Co-reporter:Shawn M. Aarde, Pai-Kai Huang, Michael A. Taffe
Pharmacology Biochemistry and Behavior 2017 Volume 163(Volume 163) pp:
Publication Date(Web):1 December 2017
DOI:10.1016/j.pbb.2017.10.008
•MDMA (Ecstasy) continues to be used by many individuals worldwide.•MDMA-induced temperature disruption may alter reinforcing efficacy in rats.•Self-administration was increased under high ambient temperature conditions.•Dance-club use of MDMA may increase its addictive potential.RationaleMDMA alters body temperature in rats with a direction that depends on the ambient temperature (TA). The thermoregulatory effects of MDMA and TA may affect intravenous self-administration (IVSA) of MDMA but limited prior reports conflict.ObjectiveTo determine how body temperature responses under high and low TA influence MDMA IVSA.MethodsMale Sprague-Dawley rats were trained to IVSA MDMA (1.0 mg/kg/infusion; 2-h sessions; FR5 schedule of reinforcement) under TA 20 °C or 30 °C. Radiotelemetry transmitters recorded body temperature and activity during IVSA.ResultsMDMA intake increased under both TA during acquisition, but to a greater extent in the 30 °C group. The magnitude of hypothermia was initially equivalent between groups but diminished over training in the 30 °C group. Within-session activity was initially lower in the 30 °C group, but by the end of acquisition and maintenance, activity was similar for both groups. When TA conditions were swapped, the hot-trained group increased MDMA IVSA under 20 °C TA and a modest decrease in drug intake was observed in the cold-trained group under 30 °C TA. Subsequent non-contingent MDMA (1.0–5.0 mg/kg, i.v.) found that rats with higher MDMA IVSA rates showed blunted hypothermia compared with rats with lower IVSA levels; however, within-session activity did not differ by group. High TA increased intracranial self-stimulation thresholds in a different group of rats and MDMA reduced thresholds below baseline at low, but not high, TA.ConclusionsHigh TA appears to enhance acquisition of MDMA IVSA through an aversive effect and not via thermoregulatory motivation.
Co-reporter:Jacques D Nguyen, Shawn M Aarde, Maury Cole, Sophia A Vandewater, Yanabel Grant and Michael A Taffe
Neuropsychopharmacology 2016 41(11) pp:2759-2771
Publication Date(Web):June 29, 2016
DOI:10.1038/npp.2016.88
Although inhaled exposure to drugs is a prevalent route of administration for human substance abusers, preclinical models that incorporate inhaled exposure to psychomotor stimulants are not commonly available. Using a novel method that incorporates electronic cigarette-type technology to facilitate inhalation, male Wistar rats were exposed to vaporized methamphetamine (MA), 3,4-methylenedioxypyrovalerone (MDPV), and mephedrone (4-methylmethcathinone) in propylene glycol vehicle using concentrations ranging from 12.5 to 200 mg/ml. Rats exhibited increases in spontaneous locomotor activity, measured by implanted radiotelemetry, following exposure to methamphetamine (12.5 and 100 mg/ml), MDPV (25, 50, and 100 mg/ml), and mephedrone (200 mg/ml). Locomotor effects were blocked by pretreatment with the dopamine D1-like receptor antagonist SCH23390 (10 μg/kg, intraperitoneal (i.p.)). MA and MDPV vapor inhalation also altered activity on a running wheel in a biphasic manner. An additional group of rats was trained on a discrete trial intracranial self-stimulation (ICSS) procedure interpreted to assess brain reward status. ICSS-trained rats that received vaporized MA, MDPV, or mephedrone exhibited a significant reduction in threshold of ICSS reward compared with vehicle. The effect of vapor inhalation of the stimulants was found comparable to the locomotor and ICSS threshold-reducing effects of i.p. injection of mephedrone (5.0 mg/kg), MA (0.5–1.0 mg/kg), or MDPV (0.5–1.0 mg/kg). These data provide robust validation of e-cigarette-type technology as a model for inhaled delivery of vaporized psychostimulants. Finally, these studies demonstrate the potential for human use of e-cigarettes to facilitate covert use of a range of psychoactive stimulants. Thus, these devices pose health risks beyond their intended application for the delivery of nicotine.
