Yasmin Mashhoon

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.

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.

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

Research with dopamine D1 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 D1 receptor agonist SKF 81297 (0.0–0.8 μg per side) were compared with those of the D1 receptor antagonist SCH 23390 (0.0–2.0 μg per side) to demonstrate directly the importance of D1 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 D1 agonist (0.4 or 0.8 μg) increased and the D1 antagonist (1.0 μg) 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 D1 agonist (0.4 μg) increased and the D1 antagonist (1.0 μg) 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‐μg dose of SCH 23390 suppressed drug‐maintained and food‐maintained responding after infusion into both subregions. Collectively, these findings indicate dissociable sensitivity to D1 receptor ligands within the caudal and rostral basolateral amygdala for altering cocaine‐seeking behavior under different conditions that model phases of addiction.

Modest abuse-related subjective effects of zolpidem in drug- naïve 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 (

Role of the Orbitofrontal Cortex and Dorsal Striatum in Regulating the Dose-Related Effects of Self-Administered Cocaine

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

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.

Cortical thinness and volume differences associated with marijuana abuse in emerging adults.

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.

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

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.

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

BACKGROUND The prevalence of marijuana (MJ) use among youth and its legalization for medical or recreational use has intensified public health endeavors of understanding MJ effects on brain structure and function. Studies indicate that MJ use is related to impaired cognitive performance, and altered functional brain activation and chemistry in adolescents and adults, but MJ effects on brain morphology in emerging adults are less understood. METHODS Fifteen MJ users (age 21.8±3.6, 2 females) and 15 non-user (NU) participants (age 22.3±3.5, 2 females) were included, demographically matched on age, education and alcohol use. High-resolution structural MR images were acquired at 3Tesla. Cortical thickness (CT) and volumetric analyses were performed using Freesurfer. A priori regions of interest (ROI) included orbitofrontal and cingulate cortices, amygdala, hippocampus and thalamus. RESULTS Whole brain CT analysis did not result in significant group differences in a priori ROIs but revealed MJ users had significantly less CT (i.e., thinness) in right fusiform gyrus (rFG) compared to NU (p<0.05). Thalamic volume was significantly smaller in MJ users compared to NU (right, p=0.05; left, p=0.01) and associated with greater non-planning (p<0.01) and overall impulsivity (p=0.04). There were no other group differences. CONCLUSIONS RFG cortical thinness and smaller thalamic volume in emerging adults is associated with MJ abuse. Furthermore, smaller thalamic volume associated with greater impulsivity contributes to growing evidence that the thalamus is neurobiologically perturbed by MJ use. Collectively, altered thalamic and rFG structural integrity may interfere with their known roles in regulating visuoperceptual and object information processing.

Deficient cortical face-sensitive N170 responses and basic visual processing in schizophrenia

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.