Immediate and sustained terminal complement inhibition with ravulizumab in patients with anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder.

Objective: To assess the pharmacokinetics and pharmacodynamics of the long-acting terminal complement 5 (C5) inhibitor ravulizumab in adults with anti-aquaporin-4 antibody-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) in the phase 3, open-label CHAMPION-NMOSD trial (NCT04201262). Methods: Patients aged 18 years or older received a weight-based intravenous loading dose of ravulizumab (2,400-3,000 mg) on day 1, followed by weight-based maintenance doses (3,000-3,600 mg) on day 15 and once every 8 weeks thereafter. Pharmacokinetic assessments were maximum observed concentration (Cmax, assessed at the end of the infusion) and concentration at the end of the dosing interval (Ctrough, assessed before dosing) for ravulizumab. Pharmacodynamic assessment was time-matched observed free C5 concentration in serum up to 50 weeks. Results: The pharmacokinetic/pharmacodynamic analysis included 58 patients treated with ravulizumab. Serum ravulizumab concentrations at or above the therapeutic threshold (175 µg/mL) were achieved in all patients after administration of the first dose and maintained for 50 weeks. At week 50, the mean (standard deviation) Cmax (n = 51) and Ctrough (n = 52) were 1,887.6 (411.38) and 764.4 (217.68) µg/mL, respectively. Immediate and complete terminal complement inhibition (free C5 serum concentrations < 0.5 µg/mL) was achieved by the end of the first ravulizumab infusion and sustained throughout the treatment period. No treatment-emergent antibodies to ravulizumab were observed. No impact on ravulizumab pharmacokinetics was seen for age, sex, race, hematocrit, hemoglobin, markers of renal and liver impairment, or medications commonly used by patients with NMOSD. Body weight and BMI were significant covariates of ravulizumab pharmacokinetics. Conclusions: Serum ravulizumab concentrations were maintained above the therapeutic threshold in all patients through 50 weeks of treatment. Ravulizumab achieved immediate and complete terminal complement inhibition that was sustained throughout the treatment period in adults with AQP4+ NMOSD.

Ravulizumab in Aquaporin-4-Positive Neuromyelitis Optica Spectrum Disorder.

OBJECTIVE: CHAMPION-NMOSD (NCT04201262) is a phase 3, open-label, externally controlled interventional study evaluating the efficacy and safety of the terminal complement inhibitor ravulizumab in adult patients with anti-aquaporin-4 antibody-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD). Ravulizumab binds the same complement component 5 epitope as the approved therapeutic eculizumab but has a longer half-life, enabling an extended dosing interval (8 vs 2 weeks). METHODS: The availability of eculizumab precluded the use of a concurrent placebo control in CHAMPION-NMOSD; consequently, the placebo group of the eculizumab phase 3 trial PREVENT (n = 47) was used as an external comparator. Patients received weight-based intravenous ravulizumab on day 1 and maintenance doses on day 15, then once every 8 weeks. The primary endpoint was time to first adjudicated on-trial relapse. RESULTS: The primary endpoint was met; no patients taking ravulizumab (n = 58) had an adjudicated relapse (during 84.0 patient-years of treatment) versus 20 patients with adjudicated relapses in the placebo group of PREVENT (during 46.9 patient-years; relapse risk reduction = 98.6%, 95% confidence interval = 89.7%-100.0%, p < 0.0001). Median (range) study period follow-up time was 73.5 (11.0-117.7) weeks for ravulizumab. Most treatment-emergent adverse events were mild/moderate; no deaths were reported. Two patients taking ravulizumab experienced meningococcal infections. Both recovered with no sequelae; one continued ravulizumab treatment. INTERPRETATION: Ravulizumab significantly reduced relapse risk in patients with AQP4+ NMOSD, with a safety profile consistent with those of eculizumab and ravulizumab across all approved indications. ANN NEUROL 2023;93:1053-1068.

Cannabis Use and Consequences.

As an increasing number of states legalize cannabis use for recreational and/or medical purposes, it is increasingly important to understand the neural and cognitive consequences of recreational cannabis use in adolescent consumers. Adolescence is marked by ongoing neuromaturational processes, making this a particularly vulnerable period, particularly regarding exposure to drugs, including cannabis. This review highlights evidence from studies documenting the neural impact of cannabis use in adolescence and explores mediating factors related to cannabis use.