Co-reporter:Michael A Taffe;Kevin M Creehan ;Sophia A Vewater
British Journal of Pharmacology 2015 Volume 172( Issue 7) pp:1783-1791
Publication Date(Web):
DOI:10.1111/bph.13024
Background and Purpose
Growing evidence shows cannabidiol (CBD) modulates some of the effects of Δ9-tetrahydrocannabinol (THC). CBD is a constituent of some strains of recreational cannabis but its content is highly variable. High CBD strains may have less memory-impairing effects than low-CBD strains and CBD can reverse behavioural effects of THC in monkeys. CBD/THC interactions in rodents are more complicated as CBD can attenuate or exacerbate the effects of THC. This study was undertaken to determine if CBD could reverse hypothermia or hypolocomotor effects caused by THC in rats.
Experimental Approaches
Male Sprague-Dawley rats were prepared with radiotelemetry devices and then given doses of THC (10–30 mg·kg−1, i.p.) with or without CBD. Experiments determined the effect of simultaneous or 30 min pretreatment with CBD in a 1:1 ratio with THC, as well as the effect of CBD in a 3:1 ratio. Additional experiments determined the effects of pretreatment with the cannabinoid CB1 receptor antagonist SR141716 (rimonabant).
Key Results
CBD did not attentuate THC-induced hypothermia or hypolocomotion but instead exaggerated these effects in some conditions. The antagonist SR141716 blocked hypolocomotor effects of THC for the first hour after injection and the hypothermia for 6 h; thus validating the pharmacological model.
Conclusions and Implications
There is no evidence from this study that elevated CBD content in cannabis could provide protection from the physiological effects of THC, in rats.
Co-reporter:Shawn M. Aarde;Kevin M. Creehan;Sophia A. Vandewater
Psychopharmacology 2015 Volume 232( Issue 16) pp:3045-3055
Publication Date(Web):2015 August
DOI:10.1007/s00213-015-3944-8
Numerous substituted cathinone drugs have appeared in recreational use. This variety is often a response to legal actions; the scheduling of 3,4-methylenedioxypyrovalerone (MDPV; “bath salts”) in the USA was followed by the appearance of the closely related drug α-pyrrolidinopentiophenone (alpha-PVP; “flakka”).This study aimed to directly compare the efficacy and potency of alpha-PVP with that of MDPV.Groups of male Wistar rats were trained in the intravenous self-administration (IVSA) alpha-PVP or MDPV under a fixed-ratio 1 schedule of reinforcement. An additional group was examined for locomotor and body temperature responses to noncontingent administration of MDVP or alpha-PVP (1.0, 5.6, and 10.0 mg/kg, i.p.).Acquisition of alpha-PVP (0.1 mg/kg/infusion) IVSA resulted in low, yet consistent drug intake and excellent discrimination for the drug-paired lever. Dose substitution (0.05–0.25 mg/kg/infusion) under a fixed-ratio 1 schedule confirmed potency was similar to MDPV in prior studies. In direct comparison to MDPV (0.05 mg/kg/infusion), rats trained on alpha-PVP (0.05 mg/kg/infusion) responded for more infusions but demonstrated similar drug-lever discrimination by the end of acquisition. However, the dose–response (0.018–0.56 mg/kg/infusion) functions of these drugs under a progressive-ratio schedule of reinforcement reflected identical efficacy and potency. Peak locomotor responses to MDPV or alpha-PVP were observed after the 1.0 mg/kg, i.p. dose and lasted ∼2 h. Modest body temperature decreases were of similar magnitude (∼0.75 °C) for each compound.The potency and efficacy of MDPV and alpha-PVP were very similar across multiple assays, predicting that the abuse liability of alpha-PVP will be significant and similar to that of MDPV.
Co-reporter:S. M. Aarde;P. K. Huang;T. J. Dickerson;M. A. Taffe
Psychopharmacology 2015 Volume 232( Issue 11) pp:1867-1877
Publication Date(Web):2015 June
DOI:10.1007/s00213-014-3819-4
Lack of access to conventional sources of reinforcement has been proposed as a risk factor for substance abuse in lower socioeconomic populations. There is laboratory evidence that behavioral alternatives (enrichment or exercise) and alternative reinforcers (e.g., sweetened solutions) can reduce self-administration of a variety of drugs.The objective of this study is to determine if drug self-administration could devalue wheel activity in an animal model.Male Wistar rats were trained to self-administer 3,4-methylenedioxypyrovalerone (MDPV; “bath salts”), 0.05 mg/kg/infusion, i.v., with concurrent access to a running wheel that was either locked (LW) or unlocked (UW).MDPV intake steadily increased across the 20-session acquisition interval but did not differ significantly between UW and LW groups. Mean wheel rotations declined significantly across the acquisition interval in the UW group. Of the rats that acquired self-administration, 60 % engaged in a binge-like behavior at the initiation of acquisition; intake was limited only by post-reinforcement time-out. The binge rats had higher post-acquisition levels of drug intake (even after excluding the binge session), and the UW binge rats showed a precipitous post-acquisition drop in wheel activity that was not observed in the UW no-binge rats.These data confirm that MDPV is a powerful reward/reinforcer and show that a relatively high rate of intake at the onset of drug taking can devalue natural rewards (wheel activity) and can predict higher subsequent drug intake levels. Thus, limiting the intensity of initial drug exposure may attenuate subsequent drug abuse/addiction by preventing the devaluation of natural alternative rewards/reinforcers.
