Research Findings - Basic Behavioral Research
Prenatal Oxycodone Impairs Spatial Learning and/or Memory in Rats
Recent changes in demographic patterns of drug abuse have resulted in increased non-medical use of prescription opiates. Prescription drugs are now abused by younger users and more females than males, with potential risk for in-utero exposure. A research team led by Dr. Schrott and colleagues has developed a rat model that simulates prescription opiate-dependence in women who become pregnant and continue to abuse these drugs. In this procedure, adult female Sprague-Dawley rats are treated for 30 days via oral gavage with ascending doses of oxycodone HCl, up to a final dose of 15mg/kg/day, and this final dose is then maintained during breeding and gestation. Controls are treated with water. In a recent study, adult male offspring of dams treated with this regimen were tested on a radial arm maze (during three phases: shaping, acquisition, and retention), a Morris water maze (with a short and a long intertrial interval), and a spatial T-maze (to test hippocampus-dependent spatial memory). The findings reveal that this oxycodone pattern of exposure caused deficits in all three tasks used to assess spatial learning or memory. More specifically, the researchers observed radial arm maze deficits characterized by a greater number of reference memory errors, especially in the beginning of testing. By contrast, in the T-maze, oxycodone-exposed rats learned the task as well as prenatal water controls but they had a modest deficit in task retention when assessed 5 days after acquisition training. For the Morris water maze, the intertrial interval affected the pattern of learning. Thus, while there was no deficit during training under a short intertrial interval, with longer intervals oxycodone-exposed rats showed poorer acquisition. The spatial learning deficit of increased latency to find, and distance traveled to, the platform in the water maze was corroborated by analyzing the animals' behavioral search strategy. During water maze training, drug-exposed animals showed a decreased use of spatial strategies and an increase in non-spatial strategies, especially wall-hugging, compared to prenatal water control rats on day 2 of acquisition. In summary, these results indicate that prenatal oxycodone exposure may impair learning and memory assessed on spatial tasks. Davis CP, Franklin LT, Johnson GS, Schrott LM. Prenatal Oxycodone Exposure Impairs Spatial Learning and/or Memory in Rats. Behav Brain Res. 2010; 212(1): 27-34.
A New Tool To Assess Statewide Capacity For Integrative Treatment of SUD With Other Psychiatric Disorders
Dr. R. Andrew Chambers, a psychiatrist at the Indiana School of Medicine, has a NIDA K08 award to study the etiology and neurobiological basis of drug addiction and comorbid psychiatric disorders in animal models. As part of this career development award, he also sees patients with dual diagnosis disorders, and he has been very active in promoting the need for integrated mental health and addiction services, as well as overcoming barriers of inadequate physician training and professional expertise in this area. In this paper, Dr. Chambers and his colleagues report on the design and implementation of a new Dual Diagnosis Physician-infrastructure Assessment Tool (DDPAT) to quantify statewide dimensions of this workforce problem. The DDPAT complements other survey instruments that are more comprehensive in assessing health systems but that don't directly assess physician workforce size, training background, or clinical roles with respect to dual diagnosis care. In the first phase of this project, they surveyed Indiana's six state psychiatric facilities, all 30 community health centers (CMHCs), and all 13 stand-alone addiction treatment centers with a simple 10 item questionnaire. They received responses from 100% of these facilities. In the second phase, they report a 75% response rate on a 10 item questionnaire from all physicians affiliated with these facilities. They found that 69% of all treatment centers, and 97% of the CMHCs reported dual diagnosis capability. However, only 29% of physicians treated both mental illness and addictions, and only 8% had certification in an addiction specialty. The addiction treatment centers had the highest percentage of addiction-certified physicians (21%), but only a minority of these centers reported dual diagnosis capability. Overall, their findings suggest a disconnection between how centers report their dual diagnosis capability and the levels of physician expertise and involvement in dual diagnosis treatment. They also found an overall shortage of psychiatrists in these facilities, and note that the workforce is aging. Their study indicates that the DDPAT is a useful and simple assessment tool to characterize a statewide physician workforce with respect to dual diagnosis capabilities and profiles of treatment centers. Given the extent to which dual diagnosis presentations are mainstream in behavioral health care, the authors hope that their findings will motivate changes in physician workforce development in Indiana and prompt the use of similar assessments in other states. Chambers RA, Connor MC, Boggs CJ, Parker GF. The Dual Diagnosis Physician-infrastructure Assessment Tool: examining physician attributes and dual diagnosis capacity. Psychiatr Serv. 2010;61(2): 184-188.
