Background and PurposeLearned associations between environmental stimuli and drugs of abuse repre... more Background and PurposeLearned associations between environmental stimuli and drugs of abuse represent a major factor in the chronically relapsing nature of drug addiction. In drug dependent subjects these associations must be presumed to include associations linked to reversal of adverse withdrawal states by drug use—“withdrawal‐associated learning” (WDL). However, their significance in drug seeking has received little experimental scrutiny.Experimental ApproachUsing alcohol as a drug of abuse, the behavioural consequences of WDL were investigated in animal models of relapse and compulsive drug seeking by comparing the effects of WD L‐associated stimuli versus stimuli associated with alcohol without WDL experience in nondependent and post‐dependent rats. Brain sites activated by exposure to the respective stimuli were identified by c‐fos immunohistochemistry.Key Results(1) WDL‐associated stimuli elicited significant alcohol seeking. In rats with WDL experience, stimuli associated with alcohol in the nondependent state no longer elicited robust alcohol seeking. (2) Responding elicited by WDL‐associated stimuli, but not stimuli conditioned to alcohol in the nondependent state, was resistant to footshock punishment and increased response effort requirements for presentation of WDL‐related stimuli. (3) Stimuli conditioned to alcohol in rats with a dependence but not WDL history did not sustain punished responding or tolerance of increased effort. (4) The central nucleus of the amygdala was identified as a site selectively responsive to WDL stimulus exposure.Conclusion and ImplicationsEnvironmental stimuli associated with reversal of adverse withdrawal states by alcohol elicit compulsive‐like alcohol seeking and establish WDL as a major, not well‐recognized factor, in relapse vulnerability.
Positive or negative allosteric modulation of metabotropic glutamate receptor 5 (mGluR5) does not... more Positive or negative allosteric modulation of metabotropic glutamate receptor 5 (mGluR5) does not alter expression of behavioral sensitization to methamphetamine [version 1; referees: 1 approved, 2 approved with reservations]
Neuropathology of Drug Addictions and Substance Misuse, 2016
Abstract Widespread abuse of amphetamine and methamphetamine remains a significant global health ... more Abstract Widespread abuse of amphetamine and methamphetamine remains a significant global health problem. Intervention efforts to reduce its use have focused on developing treatments that reverse or mitigate the neurological effects of these drugs that support addictive behaviors. Exposing rodents to amphetamine or methamphetamine and analyzing their brain tissue for genetic responses has proven to be a valuable tool for identifying the most relevant brain circuits for targeted treatment of drug abuse. Immediate early genes (IEGs), including transcription factors that coordinate stimulus-driven effects across a range of genes and signaling pathways, have been widely studied in efforts to map the neural responses to psychoactive drugs. This chapter provides an overview of studies that have examined the effects of amphetamine and methamphetamine treatment on expression patterns of the IEGs c-fos , arc , zif/268 , and bdnf to characterize the neural effects of acute and chronic drug exposure.
In recent years, there has been a dramatic increase in abuse of the synthetic cathinone 3,4-methy... more In recent years, there has been a dramatic increase in abuse of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV), often in combination with other illicit stimulants. We sought to determine if repeated exposure to MDPV would produce sensitization to the motor stimulant effects of the drug, and whether cross-sensitization would develop with the stimulant effects of methamphetamine (METH). Male Sprague-Dawley rats were administered MDPV (1 or 5 mg/kg) or saline once daily for 5 days at 24 hour intervals, or were administered MDPV (1 mg/kg) or saline once daily for 5 days at 48 hour intervals. For cross-sensitization experiments, rats were administered METH (1 mg/kg) or MDPV (1 or 5 mg/kg) once daily for 5 days at 48 hour intervals, and following a 5 day incubation period, were given an acute challenge injection of either MDPV (0.5 mg/kg) or METH (0.5 mg/kg), respectively. Rats repeatedly administered MDPV (1 mg/kg) every 48 hours, but not every 24 hours, demonstrated incre...