Co-reporter:M Jerry Wright Jr;Sophia A Vewater ;Michael A Taffe
British Journal of Pharmacology 2013 Volume 170( Issue 7) pp:1365-1373
Publication Date(Web):
DOI:10.1111/bph.12199
Background and Purpose
Recent human studies suggest that recreational cannabis strains that are relatively high in cannabidiol (CBD) content produce less cognitive impairment than do strains with negligible CBD and similar Δ9tetrahydrocannabinol (THC) content. Self-selection in such studies means it is impossible to rule out additional variables which may determine both cannabis strain selection and basal cognitive performance level. Controlled laboratory studies can better determine a direct relationship.
Experimental Approach
In this study, adult male rhesus monkeys were assessed on visuospatial Paired Associates Learning and Self-Ordered Spatial Search memory tasks, as well as additional tests of motivation and manual dexterity. Subjects were challenged with THC (0.2, 0.5 mg·kg−1, i.m.) in randomized order and evaluated in the presence or absence of 0.5 mg·kg−1 CBD.
Key Results
CBD attenuated the effects of THC on paired associates learning and a bimanual motor task without affecting the detrimental effects of THC on a Self-Ordered Spatial Search task of working memory. CBD did not significantly reverse THC-induced impairment of a progressive ratio or a rotating turntable task.
Conclusions and Implications
This study provides direct evidence that CBD can oppose the cognitive-impairing effects of THC and that it does so in a task-selective manner when administered simultaneously in a 1:1 ratio with THC. The addition of CBD to THC-containing therapeutic products may therefore help to ameliorate unwanted cognitive side-effects.
Co-reporter:MJ Wright, Jr;SA Vewater;D Angrish;TJ Dickerson;MA Taffe
British Journal of Pharmacology 2012 Volume 167( Issue 6) pp:1342-1352
Publication Date(Web):
DOI:10.1111/j.1476-5381.2012.02091.x
BACKGROUND AND PURPOSE
The novel cathinone derivative 4-methylmethcathinone (4-MMC; mephedrone) is increasingly popular with recreational users. Little scientific information is available but users report both entactogen-like and classic stimulant-like subjective properties. A recent study in humans reported psychomotor speed improvement after intranasal 4-MMC suggesting classic stimulant properties. Limitations of the user group (which was impaired on some tasks) prompt controlled laboratory investigation.
EXPERIMENTAL APPROACH
Adult male rhesus monkeys were trained to perform tasks from the non-human primate Cambridge Neuropsychological Test Automated Battery, which assess spatial working memory, visuospatial associative memory, learning and motivation for food reward. Test of bimanual motor coordination and manual tracking were also included. The subjects were challenged with 0.178–0.56 mg·kg−1 4-MMC and 0.056–0.56 mg·kg−1 d-methamphetamine (MA), i.m., in randomized order for behavioural evaluation.
KEY RESULTS
A pronounced improvement in visuospatial memory and learning was observed after the 0.32 mg·kg−1 dose of each compound, this effect was confirmed with subsequent repetition of these conditions. Spatial working memory was not improved by either drug, and the progressive ratio, bimanual motor and rotating turntable tasks were all disrupted in a dose-dependent manner.
CONCLUSIONS AND IMPLICATIONS
These studies show that 4-MMC produces behavioural effects, including improvements in complex spatial memory and learning that are in large part similar to those of MA in non-human primates. Thus, the data suggest that the effects of 4-MMC in monkeys can be classified with classical psychomotor stimulants.
