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1.  Support for 5-HT2C receptor functional selectivity in vivo utilizing structurally diverse, selective 5-HT2C receptor ligands and the 2,5-dimethoxy-4-iodoamphetamine elicited head-twitch response model 
Neuropharmacology  2013;70:112-121.
There are seemingly conflicting data in the literature regarding the role of serotonin (5-HT) 5-HT2C receptors in the mouse head-twitch response (HTR) elicited by the hallucinogenic 5-HT2A/2B/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). Namely, both 5-HT2C receptor agonists and antagonists, regarding 5-HT2C receptor-mediated Gq-phospholipase C (PLC) signaling, reportedly attenuate the HTR response. The present experiments tested the hypothesis that both classes of 5-HT2C receptor compounds could attenuate the DOI-elicited-HTR in a single strain of mice, C57Bl/6J. The expected results were considered in accordance with ligand functional selectivity. Commercially-available 5-HT2C agonists (CP 809101, Ro 60-0175, WAY 161503, mCPP, and 1-methylpsilocin), novel 4-phenyl-2-N,N-dimethyl-aminotetralin (PAT)-type 5-HT2C agonists (with 5-HT2A/2B antagonist activity), and antagonists selective for 5-HT2A (M100907), 5-HT2C (SB-242084), and 5-HT2B/2C (SB-206553) receptors attenuated the DOI-elicited-HTR. In contrast, there were differential effects on locomotion across classes of compounds. The 5-HT2C agonists and M100907 decreased locomotion, SB-242084 increased locomotion, SB-206553 resulted in dose-dependent biphasic effects on locomotion, and the PATs did not alter locomotion. In vitro molecular pharmacology studies showed that 5-HT2C agonists potent for attenuating the DOI-elicited-HTR also reduced the efficacy of DOI to activate mouse 5-HT2C receptor-mediated PLC signaling in HEK cells. Although there were differences in affinities of a few compounds at mouse compared to human 5-HT2A or 5-HT2C receptors, all compounds tested retained their selectivity for either receptor, regardless of receptor species. Results indicate that 5-HT2C receptor agonists and antagonists attenuate the DOI-elicited-HTR in C57Bl/6J mice, and suggest that structurally diverse 5-HT2C ligands result in different 5-HT2C receptor signaling outcomes compared to DOI.
doi:10.1016/j.neuropharm.2013.01.007
PMCID: PMC3754837  PMID: 23353901
Head-twitch response; DOI; Hallucinogen; C57Bl/6J; Mouse serotonin 2C receptor; Mouse serotonin 2A receptor; Functional selectivity
2.  NONHUMAN PRIMATE MODELS OF SOCIAL BEHAVIOR AND COCAINE ABUSE 
Psychopharmacology  2012;224(1):57-67.
Rationale
Although cocaine is often abused in social situations, very few animal studies examine the effects of cocaine in the context of social behavior.
Objectives
This review highlights studies investigating the behavioral effects of cocaine in the context of social housing conditions using nonhuman primates. In addition, this review presents recent findings examining the effects of self-administering cocaine on social behavior and the effects of manipulations hypothesized to be stressful or enriching on the interactions between cocaine reinforcement and social rank. The following dependent variables are examined: 1) cocaine-induced changes in social behavior and 2) cocaine self-administration in cynomolgus monkeys of varying social ranks. The independent variables examined include several environmental and pharmacological manipulations.
Conclusions
The studies reviewed here indicate that several variables can differentially affect cocaine self-administration when studied in a social context, rather than in individually housed animals. These variables include the social rank and sex of the individual, drug history, the nature of the “fear”-inducing manipulation, and the reliability of cortisol as an appropriate measure of “stress.” While the inclusion of socially housed animals necessitates larger sample sizes, animal models incorporating social behavior are more homologous to the human condition and should be implemented when possible.
doi:10.1007/s00213-012-2843-5
PMCID: PMC3469766  PMID: 22895674
aggression; submission; social interactions; social consequences; social rank; cocaine self-administration; nonhuman primates
3.  Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model 
Drug testing and analysis  2012;4(0):556-576.