Early onset cigarette smokers exhibit greater P300 reactivity to smoking-related stimuli and report greater craving.

Adolescence is a period during which a number of critical neuromaturation processes occur and the vulnerability for developing nicotine dependence is extremely high. Thus, early-onset (EO; age < 16 years old), relative to late-onset (LO; age ≥ 16 years old), tobacco smoking may be uniquely deleterious for developmentally immature systems that regulate neural signaling reactivity. This study investigated how age of tobacco smoking onset affects neurophysiological measures of smoking cue reactivity and reported craving in adult smokers. EO smokers (EOS; n = 8; 4 females), LO smokers (LOS; n = 10; 5 females), and healthy non-smokers (HNS; n = 10; 5 females) participated in an event-related potential (ERP) cue reactivity study with tactile and image stimuli. Participants handled neutral objects during one interval and smoking-related objects during a second interval. After each interval, they viewed smoking-related, neutral, or arousing images using an oddball paradigm. P300 ERPs and craving for tobacco were recorded during each session. P300 amplitudes were significantly higher in central midline (Cz) channel to smoking, but not neutral or arousing, images after handling smoking objects. Specifically, Cz P300 smoking amplitudes were significantly greater in EOS, relative to LOS and HNS, and associated with greater craving at baseline. There were no other group differences in mood or craving. EOS exhibited greater P300 reactivity to smoking-related stimuli, relative to LOS, suggesting a more sensitized neural response. EO smoking during early neuromaturation may alter neurophysiological signaling involved in responding to smoking-related stimuli, which could impact the outcome of smoking cessation interventions.

Early onset tobacco cigarette smokers exhibit deficits in response inhibition and sustained attention.

BACKGROUND: Initiation of cigarette smoking during adolescence coincides with structural and cognitive neuromaturation. Thus, early onset smokers (EOS; initiated <16 years old) may be at unique risk of altered development of executive function relative to late onset smokers (LOS; initiated >16 years old). This study quantified the effects of age of smoking onset on response impulsivity and inhibitory control using a novel smoking Go/NoGo task (Luijten et al., 2011). METHODS: Nicotine deprived adult EOS (n = 10) and LOS (n = 10) and adult healthy non-smokers (HNS; n = 10) were shown smoking-related and neutral images with either a blue (Go) or yellow (NoGo) frame. Participants were instructed to respond to blue-framed Go trials quickly and accurately, and withhold responding for yellow-framed NoGo trials. RESULTS: EOS made more Go response accuracy errors (p ≤ 0.02) and failed more frequently to inhibit responses to NoGo trials (p < 0.02) than LOS and HNS. EOS also made more errors in inhibiting responses to smoking-related (p ≤ 0.02) and neutral (p ≤ 0.02) NoGo trials. EOS reported greater baseline craving for cigarette smoking than LOS (p < 0.04), and craving was significantly associated with greater omission errors (p ≤ 0.04). CONCLUSIONS: EOS exhibited greater difficulty than LOS in responding accurately to Go stimuli and withholding responses to both smoking and neutral NoGo stimuli, indicating greater response impulsivity, poor attention, and deficits in response inhibition. These findings suggest that EO smoking, in particular, contributes to diminished task-related attention and inhibitory control behaviors in adulthood and provide support for the tobacco-induced neurotoxicity of adolescent cognitive development (TINACD) theory (DeBry and Tiffany, 2008).

Cue-induced craving to paraphernalia and drug images in opioid dependence.

BACKGROUND AND OBJECTIVES: Stimuli that are repeatedly paired with substance use, such as drug paraphernalia, can themselves elicit drug craving. The aim of this study was to examine whether particular cue types elicit greater craving responses than others among individuals with opioid dependence. METHODS: Participants seeking inpatient treatment for opioid dependence were recruited for a study of cue-induced craving. This sample (N = 50), included 25 primary heroin users, 20 primary prescription opioid users, and 5 users of heroin and prescription opioids equally. Participants completed a cue reactivity task, in which images of drug-related stimuli were presented on a computer screen, each followed by a question assessing state drug craving. RESULTS: Overall, participants reported higher craving following paraphernalia stimuli relative to drug stimuli. However, this was moderated by opioid type; there was significantly higher craving in response to images of paraphernalia cues in the heroin group, and higher craving in response to drug cues in the prescription opioid group. DISCUSSION AND CONCLUSIONS: These findings highlight potential differences in cue reactivity to opioid paraphernalia and drug cues, which appears to be moderated by drug type. SCIENTIFIC SIGNIFICANCE: Cue-induced craving is an important factor in relapse. This study adds further to the literature on cue-induced craving in opioid dependence, suggesting that craving may vary based on both cue type and opioid type. Future studies designed to discriminate the impact of substance of abuse, route of administration, and cue type will help to further clarify cue-induced craving in this population.

