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Aims Evidence indicates that obese individuals exhibit alterations in brain-reward function that are anatomically and functionally similar to what has been observed in drug addicts, which could theoretically make obese individuals vulnerable to drug abuse and drug abusers vulnerable to overeating. However, few studies have investigated the cross-generality of these phenotypes. We recently reported that the reinforcing effectiveness (i.e., value) of a fat was greater in obese Zucker rats than in their lean counterparts, but found no differences in the reinforcing effectiveness of cocaine between groups, suggesting psychostimulant reinforcement is similar in lean and obese Zucker rats. However, it is unknown if other aspects of reinforcement such as cocaine's potency as a reinforcer or its reinstating effects differ in lean and obese Zucker rats. Methods The current study compared cocaine's potency as a reinforcer in lean and obese Zucker rats self-administering intravenous cocaine (0.06–1.0 mg/kg/inj), and subsequently tested these subjects in cue- (light) and drug-primed (intraperitoneal cocaine; 10 mg/kg) reinstatement of extinguished operant responding. Results All rats acquired cocaine self-administration and generated “inverted-U” dose-response functions. Following extinction of responding, the cue- and drug-primes increased lever-pressing in both groups (i.e., reinstatement). No significant differences in the reinforcing potency or reinstating effects of cocaine were observed as a function of obesity. Conclusions These results, combined with our previous observations, demonstrate that cocaine's reinforcing effects are comparable in lean and obese Zucker rats and do not support the hypothesis that obesity is associated with an altered reinforcing effect of psychostimulants.

Examination of a drug's abuse potential at multiple levels of analysis (molecular/cellular action, whole-organism behavior, epidemiological data) is an essential component to regulating controlled substances under the Controlled Substances Act (CSA). We reviewed studies that examined several central nervous system (CNS) stimulants, focusing on those with primarily dopaminergic actions, in drug self-administration, drug discrimination, and physical dependence. For drug self-administration and drug discrimination, we distinguished between experiments conducted with rats and nonhuman primates (NHP) to highlight the common and unique attributes of each model in the assessment of abuse potential. Our review of drug self-administration studies suggests that this procedure is important in predicting abuse potential of dopaminergic compounds, but there were many false positives. We recommended that tests to determine how reinforcing a drug is relative to a known drug of abuse may be more predictive of abuse potential than tests that yield a binary, yes-or-no classification. Several false positives also occurred with drug discrimination. With this procedure, we recommended that future research follow a standard decision-tree approach that may require examining the drug being tested for abuse potential as the training stimulus. This approach would also allow several known drugs of abuse to be tested for substitution, and this may reduce false positives. Finally, we reviewed evidence of physical dependence with stimulants and discussed the feasibility of modeling these phenomena in nonhuman animals in a rational and practical fashion. This article is part of the Special Issue entitled 'CNS Stimulants'.

(+)-Methamphetamine (MA) is an illicit psychostimulant that can be synthesized from the nonprescription nasal decongestant, (+)-pseudoephedrine (PE). While MA is widely abused, PE appears to have little or no abuse liability in currently available formulations. However, PE produces centrally-mediated dopaminergic effects that are linked to the reinforcing effects of MA and other illicit psychostimulants and has been reported to function as a positive reinforcer in non-human primates. There has yet to be an assessment of the relative reinforcing effects of MA and PE. Therefore, the current study compared the reinforcing potency and strength of MA and PE, alone and combined, in four rhesus monkeys that were allowed to self-administer MA (0.003-0.3 mg/kg/inj), PE (0.1-3.0 mg/kg/inj), or combinations of the two under a progressive-ratio schedule of reinforcement. (+)-Methamphetamine functioned as a positive reinforcer in a dose-dependent manner. (+)-Pseudoephedrine also functioned as a positive reinforcer, but was less potent than MA. There were no differences in maximum injections between MA, PE, or any of the combinations of the two. Dose-addition analysis and the interaction index indicated that combinations of PE and MA were either additive or sub-additive in their reinforcing effects. These results suggest that, while MA is a more potent reinforcer than PE, the two drugs are comparable in terms of reinforcing strength. However, MA and PE do not appear to interact in a manner that enhances their relative reinforcing effects.