Activation of κ-Opioid Receptor In the Ventral Tegmental Area Attenuates Drug-Seeking Behavior In Rats
Previous research by Dr. Wenlin Sun and others indicates that glutamate-mediated activation of dopamine (DA) neurons in the VTA, and subsequent increases in DA receptor activation in the prefrontal cortex (PFC), are critically involved in cocaine-induced reinstatement of extinguished cocaine seeking in an animal model of relapse. These observations suggest that decreasing activity of VTA DA neurons projecting to the PFC may attenuate relapse. Recent studies using electrophysiological recording from brain slice preparations have shown that there are distinct subpopulations of DA neurons in the VTA. In particular, a subset of VTA neurons that express κ-opioid receptors (κORs) project to the PFC and amygdala, and not to other VTA targets, and these DA neurons are inhibited by κOR agonists. Therefore, Dr. Sun predicted that activation of κORs would inhibit cocaine-induced reinstatement. To test this hypothesis, the investigators infused the selective κOR agonist U50 588 bilaterally into the VTA in animals trained to self administer cocaine. During the maintenance phase of self-administration, the agonist had no effect on the rats' behavior. However, after self-administration was extinguished and then reinstated with a priming dose of cocaine, U50 588 in the VTA dose dependently attenuated cocaine-seeking (responses on the lever previously associated with cocaine delivery). This effect was selective for cocaine in that U50 588 did not suppress reinstatement in a separate group of rats trained to respond for food. This study used a novel approach - κOR agonist administration - to selectively inhibit the activity of a subset of VTA DA neurons. Because these DA neurons project to both PFC and amygdala, further research will be needed to determine whether decreases of DA in the PFC, the amygdala, or both accounted for the attenuation of cocaine seeking. However, other evidence converges on the PFC as the critical target for interfering with the motivation to seek drug. The κOR agonist was used in this study as a tool to test the hypothesis that this VTA-PFC/amygdala DA circuit is critically involved in relapse, but the results also suggest that κOR agonists might be considered for therapeutic approaches to relapse prevention. Sun W, Xue Y, Huang Z, Steketee JD. Regulation of cocaine-reinstated drug-seeking behavior by kappa-opioid receptors in the ventral tegmental area of rats. Psychopharmacology (Berl). 2010 Mar 16. [Epub ahead of print]
Electrical Stimulation of the Lateral Habenula Inhibits Cocaine Seeking in Rats
Deep-brain-stimulation (DBS) has had considerable success in the treatment of neurological disorders and has shown promising results in treating psychiatric disorders. DBS of nucleus accumbens has also been shown to block reinstatement of cocaine seeking in an animal model. The lateral habenula (LHb) innervates the ventral tegmental area (VTA) and prefrontal cortex with glutamatergic projections, and it known to be critical for modulation of negative reinforcement, punishment and aversive responses. In this study, supported by a NIDA CEBRA award, Dr. Yadid and his colleagues explored the use of LHb DBS to reduce cocaine self-administration, extinction, and reinstatement in rats. An electrode was implanted into the LHb and rats were trained to self-administer cocaine for 21 days until they achieved at least three days of stable performance. After that, they received DBS in either the presence or absence of cocaine. DBS reduced cocaine seeking behavior during both self-administration and extinction training. DBS also attenuated the rats' lever presses following reinstatement with a small priming dose of cocaine. They also carried out a number of control experiments to assess whether LHb DBS affected physical performance, which it did not. In tests of depressive-like behaviors, that is, anhedonia (two bottle choice test) and despair (swim test), LHb DBS was without effect. Interestingly, in contrast to the LHb DBS effect, lesions of LHb had no effect on drug self-administration or reinstatement and delayed rather than enhanced extinction. They also measured protein levels of the glutamatergic receptor subunits NR1 and GluR1, the synaptic scaffolding protein PSD95, and β subunits of the GABAA receptors in the VTA. Cocaine self-administration elevated the glutamatergic receptor subunits and PSD95, but not GABAAβ protein levels. Following DBS treatment, levels of the elevated proteins returned to control values. The results suggest that the effect of LHb DBS on cocaine reinforcement may be via attenuation of cocaine-induced increases in glutaminergic input to the VTA. Friedman A, Lax E, Dikshtein Y, Abraham L, Flaumenhaft Y, Sudai E, Ben-Tzion M, Ami-Ad L, Yaka R, Yadid G. Electrical stimulation of the lateral habenula produces enduring inhibitory effect on cocaine seeking behavior. Neuropharmacology. 2010 Jun 22. [Epub ahead of print].
