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1.  Contribution of NMDA glutamate and nicotinic acetylcholine receptor mechanisms in the discrimination of ethanol-nicotine mixtures 
Behavioural pharmacology  2013;10.1097/FBP.0b013e3283654216.
Ethanol and nicotine are commonly co-abused drugs, and the incidence of co-dependence is greater than would be expected based on the summed probability of dependence on each drug alone. Previous findings from our laboratory and others suggest that interactive mechanisms at the level of discriminative stimulus (SD) effects may contribute to this co-abuse phenomenon. Specifically, ethanol overshadows the nicotine SD whereas nicotine potentiates the stimulus salience of ethanol when the two drugs are conditioned as a drug mixture. The goal of the current study was to begin to delineate the pharmacological bases of these ethanol-nicotine interactions. Three groups of C57BL/6J mice were trained to discriminate 0.8 mg/kg nicotine + 0.5 g/kg ethanol (0.8N+0.5E), 0.8N+1.0E or 0.8N+2.0E. An NMDA receptor antagonist (MK-801) and three nACh receptor ligands were tested for their ability to generalize from or antagonize, respectively, the drug mixtures. MK-801 fully generalized from the 0.8N+1.0E and 0.8N+2.0E mixtures and partially generalized from 0.8N+0.5E. In contrast, nACh receptor ligands had minimal influence in blocking the perception of 0.8N+1.0E and 0.8N+2.0E mixtures, and only mecamylamine partially blocked 0.8N+0.5E. Reduced and enhanced contributions of nACh and NMDA receptors, respectively, in the discrimination of ethanol-nicotine mixtures may contribute to the overshadowing and potentiation phenomena previously observed.
doi:10.1097/FBP.0b013e3283654216
PMCID: PMC3925192  PMID: 23928692
drug discrimination; drug mixture; ethanol; nicotine; NMDA receptor; nACh receptor; substitution; antagonism; overshadowing; mouse
2.  [No title available] 
PMCID: PMC3884554  PMID: 24322822
3.  [No title available] 
PMCID: PMC3897127  PMID: 24370557
4.  [No title available] 
PMCID: PMC4293121  PMID: 24126218
5.  Next generation effects of female adolescent morphine exposure: sex-specific alterations in response to acute morphine emerge before puberty 
Behavioural pharmacology  2014;25(2):173-181.
Prescription opiate use by adolescent girls has increased significantly in the past decade. Preclinical studies using rats report alterations in morphine sensitivity in the adult offspring of adolescent morphine-exposed females (MOR-F1) when compared with the offspring of adolescent saline-exposed females (SAL-F1). To begin to elucidate the development of these next generation modifications, the present study examined the effects of acute morphine administration on sedation and corticosterone secretion in prepubescent SAL-F1 and MOR-F1 male and female rats. In addition, alterations in proopiomelanocortin (POMC) gene expression in the arcuate nucleus, as well as in tyrosine hydroxylase (TH) and μ-opioid receptor (OPRM1) gene expressions in the ventral tegmental area, were analyzed using quantitative PCR, to determine whether differential regulation of these genes was correlated with the observed behavioral and/or endocrine effects. Increased morphine-induced sedation, coupled with an attenuation of morphine-induced corticosterone secretion, was observed in MOR-F1 males. Significant alterations in both POMC and OPRM1 gene expressions were also observed in MOR-F1 males, with no change in TH mRNA expression. Overall, these data suggest that the transgenerational effects of adolescent morphine exposure can be discerned before pubertal development and are more pronounced in males, and suggest dysregulation of the hypothalamic–pituitary–adrenal axis in the offspring of adolescent morphine-exposed females.
doi:10.1097/FBP.0000000000000032
PMCID: PMC4270349  PMID: 24561499
arcuate nucleus; corticosterone; gene expression; locomotor activity; mu-opioid receptor; proopiomelanocortin; transgenerational; ventral tegmental area
6.  Calcium/calmodulin-dependent protein kinase IV mediates acute nicotine-induced antinociception in acute thermal pain tests 
Behavioural pharmacology  2013;24(8):10.1097/FBP.0000000000000005.