Two primary animal models persist for assessing hallucinogenic potential of novel compounds and for examining the pharmacological and neurobiological substrates underlying the actions of classical hallucinogens, the two-lever drug discrimination procedure and the drug-induced head-twitch response (HTR) in rodents. The substituted amphetamine hallucinogen, serotonin 2 (5-HT2) receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI) has emerged as the most popular pharmacological tool used in HTR studies of hallucinogens. Synthesizing classic, recent, and relatively overlooked findings, addressing ostensibly conflicting observations, and considering contemporary theories in receptor and behavioural pharmacology, this review provides an up-to-date and comprehensive synopsis of DOI and the HTR model, from neural mechanisms to utility for understanding psychiatric diseases. Also presented is support for the argument that, although both the two-lever drug discrimination and the HTR models in rodents are useful for uncovering receptors, interacting proteins, intracellular signalling pathways, and neurochemical processes affected by DOI and related classical hallucinogens, results from both models suggest they are not reporting hallucinogenic experiences in animals.
doi:10.1002/dta.1333
PMCID: PMC3722587  PMID: 22517680
5-HT2; serotonin; DOI; HTR; model; 2,5-dimethoxy-4-iodoamphetamine; phenylisopropylamine; psychedelic; hallucinogen
4.  Effects of Morphine on Thermal Sensitivity in Adult and Aged Rats 
There are contradictory data regarding older individuals’ sensitivity to pain stimulation and opioid administration. Adult (12–16 months; n = 10) and aged (27–31 months; n = 7) male F344xBN rats were tested in a thermal sensitivity procedure where the animal chooses to remain in one of two compartments with floors maintained at various temperatures ranging from hot (45°C) through neutral (30°C) to cold (15°C). Effects of morphine were determined for three temperature comparisons (ie, hot/neutral, cold/neutral, and hot/cold). Aged rats were more sensitive to cold stimulation during baseline. Morphine produced antinociception during hot thermal stimulation, but had no effect on cold stimulation. The antinociceptive (and locomotor-altering) effects of morphine were attenuated in aged rats. These data demonstrate age-related differences in baseline thermal sensitivity and responsiveness to opioids. Based on behavioral and physiological requirements of this procedure, it is suggested that thermal sensitivity may provide a relevant animal model for the assessment of pain and antinociception.
doi:10.1093/gerona/glr210
PMCID: PMC3391067  PMID: 22193548
Opioids; Chronic pain; Operant testing; Thermal preference; Animal models
5.  Usefulness of Preclinical Models for Assessing the Efficacy of Late-Life Interventions for Sarcopenia 
Caloric restriction and physical exercise have proven beneficial against age-associated changes in body composition and declining physical performance; however, little is known regarding what benefit these interventions might have when initiated late in life. The study of mimetics of diet and exercise and the combination thereof may provide additional treatments for a vulnerable elderly population; however, how and when to initiate such interventions requires consideration in developing the most safe and efficacious treatment strategies. In this review, we focus on preclinical late-life intervention studies, which assess the relationship between physical function, sarcopenia, and body composition. We provide a conceptual framework for the ever-changing definition of sarcopenia and a rationale for the use of an appropriate rodent model of this condition. We finish by providing our perspective regarding the implications of this body of work and future areas of research that may also contribute to the ultimate goal of extending healthspan.
doi:10.1093/gerona/glr042
PMCID: PMC3260483  PMID: 21636833
Renin angiotensin system; Enalapril repamycin; Physical function; Body composition
7.  Differential effects of enalapril and losartan on body composition and indices of muscle quality in aged male Fischer 344 × Brown Norway rats 
Age  2010;33(2):167-183.