Early Versus Late Onset of Cannabis Use: Differences in Striatal Response to Cannabis Cues.

Addiction theories posit that addiction is the result of a progressive transition from voluntary to habitual, compulsive drug use-changes that have been linked, in animals, to a shift from ventral to dorsal striatal control over drug-seeking behavior. Thus, we hypothesized that early-onset (EOs) cannabis users versus late-onset (LOs) cannabis users might exhibit, respectively, greater dorsal versus ventral striatal response to drug cues. We used functional magnetic resonance imaging and an event-related blood oxygen level-dependent backward-masking task to evaluate striatal responses to backward-masked cannabis cues (vs. neutral cues) in EOs (<16 years old, n = 15) and LOs (≥16 years old, n = 26) with similar recent cannabis use patterns. Direct comparisons revealed that EOs showed greater response to cannabis cues in the dorsal striatum than LOs (p < 0.01, k > 50 voxels). Within-group analyses revealed that EOs showed greater neural response to cannabis cues in the dorsal striatum, whereas LOs exhibited greater neural response to cannabis cues in the ventral striatum. Although cross-sectional, these findings are consistent with recent addiction theories suggesting a progressive shift from ventral to dorsal striatal control over drug-seeking behavior and highlight the importance of age of onset of cannabis use on the brain and cognition.

Binge alcohol consumption in emerging adults: anterior cingulate cortical "thinness" is associated with alcohol use patterns.

BACKGROUND: The brain undergoes dynamic and requisite changes into the early 20s that are associated with improved cognitive efficiency, particularly in prefrontal regions that are still undergoing neuromaturation. As alcohol consumption is typically initiated and progresses to binge drinking (BD) during this time, the objective of the present study was to investigate the impact of binge alcohol consumption on frontal lobe cortical thickness in emerging adults. METHODS: Twenty-three binge drinking (11 females, mean age 22.0 ± 1.2) and 31 light drinking (15 females, mean age 21.5 ± 1.6) emerging adults underwent high-resolution magnetic resonance imaging at 3 Tesla. Cortical surface reconstruction and thickness estimation were performed using FreeSurfer for 3 a priori brain regions of interest: bilateral anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and parieto-occipital sulcus (POS). Cortical thickness measurements were then compared between binge drinker (BD) and light drinker (LD) groups. RESULTS: Cortical thickness was significantly lower in BD than LD in the right middle ACC (mid-ACC; p ≤ 0.05) and in the left dorsal PCC (dPCC; p ≤ 0.01). No significant differences in cortical thickness were observed in the POS. Cortical thickness in the mid-ACC correlated negatively with higher quantity and frequency of drinks consumed (p < 0.01) and positively with the number of days elapsed since most recent use (p < 0.05). Furthermore, less cortical thickness in the mid-ACC in the BD group alone correlated with reported patterns of high quantity and frequency of alcohol consumption (p ≤ 0.05). CONCLUSIONS: Findings suggest that past and recent patterns of intermittent heavy alcohol consumption are associated with less frontal cortical thickness (i.e., "thinness") of the right mid-ACC and left dPCC in emerging adults, but not the POS. While cortical thinness could have predated binge drinking, this pattern of maladaptive consumption may have acute neurotoxic effects that interfere with the finalization of neuromaturational processes in the vulnerable frontal cortex, resulting in increased microarchitectural pruning.

Lower Left Thalamic Myo-Inositol Levels Associated with Greater Cognitive Impulsivity in Marijuana-Dependent Young Men: Preliminary Spectroscopic Evidence at 4T.