Tricyclics May Act at the Toll-like Receptors to Enhance Opioid Analgesia
Opioids have Toll-like receptor (TLR) activity and this action tends to produce pain. This raises the question whether other pharmacotherapies for pain may have TLR activity, contributing to or opposing their clinical effects. In the current research, NIDA grantees Dr. Mark Hutchinson (University of Adelaide) and Drs. Steven Maier and Linda Watkins (University of Colorado) and colleagues examined the actions of tricyclics on TLR4 signaling. In silico simulations revealed that several tricyclics docked to the same binding pocket on the TLR accessory protein as do opioids. Eight tricyclics were tested in rats and mice. While tricyclics had no effect on basal pain responsivity, they potentiated morphine analgesia in rank-order with their potency as TLR4 inhibitors. This potentiation was absent in TLR4 knock-out mice. These studies provide converging lines of evidence that several tricyclics or their active metabolites may exert their biological actions, in part, via modulation of TLR4 signaling and suggest that inhibition of TLR4 signaling may potentially contribute to the efficacy of tricyclics in treating chronic pain and enhancing the analgesic efficacy of opioids. Hutchinson MR, Loram LC, Zhang Y, Shridhar M, Rezvani N, Berkelhammer D, Phipps S, Foster PS, Landgraf K, Falke JJ, Rice KC, Maier SF, Yin H, Watkins LR. Evidence that tricyclic small molecules may possess toll-like receptor and myeloid differentiation protein 2 activity. Neuroscience 2010: (168): 551-563.
Opioid-Adrenergic Analgesic Synergy Involves Spinal and Peripheral Heterodimers
Agonists acting at alpha 2-adrenergic and delta opioid receptors inhibit spinal pain transmission. When co-administered, agonists activating these receptors interact in a synergistic manner. Action at heterodimers has been proposed as a molecular basis for this synergy. To examine this question, NIDA grantees Dr. George Wilcox (University of Minnesota), Dr. Laura Stone (McGill University) and colleagues used immunohistochemistry to investigate the spatial relationship between alpha 2-adrenergic and opioid receptors in the rat spinal cord to determine whether co-expression could be demonstrated between these receptors. They observed extensive co-localization between alpha 2A-adrenergic and delta-opioid receptors on substance P-immunoreactive varicosities in the superficial dorsal horn of the spinal cord and in peripheral nerve terminals in the skin. These elements were co-localized in subcellular structures of 0.5 micrometers or less in diameter in isolated nerve terminals. Furthermore, co-incubation of isolated synaptosomes with alpha 2 and delta agonists resulted in synergistic inhibition of K+-stimulated neuropeptide release. These findings suggest that co-expression of alpha 2-adrenergic and delta opioid receptors on primary afferent nociceptive fibers may represent an anatomical substrate for analgesic synergy. Riedl MS, Schnell SA, Overland AC, Chabot-Doré A-J, Taylor AM, Ribeiro-Da-Silva A, Elde RP, Wilcox GL, Stone LS. Coexpression of alpha 2A-adrenergic and delta-opioid receptors in substance P-containing terminals in rat dorsal horn. Journal of Comparative Neurology, 2009: (513): 385-398.
Central Activation of the Peroxisome Proliferator-Activated Receptor Gamma Can Induce A Chronic Pain State: Possible Target for the Treatment of Chronic Inflammatory Pain
Systemic administration of thiazolidinediones reduces peripheral inflammation in vivo, presumably by acting at peroxisome proliferator-activated receptor gamma (PPAR gamma) in peripheral tissues. NIDA-grantee Dr. Bradley Taylor (University of Kentucky) and colleagues postulated that brain PPAR gamma modulates peripheral edema and the processing of inflammatory pain signals in the dorsal horn of the spinal cord. In the rat plantar carrageenan behavioral model of inflammatory pain, Dr. Taylor examined paw edema, behavioral heat hyperalgesia, and dorsal horn expression of the immediate-early gene c-fos after intracerebroventricular (ICV) administration of PPAR gamma agonists or vehicle. PPAR gamma agonists dose-dependently reduced paw thickness, paw volume and behavioral withdrawal responses to noxious heat. Further, the number of carrageenan-induced Fos-like immunoreactive profiles was less in PPAR gamma agonist treated rats as compared to vehicle controls. Intraperitoneal and intrathecal administrations of PPAR gamma agonists did not produce a similar effect. Further, co-administration of ICV administration of PPAR gamma antagonists reversed these actions. Thus, pharmacological activation of PPAR gamma in the brain rapidly inhibits local edema and the spinal transmission of noxious inflammatory signals and may be a target for the development of novel pharmacological pain treatments. Morgenweck J, Abdel-aleem OS, McNamara KC, Donahue RR, Badr MZ, Taylor BK. Activation of peroxisome proliferator-activated receptor gamma in brain inhibits inflammatory pain, dorsal horn expression of Fos, and local edema. Neuropharmacology, 2010: (58): 337-345.