The primary purpose of the present set of studies was to provide a direct comparison of the effects of the angiotensin-converting enzyme inhibitor enalapril and the angiotensin receptor blocker losartan on body composition, physical performance, and muscle quality when administered late in life to aged rats. Overall, enalapril treatment consistently attenuated age-related increases in adiposity relative to both placebo and losartan. The maximal effect was achieved after 3 months of treatment (between 24 and 27 months of age), at a dose of 40 mg/kg and was observed in the absence of any changes in physical activity, body temperature, or food intake. In addition, the reduction in fat mass was not due to changes in pathology given that enalapril attenuated age-related increases in tumor development relative to placebo- and losartan-treated animals. Both enalapril and losartan attenuated age-related decreases in grip strength, suggesting that changes in body composition appear dissociated from improvements in physical function and may reflect a differential impact of enalapril and losartan on muscle quality. To link changes in adiposity to improvements in skeletal muscle quality, we performed gene array analyses to generate hypotheses regarding cell signaling pathways altered with enalapril treatment. Based on these results, our primary follow-up pathway was mitochondria-mediated apoptosis of myocytes. Relative to losartan- and placebo-treated rats, only enalapril decreased DNA fragmentation and caspase-dependent apoptotic signaling. These data suggest that attenuation of the severity of skeletal muscle apoptosis promoted by enalapril may represent a distinct mechanism through which this compound improves muscle strength/quality.
doi:10.1007/s11357-010-9196-y
PMCID: PMC3127467  PMID: 21153712
Age-related adiposity; Body composition; Sarcopenia; Renin–angiotensin system; Physical function; Muscle quality
8.  Effects of chronic fentanyl administration on physical performance of aged rats 
Experimental gerontology  2010;46(1):65-72.
There is growing concern over the increasing use of opioids to treat chronic pain in the elderly primarily because of the potential increased sensitivity to the adverse side effects. Here, we use a preclinical model (male Brown Norway X F344 rats aged 12, 18, 24, and 30 months) to describe the outcome of chronic fentanyl administration (1.0 mg/kg/day) on various physiological and behavioral measures. Continuous fentanyl administration resulted in an initial decrease in food consumption, followed by the development of tolerance to this effect over a 4-week period and a subsequent increase in food consumption during withdrawal. This change in food consumption was associated with decreases in body weight (predominantly due to a loss of fat mass) that was maintained through early withdrawal. After one month of withdrawal, only the 12-month old animals had fully regained body weight. Fentanyl administration resulted in a decrease in grip strength and an increase in locomotor activity that did not differ across age groups. There was no effect of fentanyl administration on rotarod performance. These results demonstrate that while there is a delayed recovery of body mass with age, the observed changes in behavioral responses are uniform across ages.
doi:10.1016/j.exger.2010.10.004
PMCID: PMC2998590  PMID: 20951790
Locomotor activity; Rotarod; Grip strength; Body composition; Osmotic minipump
9.  Persistent proteomic alterations in the medial prefrontal cortex with abstinence from cocaine self-administration 
Neuroproteomic studies of drug abuse offer the potential for a systems-level understanding of addiction. Understanding cocaine-responsive alterations in brain protein expression that persist even with extended abstinence may provide insight into relapse liability. In the current study, protein changes in the medial prefrontal cortex of cocaine self-administering rats following 1 and 100 days of enforced abstinence were quantified by 2D-DIGE. We have previously reported increased drug-seeking and drug-taking, as well as mRNA and epigenetic changes in this model even after 100 days of enforced abstinence. A number of statistically-significant changes in proteins relating to synapse function and neuronal remodeling were evident, including neurofilament medium and heat shock protein 73 (Hsp73) which increased at 1 day of abstinence, but returned to normal levels following 100 days of abstinence. −1 and synaptosome-associated protein 25 kDa (SNAP-25) were unchanged at 1 day of abstinence, but were significantly decreased after 100 days. These data demonstrate that while some protein changes return to normal levels following enforced cocaine abstinence, a number remain or become altered after long periods, up to 100 days, of cocaine abstinence. Those protein expression changes that do not reset to pre-cocaine exposure levels may contribute to the persistent relapse potential that occurs in response to cocaine abstinence.
doi:10.1002/prca.200800055
PMCID: PMC2742427  PMID: 20161123
Cocaine; medial prefrontal cortex; proteomics; withdrawal; self-administration
10.  Gene expression changes in the medial prefrontal cortex and nucleus accumbens following abstinence from cocaine self-administration 
BMC Neuroscience  2010;11:29.