Although taste aversion learning has been reported to be a function of a variety of factors, one that has received considerable attention is the subject's sex, wherein males generally display stronger taste aversions than females. An exception to these findings is with cocaine for which females have been shown to display greater aversions than males. Although suggestive of a Sex x Drug interaction, cocaine was administered subcutaneously (s.c.) in this report while others administered drug intraperitoneally (i.p.). Thus, there may be a Sex x Route interaction. To address the contributions of sex and route in cocaine aversions, the present study examined aversions in male and female Sprague-Dawley rats administered a range of doses of cocaine either s.c. or i.p. At the two higher doses of cocaine tested (20 and 32 mg/kg), aversions were a function of route with animals injected s.c. with cocaine displaying greater aversions than those injected i.p. Although there was no main effect of sex at either dose there was an interaction between sex and route at the 20 mg/kg dose. Specifically, s.c.-injected males displayed stronger aversions than i.p.-injected males. There were no differences between the two routes for females. Further, males displayed stronger aversions than females when injected s.c. There was no sex difference when both groups were injected i.p. This interaction was no longer evident at the highest does of cocaine (32 mg/kg). These data indicate that sex differences in aversion learning with cocaine are a function of the route of cocaine administration (and are dose specific).

Articular cartilage lesions remain a difficult problem for the patient and physician. A variety of procedures and treatments have been proposed to lessen symptoms and restore the articular surface. The knee joint has been the focus of the vast majority of these cartilage restoration procedures. Articular cartilage lesions of the humerus are significantly less common, and their management remains poorly defined. This paper presents a case report of a young athlete with a large full-thickness articular cartilage defect of the proximal humerus and subsequent treatment using autologous chondrocyte implantation.

Separation from conspecifics in chicks produces an increase in distress vocalizations and a decrease in response to a noxious stimulus (stress-induced analgesia). This study questioned the relative contributions of novelty to the test chamber and social separation in mediating these stress responses. Eight-day-old chicks were tested either in isolation or in the presence of two social companions for a 3-min observation period in which distress vocalizations were recorded as well as the frequency of footlifts in response to a 50-microl injection of 0.10% formalin into the plantar surface of the footpad. In Expt. 1, chicks received six, 3-min test chamber habituation trials (vs. no habituation) one per day before testing; in Expt. 2, chicks were tested with mirrors placed in the chambers (vs. no mirrors). In both studies, isolated chicks in control groups (i.e., no habituation or no mirror) exhibited increased distress vocalizations and decreased nociceptive responses. In Expt. 1, habituation to the test chamber attenuated stress-induced analgesia but did not affect distress vocalizations. In Expt. 2, placement of mirrors in the test chamber attenuated distress vocalizations but did not affect stress-induced analgesia. These findings demonstrate a dissociation of stress behaviors in the chick social-separation-stress procedure: the stress-induced analgesia response is primarily mediated by novelty to the test apparatus while the distress vocalizations response is mediated by separation from conspecifics.

problems (b= .020, p< .001), and other drug problems (b= .022, p= .002).Negativeaffect fullymediatedanxiety sensitivity relations with tobacco dependence (b [95% CI] = .037 [.027–.046]), alcohol problems (b [95% CI] = .016 [.012–.021]), and other drug problems (b [95% CI] = .021 [.015–.026]). Conclusions: Although limited by a cross-sectional design, current findings suggest that adolescents high in anxiety sensitivity tend to experience negative affect, which in turn is related to substance use problems. Treatments that target anxiety sensitivity or negative affect may be helpful in preventing and reducing adolescent substance use problems. Financial support: NIDA Grant R01-DA033296 and NCI Grant T32-CA009492.