The effects of chronic marijuana (MRJ) use on neurochemistry are not well characterized. Previously, altered global myo-Inositol (mI) concentrations and distribution in white matter were associated with impulsivity and mood symptoms in young MRJ-dependent men. The objective of this study was to retrospectively examine previously collected data, to investigate the potential regional specificity of metabolite levels in brain regions densely packed with cannabinoid receptors. Spectra were acquired at 4.0 Tesla using 2D J-resolved proton magnetic resonance spectroscopic imaging (MRSI) to quantify the entire J-coupled spectral surface of metabolites from voxels in regions of interest. For the current regional spectral analyses, a 2D-JMRSI grid was positioned over the central axial slice and shifted in the x and y dimensions to optimally position voxels over regions containing thalamus, temporal lobe, and parieto-occipital cortex. MRJ users exhibited significantly reduced mI levels in the left thalamus (lThal), relative to non-using participants, which were associated with elevated cognitive impulsivity. Other regional analyses did not reveal any significant group differences. The current findings indicate that reduced mI levels are regionally specific to the lThal in MRJ users. Furthermore, findings suggest that mI and the lThal uniquely contribute to elevated impulsivity.

A Review of Magnetic Resonance Spectroscopy Studies in Marijuana using Adolescents and Adults.

Marijuana (MJ) remains the most widely used illicit drug of abuse, and accordingly, is associated with adverse effects on mental and physical health, and neurocognitive decline. Studies investigating the neurobiology of underlying MJ effects have demonstrated structural and functional alterations in brain areas that contain moderate to high concentrations of cannabinoid (CB1) receptors and that are implicated in MJ-related cognitive decrements. Proton magnetic resonance spectroscopy (1H MRS), a non-invasive imaging technique used to assess neurochemistry, has been widely applied to probe a variety of substance-abusing populations. To date, however, there is a relative paucity of MRS published studies characterizing changes in neurometabolite concentrations in MJ users. Thus, the current review provides a summary of data from the eight existing MRS studies of MJ use in adolescents and adults, as well as interpretations and implications of study findings. Future MRS studies that address additional factors such as sex differences, onset and duration of use, abstinence and age, are warranted, and would lead to a more thorough characterization of potential neurochemical correlates of chronic MJ use, which would fill critical gaps in the existing literature.

Anterior cingulate proton spectroscopy glutamate levels differ as a function of smoking cessation outcome.

BACKGROUND: Cigarette smoking is the leading preventable cause of death. Unfortunately, the majority of smokers who attempt to quit smoking relapse within weeks. Abnormal dorsal anterior cingulate cortex (dACC) function may contribute to tobacco smoking relapse vulnerability. Growing evidence suggests that glutamate neurotransmission is involved in mediating nicotine dependence. We hypothesized that prior to a cessation attempt, dACC glutamate levels would be lower in relapse vulnerable smokers. METHODS: Proton magnetic resonance spectra (MRS) were obtained from dACC and a control region, the parieto-occipital cortex (POC), using two-dimensional J-resolved MRS at 4T and analyzed using LCModel. Nine nicotine-dependent women were scanned prior to making a quit attempt. Subjects then were divided into two groups; those able to maintain subsequent abstinence aided by nicotine replacement therapy (NRT) and those who slipped while on NRT (smoked any part of a cigarette after attaining at least 24h of abstinence). RESULTS: Slip subjects exhibited significantly reduced dACC MRS glutamate (Glu/Cr) levels (p<0.03) compared to abstinent subjects. This effect was not observed in the POC control region. CONCLUSIONS: Our preliminary findings suggest that dACC Glu levels as measured with MRS may help identify and/or be a biomarker for relapse vulnerable smokers. Future research following up on these findings may help clarify the role of dACC Glu in smoking dependence that may lead to new treatment strategies.

Modest abuse-related subjective effects of zolpidem in drug-naive volunteers.

Recent case reports suggest that the short-acting benzodiazepine-like hypnotic, zolpidem, may have abuse potential among individuals who have no personal history of abusing drugs or alcohol, particularly at doses higher than those recommended for treating insomnia. This study recruited drug-naive volunteers to assess the subjective effects of multiple doses of zolpidem (0, 5, 10, or 20 mg) administered in a within-subject double-blind design. Participants (n=11) answered computerized questionnaires (Addiction Research Center Inventory, visual analog scales, and a hypothetical Drug versus Money Choice) to address the hypothesis that a supratherapeutic dose (20 mg) would increase ratings of abuse-related subjective effects, while lower therapeutic doses (5 and 10 mg) would not. Although participants rated some effects as negative at 10 and 20 mg, the highest dose engendered predominantly positive abuse-like effects such as 'High', 'Like', and 'Good Effects'. However, no dose of zolpidem was chosen over money ($0.35-$10) when participants made hypothetical choices between them. Results suggest that although individuals without a drug abuse history are not inclined to choose zolpidem when presented with an alternative reinforcer such as money, it may possess moderate abuse potential that limits its clinical utility.