Background
Many studies of cocaine-responsive gene expression have focused on changes occurring during cocaine exposure, but few studies have examined the persistence of these changes with cocaine abstinence. Persistent changes in gene expression, as well as alterations induced during abstinence may underlie long-lasting drug craving and relapse liability.
Results
Whole-genome expression analysis was conducted on a rat cocaine binge-abstinence model that has previously been demonstrated to engender increased drug seeking and taking with abstinence. Gene expression changes in two mesolimbic terminal fields (mPFC and NAc) were identified in a comparison of cocaine-naïve rats with rats after 10 days of cocaine self-administration followed by 1, 10, or 100 days of enforced abstinence (n = 6-11 per group). A total of 1,461 genes in the mPFC and 414 genes in the NAc were altered between at least two time points (ANOVA, p < 0.05; ± 1.4 fold-change). These genes can be subdivided into: 1) changes with cocaine self-administration that do not persist into periods of abstinence, 2) changes with cocaine self-administration that persist with abstinence, 3) and those not changed with cocaine self-administration, but changed during enforced abstinence. qPCR analysis was conducted to confirm gene expression changes observed in the microarray analysis.
Conclusions
Together, these changes help to illuminate processes and networks involved in abstinence-induced behaviors, including synaptic plasticity, MAPK signaling, and TNF signaling.
doi:10.1186/1471-2202-11-29
PMCID: PMC2837051  PMID: 20187946
11.  Sensitization of the reinforcing effects of self-administered cocaine in rats: effects of dose and intravenous injection speed 
Speed of drug onset is assumed to be an important determinant of the abuse liability of a drug. Studies in human and non-human primates suggest that the subjective and reinforcing effects of cocaine can be influenced by route of administration and/or speed of intravenous injection. Sensitization to the reinforcing effects of cocaine was studied in rats and the effects of various injection durations (i.e. speed of injection) on the development of sensitization was examined using a progressive ratio schedule. In addition, the effects of cocaine dose on sensitization and the effects of injection duration on the acute reinforcing effects of cocaine were examined. The initial study demonstrated that the development of sensitization (i.e. progressive increases in breakpoints) was dose-dependent. A robust sensitization of the reinforcing effects of cocaine was replicated in animals receiving cocaine at the highest rate (i.e. shortest duration; 5 s), but not in animals receiving the same dose over 25 or 50 s. Subsequent testing revealed that injection duration did not have profound effects on the acute reinforcing effects of cocaine (assessed by breakpoints or rate of responding on a fixed ratio schedule). These findings are similar to recent studies demonstrating that the development of sensitization, but not the acute responsivity, to cocaine’s locomotor-activating effects are influenced by rate of intravenous injection. Taking these findings together, we hypothesize that the process of drug addiction involves both the acute reinforcing effects and the development of sensitization.
doi:10.1111/j.1460-9568.2005.04195.x
PMCID: PMC1488819  PMID: 16029209
abuse liability; infusion duration; locomotor activity; motivation; pharmacokinetics
12.  How to make a rat addicted to cocaine 
Procedures have been developed which provide extremely stable patterns of cocaine self-administration in rats and these have been useful in lesion and drug pretreatment studies aimed at understanding the neurobiology of cocaine reinforcement. The issue now is whether studying the neurobiology of reinforcement is the same as studying the neurobiology of addiction. If the goal is to understand a progressive and deteriorating disorder, then the self-administration procedures should model specific aspects of the progressive stages of the addiction process. Here we review theoretical strategies for modeling the addiction process and present data from a series of experiments from our laboratory showing conditions which produce a progressive change in the motivation to self-administer cocaine in rats. This phenomenon is revealed by an escalation in breakpoints on a progressive ratio schedule. The effect, which is robust and persistent, depends on dose and speed of injection. Interestingly, high drug intake can retard the development of this effect, which we argue indicates that the addiction process has a developmental sequence. Finally, we suggest that specific parameters (dose, price and availability) can be used to examine the transition from recreational use to binge-like intake.
doi:10.1016/j.pnpbp.2007.08.028
PMCID: PMC2140146  PMID: 17888555
Animal models; Motivation; Sensitization; Addiction

Results 1-12 (12)