Neuroadaptations in the Transition to Compulsive Drug Intake Suggest Glutamatergic Targets for Treatment
Dr. Friedbert Weiss has been investigating neurochemical substrates of reinforcing drug effects, with particular emphasis on the neurotransmitter, glutamate (GLU). Pharmacologic manipulation of metabotropic GLU receptors can reverse behavioral effects of acute or chronic cocaine administration, including the rewarding effects of this psychostimulant, and attenuate cue-induced relapse in an animal model. Two GLU receptors of interest in recent studies include mGluR2/3, which negatively modulates GLU transmission, and mGluR5, which increases GLU release when activated. The PI sought to determine if neuroadaptations in these receptor substrates, occurring over the course of repeated cocaine self-administration, might be important for the compulsive, uncontrollable pattern of intake that emerges over a 6h/day drug schedule of drug access. Male Wistar rats provided with one versus 6h/day of drug availability showed the usual pattern of intake over 22 days: Steady intake by the short access group (ShA, exposed to 1h/day cocaine) and gradually increasing intake by the long access group (LgA, self-administering for 6h/day). LgA rats were also willing to "work harder" to obtain the drug as evidenced by significantly higher break points on a progressive ratio schedule. Next groups were tested for break point changes consequent to treatment with either an mGluR2/3 agonist (LY) or an mGluR5 antagonist (MTEP) to dampen GLU transmission. LY dose-dependently lowered the breakpoint for cocaine in LgA rats, with decreases in ShA animals only at the highest dose. By contrast MTEP had no effect on LgA in this test, while dose-dependently lowering break points in the ShA group. These findings suggest that the two classes of GLU receptors may show differential neuroadaptations over the course of chronic cocaine self-administration. The researchers also measured mGluR with immunoblotting and binding of [35S]GTP-γS to assess receptor expression levels and functional activity (via G-protein coupling), respectively. Following escalation, only LgA rats showed a significant reduction in mGluR5 protein levels in the nucleus accumbens (NAS). While LY (the mGluR2/3 agonist) concentration-dependently stimulated [35S]GTP-γS binding in all tissues, signficiantly greater agonist-induced binding was measured in the medial prefrontal cortex mPFC) and ventral tegmental area (VTA) of LgA rats. As these regions are important cell body areas (VTA) and terminal projection regions (NAS, mPFC) of a mesocorticolimbic dopamine system that is critical for reinforcing properties of drugs, GLU receptor neuroadaptations in this system may play an important role in the emergence of addictive behavior. In summary, both pharmacologic manipulations attenuated the reinforcing effects of cocaine and indicate that mGluR2/3 and mGluR5 may be enhanced versus down-regulated, respectively, in the transition to uncontrollable drug intake. The authors caution that GLU compounds specific for these receptor targets may be plagued with non-specific effects, thus limiting the translation to human use. Therefore, additional research on putative pharmacotherapies acting on GLU receptor substrates will be needed. Hao Y, Martin-Fardon R, Weiss F. Behavioral and Functional Evidence of Metabotropic Glutamate Receptor 2/3 and Metabotropic Glutamate Receptor 5 Dysregulation in Cocaine-Escalated Rats: Factor in the Transition to Dependence. Biol Psychiat. 2010 Aug; 68(3): 240-248.