Interaction of the rostral basolateral amygdala and prelimbic prefrontal cortex in regulating reinstatement of cocaine-seeking behavior.

Previous findings in rats suggest that the rostral basolateral amygdala (rBLA) and prelimbic prefrontal cortex (plPFC) are likely components of cue reinstatement circuitry based on bilateral inactivation of each site alone. In the present investigation, we examined whether the rBLA and plPFC interact to regulate reinstatement of cocaine-seeking behavior elicited by reexposure to a combination of discrete and contextual cocaine-paired cues. After establishing stable baseline responding under a second-order schedule of cocaine reinforcement and cue presentation, rats underwent response-extinction training in which cocaine and cocaine-paired cues were withheld. To test the interaction, rats with asymmetric cannulae placements in the rBLA and plPFC received vehicle or lidocaine infusions prior to reinstatement testing during which cocaine-paired cues were presented, in the absence of cocaine availability, under a second-order schedule. Asymmetric inactivation of the rBLA and plPFC significantly attenuated reinstatement of cocaine-seeking behavior relative to vehicle treatment. As expected, inactivation of the rBLA or plPFC in rats with unilateral cannulae placements did not disrupt reinstatement relative to vehicle treatment. Findings propose critical intrahemispheric interaction between the rBLA and plPFC in regulating reinstatement of cocaine-seeking behavior elicited by reexposure to drug-paired cues.

Role of the orbitofrontal cortex and dorsal striatum in regulating the dose-related effects of self-administered cocaine.

Little is known regarding which neural systems regulate dose-related changes in responses maintained by self-administered cocaine. This empirical question is important because elucidating neural systems engaged in this process could provide clues for effectively treating cocaine addiction. It has been suggested that different cocaine doses represent reinforcers of differing magnitudes, implicating the dorsal striatum or orbitofrontal cortex as important. Rats were trained to self-administer 1.0 mg/kg cocaine under a fixed-interval based second-order schedule. Next, cocaine unit doses (0.1-3.0 mg/kg) were each non-systematically available for a 5-day block of sessions. Tests (1h) were conducted on day 3 (vehicle) and day 5 (100 microg lidocaine) of each block. Lidocaine inactivation of the lateral dorsal striatum had no effect on dose-related responding or cocaine intake. In contrast, when doses along the ascending limb were available for self-administration, lidocaine inactivation of the lateral orbitofrontal cortex caused reductions in responding and cocaine intake, resulting in overall flattening of dose-response curves. This included reductions during the entire 1-h test sessions and during the interval immediately following the first cocaine infusion of test sessions. Lidocaine inactivation of the lateral orbitofrontal cortex did not alter responding during the first cocaine-free interval of test sessions, but increased the latency to the first infusion. Collectively, the findings suggest that when the amount of experience with different cocaine unit doses is limited to a few sessions, the lateral orbitofrontal cortex regulates the dose-related effects of self-administered cocaine, likely by processing information pertaining to the reinforcing value of each unit dose.

Dissociable effects of cocaine-seeking behavior following D1 receptor activation and blockade within the caudal and rostral basolateral amygdala in rats.

