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Memory-enhancing function of drug reinforces: The cocaine puzzle
Abstracts / Drug and Alcohol Dependence 140 (2014) e86–e168
effectiveness of WaySafe for offenders who differed in terms of gender, pre-custody HIV risk, and mental health. Methods: The sample included 1055 males and females in 8 prison-based drug treatment programs randomly assigned to participate in WaySafe groups or TAU. Five WaySafe outcome measures (pre and post) included HIV Knowledge Confidence, Avoiding Risky Sex, Avoiding Risky Drug Use, HIV Testing Awareness, and Risk Reduction Skills. Pre-custody HIV risks were measured at intake using the TCU HVHPFORM (injection risk, sex risk, condom attitudes, and HIV/AIDS concerns). Mental health status was assessed with items representing psychological distress (K10; Kessler et al., 2003). Results: Due to nesting of participants in 8 different programs, multilevel analysis was used to test effectiveness of the WaySafe intervention on the five outcome measures with gender, precustody HIV risk and mental health status included as factors. Results indicated that WaySafe was effective for both males and females. The time (pre- and post-test) by group (WaySafe/TAU) interaction effect remained significant for all five WaySafe measures while controlling for gender, mental disorder, and HIV risk. Conclusions: WaySafe was designed to improve decision making regarding HIV risks and we hypothesized that high risk offenders would especially benefit. However, these results support the generalizability of WaySafe results to a wide range of offenders regardless of gender, previous HIV risk behaviors, and mental health status. Financial support: Funding was provided by NIDA/NIH through a grant to TCU R01DA025885. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.339 Memory-enhancing function of drug reinforces: The cocaine puzzle Francesco Leri, N. Rkieh, J. Cloke, R. Filc Psychology, University of Guelph, Guelph, ON, Canada, United States Aims: It has been proposed that the reinforcing properties of drugs of abuse are due, in part, to their ability to enhance memory formation. This hypothesis is primarily supported by evidence of enhanced recall in animals and humans treated with d-amphetamine immediately after training on memory tasks. The aim of the current study was to test this hypothesis using cocaine, a drug that clearly reinforces behavior in many species. Methods: Cocaine (1–20 mg/kg, IP) was administered to male Sprague-Dawley rats immediately after training on “win-stay” tasks in an automated eight-arm radial maze. In win-stay, animals are reinforced with sucrose for entering one specific arm that is illuminated by a cue light; entries in non-lit arms are considered mistakes and are not reinforced. Acquisition is analyzed by Analysis of Variance on % correct choices over successive training sessions, and several studies have found that learning of win-stay is enhanced by post-training administration of d-amphetamine. Results: In Experiment 1 (n = 32), cocaine dose-dependently impaired acquisition. The impairment, however, was attributed to an interference with performance caused by the development of sucrose avoidance. In Experiment 2 (n = 48), rats received a sensitizing regimen of cocaine exposure prior to administration of cocaine during maze learning. Although cocaine sensitization prevented the development of sucrose avoidance, no clear memory enhancing effects were observed. Experiment 3 (n = 48) was performed in sensitized rats using a more difficult version of the win-stay task but, again, cocaine failed to enhance acquisition.