Unique and Persistent Nicotine-Induced Changes in Gene Expression May Underlie Adolescent Vulnerability
Researchers at George Washington University have previously shown that chronic nicotine (nic) exposure during adolescence differentially regulates subtypes of nic receptors, in comparison to adult rats. In a new study, these NIDA funded investigators studied tissue from the ventral tegmental area (VTA) region for dopamine cell bodies after two weeks of passive infusion with nic or saline. Adult and periadolescent animals were sacrificed for whole genome microarray analysis immediately after these two weeks or after four weeks of abstinence. To validate expression data for selected genes, quantitative real-time PCR was also used. In comparison to saline-infused controls, clusters of genes were identified that represented "transient responders" (significantly changed at two weeks), "late responders" (change in expression after abstinence only) and "persistent responders" (up- or down-regulated at both time points). Some clusters revealed genes that were uniquely changed in expression during adolescent nic exposure or during adult nic exposure. Other clusters showed overlap between the two age groups. Interestingly, twice as many genes from the adolescent nic treated group were persistently regulated (remaining up- or down-regulated after four weeks of abstinence), and the number of late regulated genes (change only at the four week abstinence point) was four fold for the adolescent exposed group. These findings suggest unique genomic responses to nic exposure that may persist into adulthood and underlie teen vulnerability for rapid emergence of dependence. To investigate biological significance of unique gene changes, the researchers applied a Ingenuity Pathways Analysis. This analysis allowed for the identification of functions, networks and canonical pathways, revealing over-representation of unique adolescent genes in the synaptic long-term potentiation (LTP), circadian rhythm signaling and CDK5 signaling canonical pathways. These observations are important because they reveal nic-induced changes in adolescent gene expression within systems that regulate neuroplasticity (LTP) and neural development. In conclusion, this study further supports earlier findings to sugest that the effects of chronic nic exposure depends upon age of drug use, and that nic may induce downstream effects that persist long after exposure is halted. Doura MB, Luu TV, Lee NH, Perry DC. Persistent gene expression changes in ventral tegmental area of adolescent but not adult rats in response to chronic nicotine. Neurosci 2010, doi: 10.1016/j.neuroscience.2010.06.071 In Press, Uncorrected Proof, Available online 13 July 2010.
Measuring Behavioral Arousal to Stress and Drug Cues in Alcohol- and Cocaine-Addicted Individuals
Previous research reveals that negative emotional arousal, in response to stress or drug-associated cues, plays a role in the development and continuation of substance use disorders. Until recently, emotional arousal has been measured by self-report or electrophysiological proxy. Recent studies from Dr. Tara Chaplin and Dr. Rijita Sinha, have been using a new Behavioral Arousal Scale (BAS) to measure behavioral and bodily arousal in response to stress and drug-related cues. Individuals with alcohol dependence and cocaine dependence were compared to healthy controls in a study of ninety seven addicts between the ages of 21 and 50: Fifty-two alcohol dependent (AD), 45 cocaine-dependent (COC). Drug-using individuals were compared with 68 healthy controls (HC). All participants were exposed to individually-tailored stressful, drug-cue, and neutral (relaxing) imagery. Results from the BAS revealed acceptable inter-rater reliability and internal consistency. Also, measures correlated with self-report of subjective negative emotion and craving. In addition, BAS scores were higher in response to stress imagery than for neutral conditions in all three groups. Inter-group comparisons revealed that: COC participants showed higher BAS response to stress than AD or HC participants; and both COC and AD participants showed greater BAS response to drug cue imagery than HC participants. In conclusion, behavioral arousal is a domain in which stress and drug related arousal is expressed and assessment of this domain could provide unique information about vulnerability to craving and relapse in addicted subjects. Objective assessments made with use of the BAS might also be useful for formulating and assessing personalized treatment approaches for addiction. Chaplin TM, Hong K, Fox HC, Siedlarz KM, Bergquiat K, Sinha R. Behavioral Arousal in response to Stress and Drug Cue in Alcohol and Cocaine addicted Individuals Versus Healthy Controls. Hum Psychopharmacol. 2010 Jul;25(5): 368-376.