Calcium activated second messengers such as calcium/calmodulin-dependent protein kinase II have been implicated in drug-induced antinociception. The less abundant calcium activated second messenger, calcium/calmodulin-dependent protein kinase IV (CaMKIV), mediates emotional responses to pain and tolerance to morphine analgesia; however its role in nicotine-mediated antinociception is currently unknown. The goal of this study was to evaluate the role of CaMKIV in the acute effects of nicotine, primarily acute nicotine- induced antinociception. CaMKIV knockout (−/−), heterozygote (+/−), and wild-type (+/+) mice were injected with various doses of nicotine and evaluated in a battery of tests, including the tail-flick and hot-plate tests for antinociception, body temperature, and locomotor activity. Our results show a genotype-dependent reduction in tail-flick and hot- plate latency in CaMKIV (+/−) and (−/−) mice after acute nicotine treatment, while no difference was observed between genotypes in the body temperature and locomotor activity assessments. The results of this study support a role for CaMKIV in acute nicotine-induced spinal and supraspinal pain mechanisms, and further implicate involvement of calcium-dependent mechanisms in drug-induced antinociception.
doi:10.1097/FBP.0000000000000005
PMCID: PMC3884898  PMID: 24196027
nicotine; calcium/calmodulin-dependent protein kinase IV; antinociception; tail-flick; hot-plate, mouse
7.  The dopamine D2 antagonist eticlopride accelerates extinction and delays reacquisition of food self-administration in rats 
Behavioural pharmacology  2013;24(8):633-639.
Dopamine receptors are implicated in the reinforcing effects of food and drug reinforcement. The purpose of this study was to evaluate whether blocking D2 dopamine receptors during extinction (secondary reinforcement) would affect reacquisition of responding for food pellets (primary reinforcement). Food-restricted rats self-administered (FR1) food pellets in 1-h daily sessions for seven days. For the next seven days rats responded in extinction conditions. Prior to each extinction session rats were injected with saline or the dopamine D2 antagonist eticlopride (0.03 mg/kg, cs.c.). After the extinction phase, rats were allowed to reacquire food pellet self-administration in seven daily sessions, and received saline or eticlopride prior to each session. Four treatment groups were represented: (saline extinction, saline reacquisition); (eticlopride extinction, saline reacquisition); (saline extinction, eticlopride reacquisition); (eticlopride extinction, eticlopride reacquisition). Locomotor activity did not differ between eticlopride-treated and saline-treated rats throughout the study. Extinction was accelerated in eticlopride-treated rats. Eticlopride also delayed reacquisition of food self-administration compared to saline-treated rats. Rats administered eticlopride during extinction showed delayed reacquisition and a decreased response rate for food during the reacquisition phase. Indirectly reducing the value of a reinforcer in this way may provide a novel approach for reducing addiction-related food or drug self-administration behaviors.
doi:10.1097/FBP.0000000000000002
PMCID: PMC3896390  PMID: 24113080
dopamine; extinction; food; obesity; rat; reinforcement
8.  Locomotor Stimulant and Discriminative Stimulus Effects of “Bath Salt” Cathinones 
Behavioural pharmacology  2013;24(0):437-447.
A number of psychostimulant-like cathinone compounds are being sold as “legal” alternatives to methamphetamine or cocaine. The purpose of these experiments was to determine whether cathinone compounds stimulate motor activity and have discriminative stimulus effects similar to cocaine and/or methamphetamine. 3,4-Methylenedioxypyrovalerone (MDPV), methylone, mephedrone, naphyrone, flephedrone and butylone were tested for locomotor stimulant effects in mice and subsequently for substitution in rats trained to discriminate cocaine (10 mg/kg, i.p.) or methamphetamine (1 mg/kg, i.p.) from saline. All compounds fully substituted for the discriminative stimulus effects of cocaine and methamphetamine. Several commonly marketed cathinones produce discriminative stimulus effects comparable to those of cocaine and methamphetamine, which suggests that these compounds are likely to have similar abuse liability. MDPV and naphyrone produced locomotor stimulant effects that lasted much longer than cocaine or methamphetamine and therefore may be of particular concern, particularly since MDPV is one of the most commonly found substances associated with emergency room visits due to adverse effects from taking “bath salts”.
doi:10.1097/FBP.0b013e328364166d
PMCID: PMC4183201  PMID: 23839026
cathinones; drug discrimination; locomotor activity; abuse liability; mouse; rat
9.  Behavioral effects of the imidazoline I2 receptor ligand BU99006 in rats 
Behavioural pharmacology  2014;25(2):130-136.