Co-reporter:Stefani N Von Huben, Christopher C Lay, Rebecca D Crean, Sophia A Davis, Simon N Katner and Michael A Taffe
Neuropsychopharmacology 2007 32(3) pp:673-681
Publication Date(Web):April 12, 2006
DOI:10.1038/sj.npp.1301078
The ambient temperature (TA) under which rodents are exposed to ()3,4-methylenedioxymethamphetamine (MDMA) affects the direction and magnitude of the body temperature response, and the degree of hypo/hyperthermia generated in subjects can modify the severity of lasting brain changes in 'neurotoxicity' models. The thermoregulatory effects of MDMA have not been well described in non-human primates and it is unknown if TA has the potential to affect acute hyperthermia and therefore other lasting consequences of MDMA. The objective of this study was to determine if the temperature alteration produced by MDMA in nonhuman primates depends on TA as it does in rats and mice. Body temperature and spontaneous home cage activity were monitored continuously in six male rhesus monkeys via radiotelemetry. The subjects were challenged intramuscularly with 0.56–2.4 mg/kg ()MDMA under each of three TA conditions (18, 24, and 30°C) in a randomized order. The temperature was significantly elevated following injection with all doses of MDMA under each ambient temperature. The magnitude of mean temperature change was 1°C in most conditions suggesting a closely controlled thermoregulatory response in monkeys across a range of doses and ambient temperatures. Activity levels were generally suppressed by MDMA; however, a 50% increase over vehicle was observed after 0.56 MDMA under the 30°C condition. It is concluded that MDMA produces a similar degree of hyperthermia in rhesus monkeys across a range of TA conditions that result in hypothermia or exaggerated hyperthermia in rodents. Monkey temperature responses to MDMA appear to be more similar to humans than to rodents and therefore the monkey may offer an improved model of effects related to MDMA-induced hyperthermia.
Co-reporter:Michael A Taffe Ph.D, Sophia A Davis BS, Jie Yuan MD, Richard Schroeder MS, George Hatzidimitriou Ph.D, Loren H Parsons Ph.D, George A Ricaurte MD, Ph.D and Lisa H Gold Ph.D
Neuropsychopharmacology 2002 27(6) pp:993-1005
Publication Date(Web):
DOI:10.1016/S0893-133X(02)00380-9
Recreational users of (±)3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) exhibit poor performance on a number of neurocognitive measures, with tests of memory and attention most commonly affected. Cognitive impairments can be persistent or possibly permanent, since users who have been abstinent from MDMA for many months are also impaired. Repeated treatment of rats or nonhuman primates with MDMA has consistently been demonstrated to produce specific, lasting depletions of brain serotonin (5-HT) markers, a potential source of such cognitive symptoms. We have shown, however, that monkeys treated with a regimen of MDMA (4 days, 10 mg/kg i.m., b.i.d.), sufficient to produce a 50% reduction of the 5-HT metabolite 5-hydroxyindoleacetic acid in cerebrospinal fluid, do not exhibit lasting deficits in a range of cognitive domains. Acute drug challenges are often effective at unmasking consequences of amphetamine toxicity. Here, the performance of MDMA-treated and control monkeys on tests of spatial working memory (self-ordered spatial search), vigilance and reaction time (5-choice reaction time), reinforcer efficacy and sustained attention (progressive ratio responding) and fine motor control (bimanual motor skill task) was challenged with ketanserin (0.1–1.7 mg/kg, i.m.), 1-(3-Chlorophenyl)piperazine dihydrochloride (mCPP, 0.03–0.5 mg/kg, i.m.) and (±)8-hydroxy-DPAT hydrobromide (8-OH-DPAT, 0.032–0.1 mg/kg, i.m.). MDMA-exposed animals exhibited increased sensitivity to challenge with mCPP on the reaction time and progressive ratio tasks but otherwise were equivalently sensitive to drug challenge. Post-mortem analysis demonstrated that 76–93% reductions of 5-HT in neocortex persist 17–20 months post-MDMA. These observations suggest that large depletions of brain 5-HT produced by MDMA can persistently alter behavioral sensitivity to the disrupting effects of serotonergic agents.