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Conclusions: These data lead to three important conclusions. First, cocaine has a profile of action on memory formation that differs from that of d-amphetamine. Second, part of this difference may be due to a wider dose range of cocaine’s aversive effects. Third, cocaine sensitization produces significant tolerance to cocaine’s aversive side effects. Therefore, from the perspective of effects on memory formation, cocaine displays peculiar reinforcing efficacy. Financial support: Natural Sciences and Engineering Research Council of Canada (NSERC). http://dx.doi.org/10.1016/j.drugalcdep.2014.02.340 Effects of a morphine-conjugate vaccine on heroin self-administration in rats Mark G. LeSage 1,2 , Michael D. Raleigh 1,2 , Marco Pravetoni 1,2 , L. Tally 1 , P.R. Pentel 1,2 1
Minneapolis Medical Research Foundation, Minneapolis, MN, United States 2 University of Minnesota, Minneapolis, MN, United States Aims: Vaccines have shown substantial preclinical and preliminary clinical evidence of efficacy for treatment of nicotine and cocaine addiction. As such, vaccination could add important therapeutic options to existing therapies for opioid abuse. Several heroin vaccines have shown some promise in animal models, but findings are very preliminary with respect to immunogenicity, effects on opioid pharmacokinetics, and attenuation of opioid induced behaviors. The purpose of the present study was to examine whether immunization with a novel morphine-conjugate vaccine could reduce the reinforcing effects of heroin using a heroin selfadministration (HSA) model in rats. Methods: Two groups of rats (N = 8 vaccinated, N = 6 controls) were injected i.p. with M-KLH (morphine conjugated via a tetraglycine linker at C6 to keyhole-limpet hemocyanin) or KLH alone in Freund’s adjuvant every three weeks. One week after the third injection, rats were given access to heroin (0.06 mg/kg/infusion) during daily 2 h sessions under a fixed-ratio (FR) 1 schedule for 10 sessions, followed by five sessions each at FR 2 and FR 3. Then, the heroin unit dose was decreased every five sessions to 0.03, 0.01, 0.003, and 0 mg/kg/infusion to obtain a heroin dose–response curve. Results: Vaccinated rats showed significantly higher mean rates of HSA for the training dose at FR 3. During the dose-reduction phase in rats that had acquired HSA (all but one vaccinated rat), extinction occurred in the majority (5 of 7) of vaccinated rats at unit doses below 0.03 mg/kg, while all control rats showed robust selfadministration at all doses. Thus, vaccinated rats showed higher median HSA rates at the 0.03 and 0.06 mg/kg unit doses, but lower median rates at the 0.01 and 0.003 mg/kg doses, suggesting a rightward shift in the dose-response curve compared to controls. Conclusions: Together, these findings show that M-KLH reduced the reinforcing effects of heroin in rats, and that M-KLH has therapeutic potential as an immunotherapy for opiate abuse. Financial support: NIH/NIDA grants DA026300, DA030715 and T32-DA07097. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.341
effectiveness of WaySafe for offenders who differed in terms of gender, pre-custody HIV risk, and mental health. Methods: The sample included 1055 males and females in 8 prison-based drug treatment programs randomly assigned to participate in WaySafe groups or TAU. Five WaySafe outcome measures (pre and post) included HIV Knowledge Confidence, Avoiding Risky Sex, Avoiding Risky Drug Use, HIV Testing Awareness, and Risk Reduction Skills. Pre-custody HIV risks were measured at intake using the TCU HVHPFORM (injection risk, sex risk, condom attitudes, and HIV/AIDS concerns). Mental health status was assessed with items representing psychological distress (K10; Kessler et al., 2003). Results: Due to nesting of participants in 8 different programs, multilevel analysis was used to test effectiveness of the WaySafe intervention on the five outcome measures with gender, precustody HIV risk and mental health status included as factors. Results indicated that WaySafe was effective for both males and females. The time (pre- and post-test) by group (WaySafe/TAU) interaction effect remained significant for all five WaySafe measures while controlling for gender, mental disorder, and HIV risk. Conclusions: WaySafe was designed to improve decision making regarding HIV risks and we hypothesized that high risk offenders would especially benefit. However, these results support the generalizability of WaySafe results to a wide range of offenders regardless of gender, previous HIV risk behaviors, and mental health status. Financial support: Funding was provided by NIDA/NIH through a grant to TCU R01DA025885. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.339 Memory-enhancing function of drug reinforces: The cocaine puzzle Francesco Leri, N. Rkieh, J. Cloke, R. Filc Psychology, University of Guelph, Guelph, ON, Canada, United States Aims: It has been proposed that the reinforcing properties of drugs of abuse are due, in part, to their ability to enhance memory formation. This hypothesis is primarily supported by evidence of enhanced recall in animals and humans treated with d-amphetamine immediately after training on memory tasks. The aim of the current study was to test this hypothesis using cocaine, a drug that clearly reinforces behavior in many species. Methods: Cocaine (1–20 mg/kg, IP) was administered to male Sprague-Dawley rats immediately after training on “win-stay” tasks in an automated eight-arm radial maze. In win-stay, animals are reinforced with sucrose for entering one specific arm that is illuminated by a cue light; entries in non-lit arms are considered mistakes and are not reinforced. Acquisition is analyzed by Analysis of Variance on % correct choices over successive training sessions, and several studies have found that learning of win-stay is enhanced by post-training administration of d-amphetamine. Results: In Experiment 1 (n = 32), cocaine dose-dependently impaired acquisition. The impairment, however, was attributed to an interference with performance caused by the development of sucrose avoidance. In Experiment 2 (n = 48), rats received a sensitizing regimen of cocaine exposure prior to administration of cocaine during maze learning. Although cocaine sensitization prevented the development of sucrose avoidance, no clear memory enhancing effects were observed. Experiment 3 (n = 48) was performed in sensitized rats using a more difficult version of the win-stay task but, again, cocaine failed to enhance acquisition.