Research with dopamine D(1) receptor antagonists or neuronal inactivating agents suggests that there is dissociable regulation of cocaine-seeking behavior by the rostral and caudal basolateral amygdala. In the present study, discrete infusions of the D(1) receptor agonist SKF 81297 (0.0-0.8 microg per side) were compared with those of the D(1) receptor antagonist SCH 23390 (0.0-2.0 microg per side) to demonstrate directly the importance of D(1) receptor mechanisms within the rostral and caudal basolateral amygdala for their functional heterogeneity in regulating cocaine-seeking behavior. Under a second-order schedule, cocaine-seeking behavior was studied during maintenance (cocaine and cocaine cues present) and reinstatement (only cocaine cues present). Food-maintained responding was used to examine the specificity of maximal behaviorally effective doses of SKF 81297 and SCH 23390. The results demonstrated that the D(1) agonist (0.4 or 0.8 microg) increased and the D(1) antagonist (1.0 microg) decreased cocaine-seeking behavior during maintenance when infused into the caudal but not the rostral basolateral amygdala. Cocaine intake was not affected by the agonist, and was decreased by the antagonist. During reinstatement, the D(1) agonist (0.4 microg) increased and the D(1) antagonist (1.0 microg) decreased cocaine-seeking behavior when infused into the rostral but not the caudal basolateral amygdala. In tests for behavioral specificity, the above effective doses of SKF 81297 and SCH 23390 used in self-administration experiments did not alter food-maintained responding. However, the 2.0-microg dose of SCH 23390 suppressed drug-maintained and food-maintained responding after infusion into both subregions. Collectively, these findings indicate dissociable sensitivity to D(1) receptor ligands within the caudal and rostral basolateral amygdala for altering cocaine-seeking behavior under different conditions that model phases of addiction.

Role of dopamine D1 receptors in the prefrontal dorsal agranular insular cortex in mediating cocaine self-administration in rats.

RATIONALE: Orbital/insular areas of the prefrontal cortex (PFC) are implicated in cocaine addiction. However, the role of dopamine D1 receptors in mediating cocaine self-administration in these sub-regions remains unknown. OBJECTIVES: To define the role of the dorsal agranular insular (AId) sub-region of the PFC, we investigated the effects of D1 receptor manipulation on self-administration behavior maintained by cocaine and cocaine-related stimuli. MATERIALS AND METHODS: Rats were trained to lever press for cocaine (1 mg/kg) under a fixed-interval 5-min (fixed-ratio 5:S) second-order schedule of reinforcement in the presence of conditioned light cues and contextual sound cues. Intra-AId infusions of vehicle, the D1-like receptor agonist SKF 81297 (0.1, 0.2, 0.4 microg/side) or the D1-like receptor antagonist SCH 23390 (1.0, 2.0, 4.0 microg/side), were administered prior to 1-h self-administration test sessions. Food-maintained responding under a second-order schedule was examined in separate rats to determine if pretreatment with D1 ligands produced general impairments in responding. RESULTS: Infusion of SKF 81297 (0.2 and 0.4 microg/side) reduced active lever responses during the first 30 min of 1-h test sessions, but did not influence cocaine intake. Infusion of 4.0 microg/side SCH 23390 reduced active lever responses and cocaine intake throughout the 1-h test sessions. Additionally, this dose of SCH 23390 disrupted food-maintained responding and intake. CONCLUSIONS: D1 receptor agonists and antagonists in the AId have diverse consequences and time courses of action. D1 receptor stimulation in the AId may reduce the motivating influence of cocaine-related stimuli on responding whereas D1 receptor blockade in this PFC sub-region produces global disruptions in behavior.

Hippocampal regulation of contextual cue-induced reinstatement of cocaine-seeking behavior.

Associations between cocaine and cues facilitate development and maintenance of addiction. We hypothesized that the ventral hippocampus is important for acquisition of these associations. Rats were trained to self-administer cocaine, with or without pre-exposure to distinct sets of cocaine- and saline-paired contextual cues. Next, rats were conditioned for 3 days with the distinct sets of contextual cues paired with cocaine and saline along with distinct discrete cues. Vehicle or lidocaine was infused into the ventral hippocampus prior to conditioning sessions. Following extinction, reinstatement of cocaine-seeking behavior was examined following exposure to contextual cues, discrete cues, or their combination. Inactivation of the ventral hippocampus during conditioning blocked acquisition of the association between cocaine and cocaine-paired contextual cues in that only lidocaine-treated rats with short-term cue exposure failed to reinstate responding in the presence of cocaine-paired contextual cues. Lidocaine also prevented rats in both cue exposure groups from discriminating between cocaine- and saline-paired contextual cues during reinstatement tests. Reinstatement induced by cocaine-paired discrete cues or by contextual and discrete cues together was not impaired for either cue exposure condition. The hippocampus is important for acquisition of the association between cocaine and context and in maintaining discrimination between cocaine-relevant and -irrelevant contextual cues.