Co-reporter:Michael A Taffe Ph.D, Michael R Weed Ph.D, Sophia Davis BS, Salvador Huitrón-Resendiz Ph.D, Richard Schroeder MS, Loren H Parsons Ph.D, Steven J Henriksen Ph.D and Lisa H Gold Ph.D
Neuropsychopharmacology 2001 24(3) pp:230-239
Publication Date(Web):
DOI:10.1016/S0893-133X(00)00185-8
Six rhesus monkeys were trained to stable performance on neuropsychological tests of memory, reinforcer efficacy, reaction time and bimanual motor coordination. Three monkeys were then exposed to a high-dose, short course regimen of (±)3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) (4 days, 10 mg/kg i.m., b.i.d.). Following treatment, concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) were reduced by ~50% in the treated animals, and this effect persisted for approximately three months post-MDMA. Behavioral performance was disrupted during acute MDMA treatment but returned to baseline within one week following treatment. MDMA also produced persistent alterations in late peak latencies of brainstem auditory evoked potentials (BSAEP), lasting three months post-MDMA. Both CSF 5-HIAA concentrations and evoked potential latencies were normalized four months after treatment. These findings indicate that serotonergic alterations associated with MDMA use may result in persisting changes in brain function.
Co-reporter:Jacques D. Nguyen, Shawn M. Aarde, Sophia A. Vandewater, Yanabel Grant, David G. Stouffer, Loren H. Parsons, Maury Cole, Michael A. Taffe
Neuropharmacology (October 2016) Volume 109() pp:112-120
Publication Date(Web):1 October 2016
DOI:10.1016/j.neuropharm.2016.05.021
•Few animal studies of Δ9-tetrahydrocannabinol (THC) inhalation are available.•This study validated an e-cigarette system for delivering vaporized THC to rats.•Hypothermia, anti-nociception and hypolocomotor effects were produced.•This approach is flexible, robust and effective for use in laboratory rats.Most human Δ9-tetrahydrocannabinol (THC) use is via inhalation, and yet few animal studies of inhalation exposure are available. Popularization of non-combusted methods for the inhalation of psychoactive drugs (Volcano®, e-cigarettes) further stimulates a need for rodent models of this route of administration. This study was designed to develop and validate a rodent chamber suitable for controlled exposure to vaporized THC in a propylene glycol vehicle, using an e-cigarette delivery system adapted to standard size, sealed rat housing chambers. The in vivo efficacy of inhaled THC was validated using radiotelemetry to assess body temperature and locomotor responses, a tail-flick assay for nociception and plasma analysis to verify exposure levels. Hypothermic responses to inhaled THC in male rats depended on the duration of exposure and the concentration of THC in the vehicle. The temperature nadir was reached after ∼40 min of exposure, was of comparable magnitude (∼3 °Celsius) to that produced by 20 mg/kg THC, i.p. and resolved within 3 h (compared with a 6 h time course following i.p. THC). Female rats were more sensitive to hypothermic effects of 30 min of lower-dose THC inhalation. Male rat tail-flick latency was increased by THC vapor inhalation; this effect was blocked by SR141716 pretreatment. The plasma THC concentration after 30 min of inhalation was similar to that produced by 10 mg/kg THC i.p. This approach is flexible, robust and effective for use in laboratory rats and will be of increasing utility as users continue to adopt “vaping” for the administration of cannabis.Download high-res image (249KB)Download full-size image
Co-reporter:M. Jerry Wright Jr., Michael A. Taffe
Neuropharmacology (November 2014) Volume 86() pp:78-87
Publication Date(Web):1 November 2014
DOI:10.1016/j.neuropharm.2014.07.003
•Cognitive deficits in human alcoholics confounded by pre-existing differences.•Monkeys were balanced on behavior and alcohol preference prior to study.•Spatial working memory impaired by 6 mo of M−F binge drinking.•24 h memory retention impaired in alcohol monkeys after 6 wks of abstinence.•Alcohol monkeys more distractible on a reaction time task after 6 mo of abstinence.Although human alcoholics exhibit lasting cognitive deficits, it can be difficult to definitively rule out pre-alcohol performance differences. For example, individuals with a family history of alcoholism are at increased risk for alcoholism and are also behaviorally impaired. Animal models of controlled alcohol exposure permit balanced group assignment, thereby ruling out the effects of pre-existing differences.Periadolescent male rhesus macaques (N = 5) consumed alcohol during 200 drinking sessions (M–F) across a 10-month period (mean daily alcohol consumption: 1.38 g/kg/day). A control group (N = 5) consumed a fruit-flavored vehicle during the same period. Spatial working memory, visual discrimination learning and retention and response time behavioral domains were assessed with subtests of the Monkey CANTAB (CAmbridge Neuropsychological Test Automated Battery). Spatial working memory performance was impaired in the alcohol group after 120 drinking sessions (6 mo) in a manner that depended on retention interval. The chronic alcohol animals were also impaired in retaining a visual discrimination over 24 hrs when assessed 6–8 weeks after cessation of alcohol drinking. Finally, the presentation of distractors in the response time task impaired the response time and accuracy of the chronic alcohol group more than controls after 6 months of alcohol cessation. Chronic alcohol consumption over as little as 6 months produces cognitive deficits, with some domains still affected after acute (6–8 wks) and lasting (6 mo) discontinuation from drinking. Animals were matched on alcohol preference and behavioral performance prior to exposure, thus providing strong evidence for the causal role of chronic alcohol in these deficits.