The imidazoline I2 receptor ligand BU99006 binds to and attenuates effects mediated by I2 receptors in vitro, although its effects in vivo have not been studied. This study examined the effects of BU99006 in two behavioral assays in rats: hypothermia and 2-BFI discrimination. BU99006 (3.2 – 15 mg/kg, i.p.) produced a dose-dependent hypothermic effect (rectal temperature), which was antagonized by the I2 receptor antagonist idazoxan. BU99006 (3.2 or 10 mg/kg given 10 min or 2 hr before the session, respectively) did not significantly alter hypothermia produced by I2 receptor agonist 2-BFI (10 mg/kg). In rats discriminating 5.6 mg/kg 2-BFI, BU99006 (1.78 – 17.8 mg/kg, i.p.) produced 40% and 82% responding on the 2-BFI-associated lever when it was administered immediately or 2 hrs prior to the test sessions, respectively. BU99006 enhanced the discriminative stimulus and rate-suppressing effects of 2-BFI. Collectively, these data suggest that BU99006 is an imidazoline I2 receptor agonist with no evidence of I2 receptor antagonism in rats.
doi:10.1097/FBP.0000000000000028
PMCID: PMC4180046  PMID: 24518265
BU99006; 2-BFI; hypothermia; drug discrimination; rats
10.  Effects of Chronic Methylphenidate in Adolescence on Later Methylphenidate Self-Administration in Rhesus Monkeys 
Behavioural pharmacology  2013;24(0):478-481.
Many children diagnosed with attention deficit hyperactivity disorder are treated with methylphenidate (MPH), despite limited information on later vulnerability to drug abuse. A previous study in adolescent monkeys treated with MPH for 1 year did not reveal differences in acquisition to cocaine reinforcement compared to controls (Gill et al., 2012). The present study extended this characterization to include MPH self-administration. Adolescent male rhesus monkeys previously treated with a sustained-release formulation of MPH (beginning at ∼ 30 months old) and control monkeys (n=8/group) were used. All had prior experience of self-administering cocaine under a fixed-ratio (FR) 30 schedule of reinforcement. Responding was maintained by food (1.0-g banana-flavored pellets) and MPH (saline, 0.001 – 0.1 mg/kg per injection) was substituted for food for at least 5 consecutive sessions. MPH functioned as a reinforcer in all monkeys; there were no differences between groups in MPH self-administration. These findings extend earlier research with cocaine reinforcement showing that MPH treatment in adolescent monkeys does not increase future reinforcing effects of stimulant drugs.
doi:10.1097/FBP.0b013e328364bfee
PMCID: PMC4167420  PMID: 23903242
methylphenidate; cocaine; abuse liability; drug abuse; rhesus monkey
11.  Comparison of a drug versus money and drug versus drug self-administration choice procedure with oxycodone and morphine in opioid addicts 
Behavioural pharmacology  2013;24(0):504-516.
This double-blind, placebo-controlled study investigated effects of oral morphine (0, 45, 135 mg/70kg) and oral oxycodone (0, 15, 45 mg/70kg) in buprenorphine-maintained opioid addicts. Since a 3:1 morphine:oxycodone dose ratio had yielded equivalent subjective and physiological effects in non-dependent individuals, this ratio was used in the present study. Two self-administration laboratory procedures, i.e. a drug vs. money and a drug vs. drug procedure, were assessed. Study participants (N=12) lived in the hospital and were maintained on 4 mg/day sublingual buprenorphine. When participants chose between drug and money, money was preferred over all drug doses; only high-dose oxycodone was self-administered more than placebo. When participants chose between drug and drug, both drugs were chosen more than placebo, high doses of each drug were chosen over low doses, and high-dose oxycodone was preferred over high-dose morphine. The subjective, performance-impairing, and miotic effects of high-dose oxycodone were generally greater compared to high-dose morphine. The study demonstrated that a 3:1 dose ratio of morphine:oxycodone was not equipotent in buprenorphine-dependent subjects. Both self-administration procedures were effective for assessing the relative reinforcing effects of drugs; preference for one procedure should be driven by the specific research question of interest.
doi:10.1097/FBP.0b013e328363d1c4
PMCID: PMC4056333  PMID: 23839029
morphine:oxycodone ratio; buprenorphine-maintenance; opioid dependence; abuse liability; self-administration procedure; physiological and subjective effects
12.  Relationship Between Drug Discrimination and Ratings of Subjective Effects: Implications for Assessing and Understanding the Abuse Potential of d-Amphetamine in Humans 
Behavioural pharmacology  2013;24(0):523-532.