Pharmacological FMRI in humans involves BOLD signal acquisition before, during and after the admi... more Pharmacological FMRI in humans involves BOLD signal acquisition before, during and after the administration of a drug, and often results in a heterogeneous pattern of drug-induced hemodynamic responses in the brain. Exploratory techniques, including blind source separation, can be useful for BOLD data that contains patterns of cross-dependencies. Bayesian source separation (BSS) is a multivariate technique used to calculate the
We have previously shown that acute intravenous (i.v.) administration of cocaine increases Fos im... more We have previously shown that acute intravenous (i.v.) administration of cocaine increases Fos immunoreactivity in rats under isoflurane anesthesia. Given that Fos expression is a marker of neural activation, the results suggested that isoflurane is appropriate for imaging cocaine effects under anesthesia. However, most imaging research in this area utilizes subjects with a history of repeated cocaine exposure and this drug history may interact with anesthetic use differently from acute cocaine exposure. Thus, this study further examined Fos expression under isoflurane in rats with a history of repeated i.v. cocaine administration. Rats received daily injections of either saline or cocaine (2mg/kg, i.v.) across 7 consecutive days, followed by 5 days of no drug exposure. On the test day, rats were either nonanesthetized or anesthetized under isoflurane and were given an acute challenge of cocaine (2mg/kg, i.v.). Additional saline-exposed controls received a saline challenge. Ninety min after the drug challenge, the rats were perfused under isoflurane anesthesia and their brains were processed for Fos protein immunohistochemistry. We found that challenge injections of cocaine following a regimen of repeated cocaine exposure resulted in Fos expression in the prefrontal cortex and striatum roughly equivalent to that found in rats who had received the cocaine challenge after a history of vehicle injections. Additionally, isoflurane anesthesia resulted in a heterogeneous attenuation of cocaine-induced Fos expression, with the most robust effect in the orbital cortex but no effect in the nucleus accumbens core (NAcC). These results indicate that cocaine-induced Fos is preserved in the NAcC under isoflurane, suggesting that isoflurane can be used in imaging studies involving cocaine effects in this region.
Background and PurposeLearned associations between environmental stimuli and drugs of abuse repre... more Background and PurposeLearned associations between environmental stimuli and drugs of abuse represent a major factor in the chronically relapsing nature of drug addiction. In drug dependent subjects these associations must be presumed to include associations linked to reversal of adverse withdrawal states by drug use—“withdrawal‐associated learning” (WDL). However, their significance in drug seeking has received little experimental scrutiny.Experimental ApproachUsing alcohol as a drug of abuse, the behavioural consequences of WDL were investigated in animal models of relapse and compulsive drug seeking by comparing the effects of WD L‐associated stimuli versus stimuli associated with alcohol without WDL experience in nondependent and post‐dependent rats. Brain sites activated by exposure to the respective stimuli were identified by c‐fos immunohistochemistry.Key Results(1) WDL‐associated stimuli elicited significant alcohol seeking. In rats with WDL experience, stimuli associated with alcohol in the nondependent state no longer elicited robust alcohol seeking. (2) Responding elicited by WDL‐associated stimuli, but not stimuli conditioned to alcohol in the nondependent state, was resistant to footshock punishment and increased response effort requirements for presentation of WDL‐related stimuli. (3) Stimuli conditioned to alcohol in rats with a dependence but not WDL history did not sustain punished responding or tolerance of increased effort. (4) The central nucleus of the amygdala was identified as a site selectively responsive to WDL stimulus exposure.Conclusion and ImplicationsEnvironmental stimuli associated with reversal of adverse withdrawal states by alcohol elicit compulsive‐like alcohol seeking and establish WDL as a major, not well‐recognized factor, in relapse vulnerability.