Co-reporter:Kevin M. Creehan, Sophia A. Vandewater, Michael A. Taffe
Neuropharmacology (May 2015) Volume 92() pp:90-97
Publication Date(Web):1 May 2015
DOI:10.1016/j.neuropharm.2015.01.003
•Methylone and mephedrone exhibit MDMA-like neurochemical properties.•Intravenous self-administration of MDMA is inconsistent.•Mephedrone was a more effective reinforcer than MDMA or methylone.•Within training groups, all three drugs were of identical efficacy and potency.•Mephedrone-trained rats self-administered more than the other groups.Male rats will intravenously self-administer (IVSA) the substituted cathinone stimulants (“bath salts”) mephedrone (4-methylmethcathione) and methylone (3,4-methylenedioxymethcathinone) robustly, whereas the IVSA of 3,4-methylenedioxymethamphetamine (MDMA) is inconsistent in many rat models. There are no data available on the self-administration of these drugs in female rats, thus a study was undertaken to contrast them directly. Groups of female Wistar rats were trained to self-administer mephedrone, methylone or MDMA (0.5 mg/kg/inf) under a Fixed-Ratio (FR) 1 schedule of reinforcement for 14 sessions. Following the acquisition interval, animals were evaluated in FR (0.0, 0.125, 0.25, 0.5, 1.0, 2.5 mg/kg/inf) and PR (0.125, 1.0 mg/kg/inf) dose-substitution procedures. The results show that female rats acquired the self-administration of all three compounds with intakes in mephedrone-trained rats that were significantly higher than that of methylone-trained or MDMA-trained rats. In dose-substitution under either FR or PR contingencies, however, the potencies of all three drugs were similar within the original training groups. The mephedrone-trained animals exhibited higher intakes of all drugs during dose-substitution, indicating lasting consequences of the training drug. Abuse liability of these three compounds is therefore predicted to be similar in established stimulant users but may differ in liability if they are primary drugs of initiation.
Co-reporter:Sophia A. Vandewater, Kevin M. Creehan, Michael A. Taffe
Neuropharmacology (December 2015) Volume 99() pp:538-545
Publication Date(Web):1 December 2015
DOI:10.1016/j.neuropharm.2015.08.030
•Intravenous self-administration of MDMA is inconsistent.•Long-access to MDMA led to escalated 6 h intake but not 2 h intake.•Mephedrone was a more effective reinforcer than MDMA or methylone.•Male rats self-administer at slightly lower rates than female rats.The intravenous self-administration (IVSA) of 3,4-methylenedioxymethamphetamine (MDMA) is inconsistent in rats, with up to half of subjects failing to acquire reliable drug intake. It is unknown if this changes under long-access conditions (6 h sessions) under which the IVSA of cocaine and methamphetamine escalates. The entactogen class cathinone stimulants which exhibit MDMA-like monoamine effects in the nucleus accumbens, mephedrone (4-methylmethcathinone) and methylone (3,4-methylenedioxymethcathinone), may support more reliable IVSA but results have been mixed. This study was designed to directly compare the IVSA of these three compounds. Groups of male Wistar rats were trained to self-administer mephedrone, methylone or MDMA (0.5 mg/kg/inf) under a Fixed-Ratio (FR) 1 schedule of reinforcement for 14 sessions. Following the acquisition interval, animals were evaluated in FR (0.0, 0.125, 0.25, 0.5, 1.0, 2.5 mg/kg/inf) and Progressive Ratio (PR; 0.125, 1.0 mg/kg/inf) dose-substitution procedures. Long access conditions escalated MDMA intake over the 6 h session but not in the first 2 h. In short access, drug intake was significantly higher in mephedrone-trained rats compared with either the methylone-trained or MDMA-trained groups during acquisition. Mephedrone resulted in the highest intakes during FR and PR dose-substitution in MDMA- and mephedrone-trained groups. Overall it was found that mephedrone is a more effective reinforcer than methylone or MDMA and represents a higher risk for compulsive use.