The discriminative and subjective effects of drugs in humans are related, but the full extent of this relationship remains to be determined. To further explore this relationship, a retrospective analysis was conducted on data from six studies completed in our laboratory that used identical procedures. The relationship between the discriminative and subjective effects of a range of doses of d-amphetamine (i.e., 2.5–15 mg) was examined using correlational analyses. Significant correlations with discrimination performance were observed on 15 of 20 items from the Drug-Effect Questionnaire across a range of qualities (e.g., Pay For [a positive effect indicative of abuse potential] and Active [a stimulant-like effect]), but the magnitude of these relationships was modest (r < 0.52). The current findings demonstrate that diverse subjective effects contribute to the discriminative effects of d-amphetamine and indicate that the former are a more practical means to assess abuse potential of drugs. Although these procedures are fundamentally related in that they rely on the presence of an interoceptive drug state, they differ in the dimension(s) of the interoceptive effects that participants must quantify. The simultaneous use of drug discrimination and subjective effects may, therefore, reveal complimentary aspects of drug effects that underlie their potential for abuse.
doi:10.1097/FBP.0b013e328364505f
PMCID: PMC4058093  PMID: 23851485
Abuse potential; d-amphetamine; drug discrimination; subjective effects
13.  The Relative Reinforcing Strength of Methamphetamine and d-Amphetamine in Monkeys Self-Administering Cocaine 
Behavioural pharmacology  2013;24(0):10.1097/FBP.0b013e3283644d44.
Epidemiological data indicate that rates of methamphetamine misuse surpass those of d-amphetamine, but self-administration research in animals and humans has not typically demonstrated differences in their reinforcing effects. The present study used a within-session, exponentially-increasing progressive-ratio schedule and extended-access conditions to assess the relative reinforcing strength of d-amphetamine and methamphetamine in rhesus monkeys (n=5) trained to self-administer cocaine. A range of doses of methamphetamine (0.003–0.1 mg/kg/injection), d-amphetamine (0.003–0.1 mg/kg/injection) and cocaine (0.003–0.3 mg/kg/injection) was tested to capture the ascending and descending limbs of the dose-effect functions. Each drug functioned as a reinforcer, but the peak number of self-administered d-amphetamine injections was significantly lower compared to methamphetamine and cocaine; the peak number of self-administered injections of cocaine and methamphetamine did not differ. Although differences in availability and other social factors likely impact relative rates of abuse, the present data suggest that the greater reinforcing strength of methamphetamine contributes to its increased use compared to d-amphetamine.
doi:10.1097/FBP.0b013e3283644d44
PMCID: PMC3857529  PMID: 23907377
Cocaine; amphetamine; drug abuse; abuse liability; abuse potential; reinforcing strength; rhesus monkey
14.  Escalation of drug self-administration as a hallmark of persistent addiction liability 
Behavioural pharmacology  2013;24(0):10.1097/FBP.0b013e3283644d15.
Drug addiction is a progressive, relapsing disease comprised of interlocking stages of disordered motivation. Numerous animal models describing various stages of the addiction process have been developed over the past few decades, providing considerable advantages for the modeling of drug addiction compared with other complex psychiatric disease states. Escalation of drug self-administration has emerged as a widely accepted operant conditioning model of excessive drug intake. We further argue here that drug-escalated animals represent a comprehensive model of addiction according to the manifestations of behavioral neuroadaptations resulting directly or indirectly from excessive drug consumption. In particular, drug-escalated animals exhibit a host of symptoms in line with multiple Diagnostic and Statistical Manual of Mental Disorders criteria for substance dependence, which can be summarized as an emergence of uncontrollable drug-taking and drug-seeking behaviors as a consequence of within-circuit and between-circuit neuroadaptations. Such a transition from impulsive drug sampling to compulsive intake represents a highly valid conceptualization of the addiction timeline in humans, and further investigation of persistent or near-permanent (e.g. epigenetic) neuroadaptations generated by operant drug intake escalation models will continue to provide mechanisms and therapeutic interventions for reversing the aberrant neuroplasticity underlying addiction.
doi:10.1097/FBP.0b013e3283644d15
PMCID: PMC3866817  PMID: 23839030
addiction; alcohol; cocaine; escalation; heroin; self-administration
15.  Relationship Between Oral d-Amphetamine Self-Administration and Ratings of Subjective Effects: Do subjective-effects ratings correspond with a progressive-ratio measure of drug-taking behavior? 