Positive or negative allosteric modulation of metabotropic glutamate receptor 5 (mGluR5) does not... more Positive or negative allosteric modulation of metabotropic glutamate receptor 5 (mGluR5) does not alter expression of behavioral sensitization to methamphetamine [version 1; referees: 1 approved, 2 approved with reservations]
Neuropathology of Drug Addictions and Substance Misuse, 2016
Abstract Widespread abuse of amphetamine and methamphetamine remains a significant global health ... more Abstract Widespread abuse of amphetamine and methamphetamine remains a significant global health problem. Intervention efforts to reduce its use have focused on developing treatments that reverse or mitigate the neurological effects of these drugs that support addictive behaviors. Exposing rodents to amphetamine or methamphetamine and analyzing their brain tissue for genetic responses has proven to be a valuable tool for identifying the most relevant brain circuits for targeted treatment of drug abuse. Immediate early genes (IEGs), including transcription factors that coordinate stimulus-driven effects across a range of genes and signaling pathways, have been widely studied in efforts to map the neural responses to psychoactive drugs. This chapter provides an overview of studies that have examined the effects of amphetamine and methamphetamine treatment on expression patterns of the IEGs c-fos , arc , zif/268 , and bdnf to characterize the neural effects of acute and chronic drug exposure.
In recent years, there has been a dramatic increase in abuse of the synthetic cathinone 3,4-methy... more In recent years, there has been a dramatic increase in abuse of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV), often in combination with other illicit stimulants. We sought to determine if repeated exposure to MDPV would produce sensitization to the motor stimulant effects of the drug, and whether cross-sensitization would develop with the stimulant effects of methamphetamine (METH). Male Sprague-Dawley rats were administered MDPV (1 or 5 mg/kg) or saline once daily for 5 days at 24 hour intervals, or were administered MDPV (1 mg/kg) or saline once daily for 5 days at 48 hour intervals. For cross-sensitization experiments, rats were administered METH (1 mg/kg) or MDPV (1 or 5 mg/kg) once daily for 5 days at 48 hour intervals, and following a 5 day incubation period, were given an acute challenge injection of either MDPV (0.5 mg/kg) or METH (0.5 mg/kg), respectively. Rats repeatedly administered MDPV (1 mg/kg) every 48 hours, but not every 24 hours, demonstrated incre...
Pharmacological FMRI in humans involves BOLD signal acquisition before, during and after the admi... more Pharmacological FMRI in humans involves BOLD signal acquisition before, during and after the administration of a drug, and often results in a heterogeneous pattern of drug-induced hemodynamic responses in the brain. Exploratory techniques, including blind source separation, can be useful for BOLD data that contains patterns of cross-dependencies. Bayesian source separation (BSS) is a multivariate technique used to calculate the
We have previously shown that acute intravenous (i.v.) administration of cocaine increases Fos im... more We have previously shown that acute intravenous (i.v.) administration of cocaine increases Fos immunoreactivity in rats under isoflurane anesthesia. Given that Fos expression is a marker of neural activation, the results suggested that isoflurane is appropriate for imaging cocaine effects under anesthesia. However, most imaging research in this area utilizes subjects with a history of repeated cocaine exposure and this drug history may interact with anesthetic use differently from acute cocaine exposure. Thus, this study further examined Fos expression under isoflurane in rats with a history of repeated i.v. cocaine administration. Rats received daily injections of either saline or cocaine (2mg/kg, i.v.) across 7 consecutive days, followed by 5 days of no drug exposure. On the test day, rats were either nonanesthetized or anesthetized under isoflurane and were given an acute challenge of cocaine (2mg/kg, i.v.). Additional saline-exposed controls received a saline challenge. Ninety min after the drug challenge, the rats were perfused under isoflurane anesthesia and their brains were processed for Fos protein immunohistochemistry. We found that challenge injections of cocaine following a regimen of repeated cocaine exposure resulted in Fos expression in the prefrontal cortex and striatum roughly equivalent to that found in rats who had received the cocaine challenge after a history of vehicle injections. Additionally, isoflurane anesthesia resulted in a heterogeneous attenuation of cocaine-induced Fos expression, with the most robust effect in the orbital cortex but no effect in the nucleus accumbens core (NAcC). These results indicate that cocaine-induced Fos is preserved in the NAcC under isoflurane, suggesting that isoflurane can be used in imaging studies involving cocaine effects in this region.
Uploads
Papers by Peter Kufahl