the forced swim test or anxiety‐like behaviors with the elevated plus maze. Brains from nicotine‐ or saline‐exposed mice were processed with Golgi stain for whole neuron reconstruction in the CA1 and CA3 regions of the hippocampus. Results demonstrate higher depression‐like responses in both adolescent and adult mice when tested during acute nicotine withdrawal. Heightened depression‐like behaviors persisted when tested after 30 days of nicotine abstinence in mice exposed as adolescents, but not adults. Adult, but not adolescent, exposure to nicotine resulted in increased open‐arm time when tested after 30 days of abstinence. Nicotine exposure during adolescence caused deficits in contextual fear learning indicated by lower levels of freezing to the context as compared with controls when tested 30 days later. In addition, reduced dendritic length and complexity in the apical CA1 branches in adult mice exposed to nicotine during adolescence were found. These results demonstrate that nicotine exposure and withdrawal can have long‐term effects on emotional and cognitive functioning, particularly when nicotine exposure occurs during the critical period of adolescence.

Sex differences in the effects of nicotine on contextual fear extinction

ABSTRACT Anxiety and stress disorders occur at a higher rate in women compared to men as well as in smokers in comparison to non‐smoker population. Nicotine is known to impair fear extinction, which is altered in anxiety disorders. However, nicotine differentially affects fear learning in men and women, which may mean that sex and nicotine‐product use can interact to also alter fear extinction. For this study, we examined sex differences in the effects of acute and chronic nicotine administration on fear memory extinction in male and female C57BL/6J mice. To study the acute effects of nicotine, animals trained in a background contextual fear conditioning paradigm were administered nicotine (0.09, 0.18 or 0.36 mg/kg) prior to extinction sessions. For chronic nicotine, animals continuously receiving nicotine (12.6, 18, or 24 mg/kg/day) were trained in a background contextual fear conditioning paradigm followed by fear extinction sessions. Males exhibited contextual fear extinction deficits following acute and chronic nicotine exposure. Females also exhibited extinction deficits, but only at the highest doses of acute nicotine (0.36 mg/kg) while chronic nicotine did not result in extinction deficits in female mice. These results suggest that sex mediates sensitivity to nicotines effects on contextual fear memory extinction. HIGHLIGHTSMales exhibited contextual fear extinction deficits following acute and chronic nicotine exposure.Females also exhibited extinction deficits, but only at the highest doses of acute nicotine (0.36 mg/kg).Chronic nicotine did not result in extinction deficits in female mice.

Chemokines and ‘bath salts’: CXCR4 receptor antagonist reduces rewarding and locomotor-stimulant effects of the designer cathinone MDPV in rats

BACKGROUND AND PURPOSE Little is known about how chemokine systems influence the behavioral effects of designer cathinones and psychostimulants. The chemokine CXCL12 and its principal receptor target, CXCR4, are of particular interest because CXCR4 activation enhances mesolimbic dopamine output that facilitates psychostimulant reward, reinforcement, and locomotor activation. Repeated cocaine enhances CXCL12 gene expression in the midbrain and produces conditioned place preference (CPP) that is inhibited by a CXCR4 antagonist. Yet, interactions between chemokines and synthetic cathinones remain elusive. METHODS We tested the hypothesis that an FDA-approved CXCR4 antagonist (AMD3100) inhibits MDPV-induced reward, locomotor activation and positive affective state in rats using a triad of behavioral assays (CPP, open field, and 50-kHz ultrasonic vocalizations [USVs]). KEY RESULTS AMD3100 (1, 2.5, 5, 10 mg/kg, ip) significantly reduced MDPV (2 mg/kg, ip)-evoked hyper-locomotion in a dose-related manner. AMD3100 (1, 5, 10 mg/kg) administered during CPP conditioning caused a significant, dose-dependent reduction of MDPV (2 mg/kg x 4 days) place preference. MDPV injection elicited significantly greater 50 kHz USVs in vehicle-pretreated rats but not in AMD3100-pretreated rats. CONCLUSION AND IMPLICATION A CXCR4 antagonist reduced the rewarding and locomotor-activating effects of MDPV. Our results identify the existence of chemokine/cathinone interactions and suggest the rewarding and stimulant effects of MDPV, similar to cocaine, require an active CXCL12/CXCR4 system.

Repeated recall and PKMζ maintain fear memories in juvenile rats

We examined the neural substrates of fear memory formation and maintenance when repeated recall was used to prevent forgetting in young animals. In contrast to adult rats, juveniles failed to show contextual fear responses at 4 d post-fear conditioning. Reconsolidation sessions 3 and 6 d after conditioning restored contextual fear responses in juveniles 7 d after initial training. In juveniles that received reconsolidation sessions, protein kinase M zeta (PKMζ) increased in the amygdala, but not in the hippocampus. These data suggest that repeated reminders and increased PKMζ maintain fear responses in juvenile animals that otherwise would not exhibit this behavior.

Synthetic cathinone adulteration of illegal drugs

RationaleCurrent prevalence estimates of synthetic cathinone (“bath salt”) use may be underestimates given that traditional metrics (e.g., surveys, urinalysis) often fail to capture the emergent issue of synthetic cathinone adulteration of more common illegal drugs, such as ecstasy (3,4-methylenedioxymethamphetamine).ObjectivesThis review examines the evolution of synthetic cathinones and prevalence of use over the past decade in the United States. We also review methods of self-report and biological testing of these compounds as well as adverse outcomes associated with adulterated drug use.ResultsSynthetic cathinone use emerged in the United States by 2009 with use associated with tens of thousands of poisonings. Reported poisonings and self-reported use have substantially decreased over the past five years. However, our review suggests that current estimates of use are underestimates due to underreporting stemming primarily from unknown or unintentional use of adulterated formulations of relatively popular illegal drugs, such as ecstasy.ConclusionsWhile intentional synthetic cathinone use has decreased in recent years, evidence suggests that prevalence of use is underestimated. Testing of drugs and/or biological specimens can improve the accuracy of synthetic cathinone use estimates. Furthermore, we advocate that researchers and clinicians should become better aware that exposure to these potent compounds (e.g., as adulterants) often occurs unknowingly or unintentionally. To improve our understanding of synthetic cathinone adulteration, research utilizing a combinatorial approach (survey and biological testing) will help more accurately estimate the prevalence and impact of this public health issue.