Gender Differences in Caregiver Emotion Socialization of Low-Income Toddlers
Previous research reveals that low-income children are at elevated risk for emotion-related problems. Very little research has examined gender and emotion socialization in low-income families, however. Dr. Tara Chaplin and her mentor, Dr. Rajita Sinha, recently published a chapter on gender and emotion socialization in New Directions for Child and Adolescent Development, proposing two models for understanding the relationship between emotion socialization and the development of psychopathology, particularly in low-income children. These models are based on new data from a study designed to examine emotion socialization responses by low-income female caregivers to their toddlers' sadness/anxiety and anger displays. Sixty-five 2 1/2 year olds (33 boys and 32 girls) participated in this laboratory-based study. Children were exposed to a frustrating, toy wait task with their primary caregivers present. Sadness and anxiety were coded from facial, vocal and postural cues in the children. Caregiver responses to child emotion were coded based on verbalizations, behaviors and/or emotion expressions and were classified as no response, support/reward, override (dismissing or distracting the child), punishment and caregiver distress. Results of the coding show that girls showed slightly less sadness/anxiety and slightly greater anger than boys. For those children expressing one or more emotion in the task, caregiver responses indicated more supportive reactions to boys than to girls. However they responded to anger with punishment about twice as often for girls than boys, and with caregiver distress about six times more often for girls than boys. These descriptive data suggest that low-income (primarily African American) female caregivers respond in ways that encourage boys' anger and discourage or punish girls' anger. There were few consistent differences in caregiver responses to sadness/anxiety. The authors conclude that implications of caregiver response in children's social-emotional development might be explained by (1) an Emotion Competence Model, in which parental responses that support child emotions lead to greater emotional competence, or by (2) the Differential Emotions Model, that theorizes encouragement/reward of particular emotions leads children to express patterns of emotion that may, in conjunction with other risk factors, lead them toward particular forms of psychopathology. Chaplin TM, Casey J, Sinha R, Mayes LC. Gender Differences in Caregiver Emotion Socialization of Low-Income Toddlers. New Dir Child Adolec Dev. 2010 128; 11-27.
Access to a Running Wheel Reduces Both Extinction and Reinstatement Responding in Female Rats
Access to exercise in a running wheel acts as a positive reinforcer for rats and Dr. Marilyn Carroll and colleagues at the University of Minnesota have previously shown that it can reduce both acquisition and maintenance of cocaine self-administration when concurrently available. The present study examined the effect of wheel running access on extinction and reinstatement of cocaine seeking in female rats. After the rats were trained to run in a wheel during 6-h sessions, they were then catheterized and placed in an operant conditioning chamber where they did not have access to the wheel but were allowed to self-administer iv cocaine. Following maintenance of cocaine self-administration, the rats were divided into four groups and were tested on extinction and cocaine-primed reinstatement of cocaine seeking while they had varying access to a wheel in an adjoining compartment. The four groups were based on the following wheel access conditions: (1) access during both extinction and reinstatement (WER), (2) access only during extinction (WE), (3) access only during reinstatement (WR), and (4) access during neither extinction nor reinstatement (WL). Results indicated that during extinction, both groups that had access to running (WE and WER) responded less than the groups that did not have access (WR and WL). Similarly, both groups that had access to running during reinstatement (WR and WER) had lower cocaine-primed reinstatement than the groups without access (WE and WL). The finding that group WE did not have suppressed reinstatement indicated that their suppressed responding during extinction did not carry forward into reinstatement, i.e., it was not enduring. However, a probe session of wheel exposure in the WE rats did induce suppression of cocaine-primed reinstatement. These data show that wheel running immediately and effectively reduces cocaine-seeking behavior, but concurrent access to running is necessary for the suppressive effect. Results indicated that the attenuating effects of wheel running on cocaine seeking was not due to competition for time, but rather suggest that the reinforcing value of wheel running competed with the reinforcing value of cocaine. These data suggest that exercise may be a useful and self-sustaining intervention to reduce cocaine-seeking behavior. Zlebnik NE, Anker JJ, Gliddon LA, Carroll ME. Reduction of extinction and reinstatement of cocaine seeking by wheel running in female rats. Psychopharmacology. 2010; 209(1): 113-125.