s / Drug and Alcohol Dependence 156 (2015) e102–e182 e161 The role of carbonyl reductases in biotransformation of bupropion and 4-methylnitrozamino-1-(3-pyridyl)-1-butanone by human placenta Tatiana Nanovskaya1, Valentina M. Fokina1,2, X. Wang1, Cheryl Oncken3, Mahmoud S. Ahmed1, Gary Hankins1 1 OBG the reaction is catalyzed primarily by 11 hydroxisteroid dehydrogenase (11 -HSD) and aldoketoreductases. Maternal cigarette smoking has been associated with prenatal exposure to NNK, which is the most abundant and potent carcinogen of cigarette smoke. One of the metabolic pathways of NNK is carbonyl reduction to 4-methylnitrosamino-1-(3-pyridyl)1-butanol (NNAL) that initiates NNK detoxification. The goal of the current investigation is to determine placental metabolism of NNK and to identify placental enzymes responsible for its reduction. Methods: Term placentas were collected from women who smoked during pregnancy and from non-smokers. NNK metabolism was determined in vitro using placental microsomal and cytosolic subcellular fractions; the formation of NNAL was quantified by HPLC-UV. Results: The apparent Km and Vmax values for the reaction in placental subcellular fractions were determined. The formation of NNAL in placentas of heavy smokers was lower than in placentas of non-smokers: 12.1±3.5 vs. 17±6.3nmolmgP−1 for cytosolic fraction (p methamphetamine>4-MePPP>4-MEC. Conclusions: The current findings demonstrated that three second-generation synthetic cathinones functioned as reinforcers in rats, providing some justification for permanent scheduling of these drugs by regulatory agencies. Future research in our laboratory will assess the reinforcing effectiveness of these three compounds with a behavioral economics approach. Financial support: This research was supported by the UMMC Drug Abuse Development Fund and R01 DA12970 to BB. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.439 Serotonin 5-HT2C receptors in the ventral subiculum regulate cocaine-evoked hyperactivity in rats Harshini Neelakantan1, Sonja J. Stutz1, Marcy J. Bubar1, Robert M. Sears3, Ralph J. DiLeone3, Kathryn A. Cunningham1,2 1 Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, United States 2 Department of Pharmacy, University of Texas Medical Branch, Galveston, TX, United States 3 Department of Psychiatry, Yale University, New Haven, CT, United States Aims: The ventral subiculum (vSUB) interconnects with limbiccorticostriatal circuit which regulates the behavioral effects of cocaine. Serotonin neurons innervate the vSUB, however, little is known about its role or the 5-HT receptors that are functionally relevant in this region. We investigated the vSUB localization of the 5-HT2C receptor (5-HT2CR) and its role in the control of cocaineevoked hyperactivity. Methods: The expression of the 5-HT2CR and co-localization with GAD 67 (marker for GABA) in the vSUB were evaluated using immunohistochemical analyses in rats (n=3).We employed virally mediated genetic knockdown strategy to test the hypothesis that knockdown of the 5-HT2CR in the vSUB of rats (n=5) will modulate cocaine-evoked hyperactivity. Motor activity was assessed after saline or cocaine (10–20mg/kg) in modified open-field chambers and analyzed using repeated measures two-way ANOVA. Results:Dense immunoreactivity (IR) for 5-HT2CRwasobserved throughout the vSUB. Only a small proportion of 5-HT2CR-IR was co-localized with GAD 67-IR that was restricted to the distal end

The present commentary describes the availability of a database on conditioned taste aversion learning, the avoidance of fluids and foods previously associated with the aversive effects of a variety of drugs. The database includes articles as early as 1955 by Garcia and his colleagues [Science 122 (1955) 127] (reporting such avoidance in rats) and papers just published given that the database is ongoing and constantly updated. At the printing of this announcement, approximately 2600 papers are included in the database. The database allows the user to search for articles by author(s), key word(s), date, title and journal. These terms can be used as single entries or multiple combinations. Finally, the full database can be viewed by performing the search function without entering any terms in the query window. The database can be accessed at http://www.CTALearning.com.