Behavioural pharmacology  2013;24(0):533-542.
The abuse potential of drugs has traditionally been determined in humans using subjective ratings of drug effects. However, drug self-administration procedures also provide valuable information about the reinforcing effects of drugs that may contribute to their potential for abuse. Although ratings of subjective effects and drug self-administration data are generally concordant, some divergent findings have been reported. Therefore, the aim of the present analysis was to directly investigate the relationship between the subjective-effects profile and self-administration of oral d-amphetamine in healthy volunteers with a history of stimulant use or abuse using Pearson correlational analyses. The results indicated that positive subjective and reinforcing effects significantly increased as a function of d-amphetamine dose. Furthermore, significant, but modest, correlations were observed between ratings of 6 of 17 total items (Any Effect, High, Like Drug, Good Effects, Willing to Pay For, and Willing to Take Again) and d-amphetamine self-administration under a progressive-ratio schedule of reinforcement. The current findings suggest that, at least under the current set of conditions with oral d-amphetamine, subjective-effects measures and drug self-administration data likely provide different but complimentary information about abuse potential. The most informative findings will thus be obtained from studies that employ ratings of subjective effects and drug self-administration methods.
doi:10.1097/FBP.0b013e3283645047
PMCID: PMC4012251  PMID: 23881044
d-amphetamine; subjective effects; drug self-administration; humans
16.  A review of human drug self-administration procedures 
Behavioural pharmacology  2013;24(0):384-395.
Drug self-administration procedures in laboratory settings allow us to closely model drug-taking behavior in real-world settings. This review provides an overview of many of the common self-administration methods used in human laboratory research. Typically, self-administration studies provide a quantifiable measure of the reinforcing effect of a drug, which is believed to be predictive of its potential for abuse. Several adaptations of the self-administration paradigm exist, the simplest of which allows participants free access to the drug under investigation. Free-access procedures allow investigators to observe patterns of drug self-administration and drug effects in a controlled setting. Allowing participants to choose between two simultaneously available reinforcers (choice procedures) is another well-established method of assessing the reinforcing effects of a drug. Offering a choice between two reinforcers (e.g. two different doses of the same drug, two different drugs, or drug and nondrug reinforcers) provides researchers with a point of comparison (e.g. between a drug of known abuse potential and a novel drug). When combined with other endpoints, such as subjective effects ratings, physiological responses, and cognitive performance, human self-administration paradigms have contributed significantly to our understanding of the factors that contribute to, maintain, and alter drug-taking behavior including: craving, positive subjective effects, toxicity, drug interactions and abstinence. This area of research has also begun to incorporate other techniques such as imaging and genetics to further understand the multifaceted nature of substance abuse. The present paper summarizes the different self-administration techniques that are commonly used today and the application of other procedures that may complement interpretation of the drug
doi:10.1097/FBP.0b013e3283641c3d
PMCID: PMC4080726  PMID: 23839027
abuse potential; choice procedures; drug abuse; free-access; reinforcer; self-administration
17.  Narp expressed in medial prefrontal cortex neurons is not necessary for extinction of heroin self-administration 
Behavioural pharmacology  2013;24(4):332-336.
The medial prefrontal cortex (mPFC) plays a key role in extinction learning. Previously, we found that expression of a Narp dominant-negative construct in the mPFC of mice blocked extinction of morphine conditioned place preference. In order to further investigate the role of mPFC Narp in the extinction of drug seeking, we tested whether mPFC Narp is necessary for the extinction of heroin self-administration in rats. Specifically, we injected an adeno-associated viral vector (AAV) expressing a dominant-negative form of Narp (NarpN) into the infralimbic region (IL) of the mPFC of rats and compared lever presses during extinction to those of rats injected with a control virus. In contrast to our previous study, we found that injection of NarpN did not affect extinction of heroin self-administration. Our findings suggest that mPFC Narp is necessary for extinction of opiate seeking in the Pavlovian conditioned place preference paradigm but not in the operant paradigm of drug self-administration.
doi:10.1097/FBP.0b013e328363367b
PMCID: PMC3779366  PMID: 23751516
Narp; extinction; heroin; self-administration; addiction; prefrontal cortex
18.  Restricted psychological horizon in active methamphetamine users: future, past, probability, and social discounting 
Behavioural pharmacology  2012;23(4):358-366.