Differential Sensitivity to Reinstatement in Adolescent and Adult Male Rats
Animal studies have shown that in general, the reinforcing effects of stimulant drugs is greater in adolescents than adults during acquisition and maintenance of drug self-administration. No studies, however, have compared adults and adolescents in other phases of drug abuse, including extinction (when the drug is discontinued) and during models of relapse when responding is reinstated with either a priming dose of the drug, a stressor, or cues previously associated with drug delivery. Male adolescent and adult rats were recently compared in these paradigms by Dr. Marilyn Carroll and her colleague Justin Anker at the University of Minnesota. On postnatal days 23 (adolescents) and 90 (adults), rats were implanted with intravenous (i.v.) catheters and trained to lever press for i.v. infusions of cocaine (0.4 mg/kg) during two daily 2-h sessions. The rats then self-administered i.v. cocaine for ten additional sessions. Subsequently, visual and auditory stimuli that previously signaled drug delivery were turned off and rats underwent extinction, during which time drug and cues were not available for 20 sessions. Next, in reinstatement testing (a procedure used to model human relapse) rats were tested for cocaine-, cue-, and yohimbine (stress)-induced cocaine seeking using a within-subject multicomponent procedure. Results indicated that during maintenance and extinction, adolescents self-administered more cocaine than adults. During reinstatement, adolescents exhibited greater drug seeking (responding on the lever which previously delivered i.v. cocaine) than adults following cocaine priming injections and yohimbine administration (to activate a stress response). However, adults responded more than adolescents following presentation of drug-associated cues. These results demonstrate that vulnerability to relapse in adolescents and adults differ across measures of drug-seeking behavior, and that adolescents may be especially vulnerable to relapse precipitated by drugs and stress. The authors speculate that these findings may be linked to development of key brain areas involved in reward-, inhibitory-, and memory-related processes during adolescence. Anker JJ, Carroll ME. Reinstatement of cocaine seeking induced by drugs, cues, and stress in adolescent and adult rats. Psychopharmacology, 2010; 208(2): 211-222.
Adolescent Rats Repeatedly Treated with δ9-THC Display Cognitive Deficits Upon Subsequent Drug Challenge in Adulthood
Early-onset marijuana use has been associated with short- and long-term deficits in cognitive processing. In human users, self-selection bias prevents determination of the extent to which these effects result only from drug use, rather than pre-existing conditions. Dr. Jenny Wiley at the Research Triangle Institute (formerly, a NIDA grantee at the Virginia Commonwealth University) examined long-term effects of δ9-tetrahydrocannabinol (δ9-THC, the major psychoactive constituent of marijuana), administered to male rats during adolescence, on a delayed nonmatch-to-position task (DNMP) in adulthood. DNMP is an operant procedure that is commonly used to examine the effects of drugs on short-term memory in rats. This procedure consists of a series of trials in which initially one of two levers is extended into an operant chamber. Five presses on the lever results in presentation of food and withdrawal of the lever. Following varying delays, both levers are introduced together and the next food reinforcement is contingent upon pressing the lever that was previously extended. In the present experiment, rats were injected daily with 10 mg/kg δ9-THC during or after adolescence [postnatal days (PN) 21-50 or PN50-79), respectively] or with vehicle. On PN91, training in DNMP was initiated in the three groups. Pharmacological challenge began on approximately PN300. Rats were challenged sequentially with δ9-THC and anandamide (an endogenous cannabinoid receptor ligand) in order to determine differential inter-group sensitivity to the disruptive effects of these cannabinoids on accuracy in the procedure. For comparison purposes, scopolamine was tested as a positive control and amphetamine as a negative control. The researchers found that vehicle-treated rats required more sessions to reach criterion performance than the two δ9-THC groups, but that once criterion was achieved, there were no differences in accuracy among the three groups. When tested under the δ9-THC challenge (drug administered before testing), however, differences emerged. Whereas doses of δ9-THC up to 30 mg/kg did not impair accuracy in the vehicle-treated rats, both groups that received daily administration of δ9-THC exhibited decreases in accuracy when tested under 10 mg/kg, with 3 mg/kg decreasing accuracy only in rats treated during adolescence. While anandamide did not decrease accuracy in any group, rats treated with δ9-THC during adolescence initiated fewer trials at the 30 mg/kg dose of anandamide than did rats in the other groups. To the extent tested, these differences were pharmacologically selective for cannabinoids, as scopolamine decreased accuracy at the same dose in all groups and amphetamine did not affect accuracy in any of the groups at doses that did not impair overall responding. These results suggest that in rats repeated administration of a modest dose of δ9-THC during adolescence (PN21-50) or shortly thereafter (PN50-79) produces a long-term increase in latent sensitivity to cannabinoid-induced impairment of performance in a complex operant task. These results suggest that in humans, regular administration of δ9-THC during adolescence may also have long-term effects on cognitive performance that remain latent until revealed later under δ9-THC challenge. Wiley JL. Burston JJ. Chronic Æ9-tetrahydrocannabinol during adolescence in male rats increases sensitivity to subsequent cannabinoid effects in delayed nonmatch-to-position in rats. Pharmacol Biochem Behavior 2010; 94(4): 516-523.