Co-reporter:S.M. Aarde, P.K. Huang, K.M. Creehan, T.J. Dickerson, M.A. Taffe
Neuropharmacology (August 2013) Volume 71() pp:130-140
Publication Date(Web):1 August 2013
DOI:10.1016/j.neuropharm.2013.04.003
•The novel recreational drug 3,4-methylenedioxypyrovalerone (MDPV) is underexplored in scientific studies.•MDPV is more potent and efficacious than d-methamphetamine (METH) in rat self-administration.•MDPV produces biphasic dose-dependent effects on locomotor activity, similar to those of METH.•Stereotyped behavior was observed after self-administration of over 1.5 mg/kg/h of MDPV.Recreational use of the cathinone derivative 3,4-methylenedioxypyrovalerone (MDPV; “bath salts”) has increased worldwide in past years, accompanied by accounts of health and legal problems in the popular media and efforts to criminalize possession in numerous jurisdictions. Minimal information exists on the effects of MDPV in laboratory models. This study determined the effects of MDPV, alongside those of the better studied stimulant d-methamphetamine (METH), using rodent models of intravenous self-administration (IVSA), thermoregulation and locomotor activity. Male Wistar rats were trained to self-administer MDPV or METH (0.05 mg/kg/infusion, i.v.) or were prepared with radiotelemetry implants for the assessment of body temperature and activity responses to MDPV or METH (0–5.6 mg/kg s.c.). METH and MDPV were consistently self-administered within 10 training sessions (mg/kg/h; METH Mean = 0.4 and Max = 1.15; MDPV Mean = 0.9 and Max = 5.8). Dose-substitution studies demonstrated that behavior was sensitive to dose for both drugs, but MDPV (0.01–0.50 mg/kg/inf) showed greater potency and efficacy than METH (0.1–0.25 mg/kg/inf). In addition, both MDPV and METH increased locomotor activity at lower doses (0.5–1.0 mg/kg, s.c.) and transiently decreased activity at the highest dose (5.6 mg/kg, s.c.). Body temperature increased monotonically with increasing doses of METH but MDPV had a negligible effect on temperature. Stereotypy was associated with relatively high self-administered cumulative doses of MDPV (∼1.5 mg/kg/h) as well as with non-contingent MDPV administration wherein the intensity and duration of stereotypy increased as MDPV dose increased. Thus, MDPV poses a substantial threat for compulsive use that is potentially greater than that for METH.
Co-reporter:Jacques D. Nguyen, Paul T. Bremer, Alex Ducime, Kevin M. Creehan, Brent R. Kisby, Michael A. Taffe, Kim D. Janda
Neuropharmacology (April 2017) Volume 116() pp:1-8
Publication Date(Web):1 April 2017
DOI:10.1016/j.neuropharm.2016.12.005
•The novel drugs alpha-pyrrolidinopentiophenone (α-PVP) and 3,4-methylenedioxypyrovalerone (MDPV) have high abuse potential.•There are no currently available therapies to treat stimulant abuse, including MDPV and α-PVP.•Drug-conjugate vaccines were created to generate antibodies to neutralize MDPV and α-PVP.•Increased wheel activity was produced by α-PVP or MDPV in the controls but not the vaccinated groups.•Self-administration of α-PVP was disrupted in the vaccinated group.Recreational use of substituted cathinones continues to be an emerging public health problem in the United States; cathinone derivatives α-pyrrolidinopentiophenone (α-PVP) and 3,4-methylenedioxypyrovalerone (MDPV), which have been linked to human fatalities and show high potential for abuse liability in animal models, are of particular concern. The objective of this study was to develop an immunotherapeutic strategy for attenuating the effects of α-PVP and MDPV in rats, using drug-conjugate vaccines created to generate antibodies with neutralizing capacity. Immunoconjugates (α-PVP-KLH and MDPV-KLH) or the control carrier protein, keyhole limpet hemocyanin (KLH), were administered to groups (N = 12) of male Sprague-Dawley rats on Weeks 0, 2 and 4. Groups were administered α-PVP or MDPV (0.0, 0.25, 0.5, 1.0, 5.0 mg/kg, i.p.) in acute drug challenges and tested for changes in wheel activity. Increased wheel activity produced by α-PVP or MDPV in the controls was attenuated in the α-PVP-KLH and MDPV-KLH vaccinated groups, respectively. Rectal temperature decreases produced by MDPV in the controls were reduced in duration in the MDPV-KLH vaccine group. A separate group (N = 19) was trained to intravenously self-administer α-PVP (0.05, 0.1 mg/kg/inf) and vaccinated with KLH or α-PVP-KLH, post-acquisition. Self-administration in α-PVP-KLH rats was initially higher than in the KLH rats but then significantly decreased following a final vaccine booster, unlike the stable intake of KLH rats. The data demonstrate that active vaccination provides functional protection against the effects of α-PVP and MDPV, in vivo, and recommend additional development of vaccines as potential therapeutics for mitigating the effects of designer cathinone derivatives.