Methamphetamine users (MAU) exhibit an exaggerated bias for immediate rewards that reflects a restricted time horizon, where outcomes in the future are excessively discounted. An accumulating literature indicates that time in the future shares features with other dimensions of psychological distances including time in the past probability, and social distance, suggesting that bias for immediacy may be reducible to a more general restriction of psychological horizon. The purpose of the present study was to explore generalized restricted psychological horizon in active MAU by assessing future, past, probability, and social discounting. Compared with nonusing controls, MAU preferred psychologically proximal outcomes, resulting in higher rates for all types of discounting, which supports the conceptualization that MAU insufficiently integrate outcomes of psychological distance (i.e. in the future, the past, probabilistic, for others) into the valuation of current behavioral alternatives. The present results are suggestive of a more fundamental process of problematic decision-making associated with methamphetamine use, indicating the necessity of more comprehensive approaches to address the generalized limitations of restricted psychological horizon.
doi:10.1097/FBP.0b013e3283564e11
PMCID: PMC4104478  PMID: 22743602
behavioral economics; discounting; methamphetamine; psychological horizon
19.  Withdrawal from chronic exposure to amphetamine, but not nicotine, leads to an immediate and enduring deficit in motivated behavior without affecting social interaction in rats 
Behavioural pharmacology  2010;21(4):359-368.
Psychostimulant withdrawal leads to depressive symptoms, such as anhedonia and social dysfunction. We determined the effects of withdrawal from chronic exposure to nicotine (9 mg/kg/day salt, 28 days) or amphetamine (10 mg/kg/day salt, 7 days) on the motivated response for a sucrose reward and on social interaction in rats. Both nicotine and amphetamine exposure increased the motivated response for sucrose. However, only spontaneous amphetamine withdrawal led to an immediate and persistent decrease in motivated behavior, which was not correlated with body weight loss. Social interaction was not affected during withdrawal from either drug. These results indicate that withdrawal from chronic amphetamine exposure leads to an immediate and enduring anhedonic state.
doi:10.1097/FBP.0b013e32833c7cc8
PMCID: PMC4082429  PMID: 20571366
psychostimulant; dependence; depression; reward; anhedonia; motivation
20.  In-vivo pharmacological evaluation of the CB1-receptor allosteric modulator Org-27569 
Behavioural pharmacology  2014;25(2):182-185.
Several allosteric modulators (AMs) of the CB1 receptor have been characterized in vitro, including Org27569, which enhances CB1-specific binding of [3H]CP55,940, but behaves as an insurmountable CB1-receptor antagonist in several biochemical assays. Although a growing body of research has investigated the molecular actions of this unusual AM, it is unknown whether these actions translate to the whole animal. The purpose of the present study was to determine whether Org27569 would produce effects in well-established mouse behavioral assays sensitive to CB1 orthosteric agonists and antagonists. Similar to the orthosteric CB1 antagonist/inverse agonist rimonabant, Org27569 reduced food intake; however, this anorectic effect occurred independently of the CB1 receptor. Org27569 did not elicit CB1-mediated effects alone and lacked efficacy in altering antinociceptive, cataleptic, and hypothermic actions of the orthosteric agonists anandamide, CP55,940, and Δ9-tetrahydrocannabinol. Moreover, it did not alter the discriminative stimulus effects of anandamide in FAAH-deficient mice or Δ9-tetrahydrocannabinol in wild-type mice in the drug discrimination paradigm. These findings question the utility of Org27569 as a ‘gold standard’ CB1 AM and underscore the need for the development of CB1 AMs with pharmacology that translates from the molecular level to the whole animal.
doi:10.1097/FBP.0000000000000027
PMCID: PMC4042670  PMID: 24603340
allosteric modulator; anandamide; cannabinoid; CB1; CP55; 940; Δ9-tetrahydrocannabinol; mouse; rimonabant
21.  Rate-Dependent Effects of Monoamine Releasers on Intracranial Self-Stimulation in Rats: Implications for Abuse Liability Assessment 
Behavioural pharmacology  2013;24(0):448-458.