e119
Conclusions: These data lead to three important conclusions. First, cocaine has a profile of action on memory formation that differs from that of d-amphetamine. Second, part of this difference may be due to a wider dose range of cocaine’s aversive effects. Third, cocaine sensitization produces significant tolerance to cocaine’s aversive side effects. Therefore, from the perspective of effects on memory formation, cocaine displays peculiar reinforcing efficacy. Financial support: Natural Sciences and Engineering Research Council of Canada (NSERC). http://dx.doi.org/10.1016/j.drugalcdep.2014.02.340 Effects of a morphine-conjugate vaccine on heroin self-administration in rats Mark G. LeSage 1,2 , Michael D. Raleigh 1,2 , Marco Pravetoni 1,2 , L. Tally 1 , P.R. Pentel 1,2 1
Minneapolis Medical Research Foundation, Minneapolis, MN, United States 2 University of Minnesota, Minneapolis, MN, United States Aims: Vaccines have shown substantial preclinical and preliminary clinical evidence of efficacy for treatment of nicotine and cocaine addiction. As such, vaccination could add important therapeutic options to existing therapies for opioid abuse. Several heroin vaccines have shown some promise in animal models, but findings are very preliminary with respect to immunogenicity, effects on opioid pharmacokinetics, and attenuation of opioid induced behaviors. The purpose of the present study was to examine whether immunization with a novel morphine-conjugate vaccine could reduce the reinforcing effects of heroin using a heroin selfadministration (HSA) model in rats. Methods: Two groups of rats (N = 8 vaccinated, N = 6 controls) were injected i.p. with M-KLH (morphine conjugated via a tetraglycine linker at C6 to keyhole-limpet hemocyanin) or KLH alone in Freund’s adjuvant every three weeks. One week after the third injection, rats were given access to heroin (0.06 mg/kg/infusion) during daily 2 h sessions under a fixed-ratio (FR) 1 schedule for 10 sessions, followed by five sessions each at FR 2 and FR 3. Then, the heroin unit dose was decreased every five sessions to 0.03, 0.01, 0.003, and 0 mg/kg/infusion to obtain a heroin dose–response curve. Results: Vaccinated rats showed significantly higher mean rates of HSA for the training dose at FR 3. During the dose-reduction phase in rats that had acquired HSA (all but one vaccinated rat), extinction occurred in the majority (5 of 7) of vaccinated rats at unit doses below 0.03 mg/kg, while all control rats showed robust selfadministration at all doses. Thus, vaccinated rats showed higher median HSA rates at the 0.03 and 0.06 mg/kg unit doses, but lower median rates at the 0.01 and 0.003 mg/kg doses, suggesting a rightward shift in the dose-response curve compared to controls. Conclusions: Together, these findings show that M-KLH reduced the reinforcing effects of heroin in rats, and that M-KLH has therapeutic potential as an immunotherapy for opiate abuse. Financial support: NIH/NIDA grants DA026300, DA030715 and T32-DA07097. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.341