Co-reporter:Michael A. Taffe, William J. Taffe
Brain Research (21 September 2011) Volume 1413() pp:43-50
Publication Date(Web):21 September 2011
DOI:10.1016/j.brainres.2011.07.048
Several nonhuman primate species have been reported to employ a distance-minimizing, traveling salesman-like, strategy during foraging as well as in experimental spatial search tasks involving lesser amounts of locomotion. Spatial sequencing may optimize performance by reducing reference or episodic memory loads, locomotor costs, competition or other demands. A computerized self-ordered spatial search (SOSS) memory task has been adapted from a human neuropsychological testing battery (CANTAB, Cambridge Cognition, Ltd) for use in monkeys. Accurate completion of a trial requires sequential responses to colored boxes in two or more spatial locations without repetition of a previous location. Marmosets have been reported to employ a circling pattern of search, suggesting spontaneous adoption of a strategy to reduce working memory load. In this study the SOSS performance of rhesus monkeys was assessed to determine if the use of a distance-minimizing search path enhances accuracy. A novel strategy score, independent of the trial difficulty and arrangement of boxes, has been devised. Analysis of the performance of 21 monkeys trained on SOSS over 2 years shows that a distance-minimizing search strategy is associated with improved accuracy. This effect is observed within individuals as they improve over many cumulative sessions of training on the task and across individuals at any given level of training. Erroneous trials were associated with a failure to deploy the strategy. It is concluded that the effect of utilizing the strategy on this locomotion-free, laboratory task is to enhance accuracy by reducing demands on spatial working memory resources.Highlights► An examination of sequencing strategy in a spatial search task for monkeys. ► Data show a distance-minimizing response “path” is associated with accuracy. ► A traveling-salesman-like strategy emerges despite the lack of locomotor cost. ► Monkeys use such strategies to decrease working memory load.
Co-reporter:Michelle L. Miller, Amira Y. Moreno, Shawn M. Aarde, Kevin M. Creehan, Sophia A. Vandewater, Brittani D. Vaillancourt, M. Jerry Wright Jr., Kim D. Janda, Michael A. Taffe
Biological Psychiatry (15 April 2013) Volume 73(Issue 8) pp:721-728
Publication Date(Web):15 April 2013
DOI:10.1016/j.biopsych.2012.09.010
Co-reporter:Simon N. Katner, Stefani N. Von Huben, Sophia A. Davis, Christopher C. Lay, Rebecca D. Crean, Amanda J. Roberts, Howard S. Fox, Michael A. Taffe
Drug and Alcohol Dependence (1 December 2007) Volume 91(Issues 2–3) pp:236-243
Publication Date(Web):1 December 2007
DOI:10.1016/j.drugalcdep.2007.06.002
Face validity in animal models of alcohol abuse and dependence is often at odds with robust demonstrations of ethanol-seeking. This study determined the relative influence of ethanol and a flavorant in maintaining ethanol intake in a nonhuman primate model of “cocktail” drinking. Four-year-old male monkeys were maintained on a 6% ethanol/6% Tang® solution made available in daily (M–F) 1-h sessions. Experiments determined the effect of (1) a second daily access session, (2) concurrent presentation of the Tang® vehicle, (3) sequential presentation of the vehicle in the first daily session and the ethanol solution in the second session, (4) altering the Tang® concentration, (5) altering the ethanol concentration, and (6) removal of the flavorant. Mean daily intake (2.7 ± 0.2 g/kg/day) was stable over 7 months. Simultaneous availability of a large, but not a low–moderate, volume of the vehicle reduced ethanol intake by about 50%. Decreasing the concentration of Tang® in the first daily session reduced ethanol intake, whereas intake of the standard solution was increased in the second session. Ethanol consumption was decreased by only 27% when the flavorant was removed. In summary, alterations that reduced intake in the first daily session resulted in compensatory increases in ethanol intake in the second session, suggesting that animals sought a specific level of ethanol intake per day. It is concluded that models with excellent face validity (flavored beverages) can produce reliable ethanol intake in patterns that are highly consistent with ethanol-seeking behavior.
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