“Rate-dependency” in the discipline of behavioral pharmacology describes a phenomenon wherein the effect of a drug on the rate of a behavior varies systematically as a function of the baseline, pre-drug rate of that behavior. Historically, rate-dependency studies have compared drug effects on different baseline rates of behavior maintained either by different schedules of reinforcement or during sequential segments of a fixed-interval schedule. The current experiment generated different baseline rates of behavior by altering frequency of electrical stimulation in an assay of intracranial self-stimulation. Amphetamine and 10 other monoamine releasers were analyzed for their ability to produce rate-dependent effects in this assay. There were three main findings. First, all compounds produced rate-dependent effects at some dose. Second, one parameter of rate-dependency plots (peak Y-intercept of the regression line) correlated with in vitro neurochemical data on selectivity of these compounds to release dopamine versus serotonin (p-value = 0.0223, R2 =0.4997). Lastly, a correlation between peak Y-intercept and breakpoints under a progressive-ratio procedure in nonhuman primates was also significant (p-value = 0.0314, R2 = 0.6374). Overall, these results extended the rate dependent effects of monoamine releasers to behavior maintained under ICSS and suggest that, at least for monoamine releasers, the Y-intercept parameter of rate dependency plots might be a useful metric of drug reward and predictor of drug self-administration metrics of drug reinforcement.
doi:10.1097/FBP.0b013e328363d1a4
PMCID: PMC4028167  PMID: 23851484
Rate-dependency; ICSS; amphetamine; monoamine releasers
22.  Exposure to histone deacetylase inhibitors during Pavlovian conditioning enhances subsequent cue-induced reinstatement of operant behavior 
Behavioural pharmacology  2013;24(3):164-171.
Histone deacetylase inhibitors (HDACIs) strengthen memory following fear conditioning and cocaine-induced conditioned place preference. Here, we examined the effects of two non-specific HDACIs, valproic acid (VPA) and sodium butyrate (NaB), on appetitive learning measured via conditioned stimulus (CS)-induced reinstatement of operant responding. Rats were trained to lever press for food reinforcement and then injected with VPA (50–200 mg/kg, i.p.), NaB (250–1000 mg/kg, i.p.), or saline vehicle (1.0 ml/kg), 2h before receiving pairings of noncontingent presentation of food pellets preceded by a tone+light cue CS. Rats next underwent extinction of operant responding followed by response-contingent re-exposure to the CS. Rats receiving VPA (100 mg/kg) or NaB (1000 mg/kg) prior to conditioning displayed significantly higher cue-induced reinstatement than did saline controls. Rats that receiving either vehicle or VPA (100 mg/kg) prior to a conditioning session with a randomized relation between presentation of food pellets and the CS failed to show subsequent cue-induced reinstatement with no difference between the two groups. These findings indicate that, under certain contexts, HDACIs strengthen memory formation by specifically increasing the associative strength of the CS, not through an increasing motivation to seek reinforcement.
doi:10.1097/FBP.0b013e32836104ea
PMCID: PMC4002259  PMID: 23604166
histone deacetylase inhibitors; learning; reinforcement; reinstatement
23.  Ovarian hormones and the heterogeneous receptor mechanisms mediating the discriminative stimulus effects of ethanol in female rats 
Behavioural pharmacology  2013;24(2):10.1097/FBP.0b013e32835efc5f.
Past studies have suggested that progesterone-derived ovarian hormones contribute to the discriminative stimulus effects of ethanol, particularly via progesterone metabolites that have activity at γ-aminobutyric acid type A (GABAA) receptors. It is unknown whether loss of ovarian hormones in women, for example, after menopause, may be associated with altered receptor mediation of the effects of ethanol. The current study measured the substitution of allopregnanolone, pregnanolone, pentobarbital, midazolam, dizocilpine, TFMPP, and RU 24969 in female sham and ovariectomized (OVX) rats trained to discriminate 1.0 g/kg ethanol from water. The groups did not differ in the substitution of GABAA-positive modulators (barbiturates, benzodiazepines, neuroactive steroids) or the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine. Similarly, blood-ethanol concentration (BEC) did not differ between the groups, and plasma adrenocorticotropic hormone (ACTH), progesterone, pregnenolone, and deoxycorticosterone (DOC) were unchanged 30 min after administration of 1.0 g/kg ethanol or water. However, substitution of neuroactive steroids and RU 24969, a 5-HT1A/1B receptor agonist, was lower than observed in previous studies of male rats, and TFMPP substitution was decreased in OVX rats. Ovarian hormones appear to contribute to 5-HT receptor mediation of the discriminative stimulus effects of ethanol in rats.
doi:10.1097/FBP.0b013e32835efc5f
PMCID: PMC3864632  PMID: 23399883
discriminative stimulus effects; ethanol; ethanol discrimination; females; neuroactive steroids; ovariectomy; rat
24.  Withdrawal from chronic, intermittent access to a highly palatable food induces depressive-like behavior in compulsive eating rats 
Behavioural pharmacology  2012;23(0):593-602.
The increased availability of highly palatable foods is a major contributing factor toward the development of compulsive eating in obesity and eating disorders. It has been proposed that compulsive eating may develop as a form of self-medication to alleviate the negative emotional state associated with withdrawal from highly palatable foods. This study was aimed at determining whether withdrawal from chronic, intermittent access to a highly palatable food was responsible for the emergence of depressive-like behavior. For this purpose, a group of male Wistar rats was provided a regular chow diet 7 days a week (Chow/Chow), whereas a second group of rats was provided chow for 5 days a week, followed by a 2-day access to a highly palatable sucrose diet (Chow/Palatable). Following 7 weeks of diet alternation, depressive-like behavior was assessed during withdrawal from the highly palatable diet and following renewed access to it, using the forced swim test, the sucrose consumption test, and the intracranial self-stimulation threshold procedure. It was found that Chow/Palatable rats withdrawn from the highly palatable diet showed increased immobility time in the forced swim test and decreased sucrose intake in the sucrose consumption test compared with the control Chow/Chow rats. Interestingly, the increased immobility in the forced swim test was abolished by renewing access to the highly palatable diet. No changes were observed in the intracranial self-stimulation threshold procedure. These results validate the hypothesis that withdrawal from highly palatable food is responsible for the emergence of depressive-like behavior, and they also show that compulsive eating relieves the withdrawal-induced negative emotional state.
doi:10.1097/FBP.0b013e328357697f
PMCID: PMC3934429  PMID: 22854309
anhedonia; brain stimulation reward; depression; eating disorders; food addiction; forced swim test; rat; sucrose
25.  Prepulse inhibition in HIV-1 gp120 transgenic mice after withdrawal from chronic methamphetamine 
Behavioural pharmacology  2014;25(1):12-22.
HIV infection is frequently comorbid with methamphetamine (METH) dependence. Both factors are associated with impairment in inhibitory function that continues even after abstinence from the drug. Deficits in prepulse inhibition (PPI), a measure of sensorimotor gating, are induced by acute stimulant administration, but the combined effect of HIV and chronic METH exposure on PPI is not well characterized. We quantified baseline acoustic startle and PPI in mice expressing the HIV-1 gp120 envelope protein (gp120tg) and in wild-type (WT) littermates; thereafter, we administered a chronic regimen of METH or vehicle and tested startle and PPI after 7 days of drug withdrawal. We hypothesized that METH-treated gp120tg mice would exhibit PPI deficits compared with vehicle-treated WT or gp120tg animals. Before METH administration, drug-naive female gp120tg mice exhibited decreased PPI compared with female WT mice, whereas male gp120tg mice exhibited increased startle compared with other groups. After drug withdrawal, no consistent genotype effect was observed, but METH-treated mice exhibited increased PPI compared with vehicle, in contrast to previous reports of acute METH-induced PPI deficits. In summary, PPI impairment in HIV could depend on factors such as sex, whereas changes in PPI following METH withdrawal may depend on the quantity and duration of drug exposure.
doi:10.1097/FBP.0000000000000012
PMCID: PMC3926694  PMID: 24281153
gp120; HIV; methamphetamine; mouse; prepulse inhibition; sensorimotor gating

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