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1.  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
2.  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
3.  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
4.  Interactions between delta9-tetrahydrocannabinol and heroin: self-administration in rhesus monkeys 
Behavioural pharmacology  2012;23(8):754-761.
The cannabinoid receptor agonist delta9-tetrahydrocannabinol (THC) enhances the antinociceptive effects of mu opioid receptor agonists, raising the possibility of using a combination of THC and opioids for treating pain. This study examined the effects of noncontingent and contingent administration of THC on i.v. heroin self-administration in rhesus monkeys. Self-administration of different unit doses of heroin (0.0001–0.1 mg/kg/infusion) generated a typical inverted U-shaped dose-response curve. In one experiment (n=4), noncontingent THC (0.1–1.0 mg/kg) dose-dependently shifted the heroin dose-response curve downward in three monkeys and slightly leftward in one monkey. In a second experiment (n=4), monkeys could self-administer THC alone (0.0032–0.032 mg/kg/infusion), heroin alone, or a mixture of THC and heroin. THC alone did not maintain responding above that obtained with saline; however, increasing the THC dose with heroin dose-dependently decreased the number of infusions received and the rate of responding, as compared to data that were obtained with heroin alone. These results indicate that THC does not significantly enhance the positive reinforcing effects of heroin, further supporting the view that combining cannabinoid and opioid receptor agonists (e.g., for treating pain) does not increase, and might decrease, the abuse liability of the individual drugs.
doi:10.1097/FBP.0b013e32835a3907
PMCID: PMC3916935  PMID: 23044830
Heroin; THC; self-administration; rhesus monkey
5.  Impaired conditioned fear response and startle reactivity in epinephrine deficient mice 
Behavioural pharmacology  2013;24(1):1-9.
Norepinephrine and epinephrine signaling is thought to facilitate cognitive processes related to emotional events and heightened arousal, however, the specific role of epinephrine in these processes is less known. To investigate the selective impact of epinephrine on arousal and fear-related memory retrieval, mice unable to synthesize epinephrine (phenylethanolamine N-methyltransferase knockout, PNMT-KO) were tested in context and cued fear conditioning. To assess the role of epinephrine in other cognitive and arousal-based behaviors these mice were also tested for acoustic startle, prepulse inhibition, novel object recognition and open field activity. Our results show that compared to wild-type (WT) mice, PNMT-KO mice displayed reduced context fear but normal cued fear. Mice exhibited normal memory performance in the short-term version of the novel object recognition task suggesting PNMT mice exhibit more selective memory effects on highly emotional and/or long term memories. Similarly, open field activity was unaffected by epinephrine deficiency, suggesting differences in freezing are not related to changes in overall anxiety or exploratory drive. Startle reactivity to acoustic pulses was reduced in PNMT-KO mice while prepulse inhibition was increased. These findings provide further evidence for a selective role of epinephrine in contextual fear learning, and support its potential role in acoustic startle.
doi:10.1097/FBP.0b013e32835cf408
PMCID: PMC3558035  PMID: 23268986
PNMT; epinephrine; conditioned fear; memory; acoustic startle; prepulse inhibition; arousal
6.  A quantitative analysis of the reward-enhancing effects of nicotine using reinforcer demand 
Behavioural pharmacology  2012;23(8):781-789.
Reward enhancement by nicotine has been suggested as an important phenomenon contributing toward tobacco abuse and dependence. Reinforcement value is a multifaceted construct not fully represented by any single measure of response strength. The present study evaluated the changes in the reinforcement value of a visual stimulus in 16 male Sprague–Dawley rats using the reinforcer demand technique proposed by Hursh and Silberberg. The different parameters of the model have been shown to represent differing facets of reinforcement value, including intensity, perseverance, and sensitivity to changes in response cost. Rats lever-pressed for 1-min presentations of a compound visual stimulus over blocks of 10 sessions across a range of response requirements (fixed ratio 1, 2, 4, 8, 14, 22, 32). Nicotine (0.4 mg/kg, base) or saline was administered 5 min before each session. Estimates from the demand model were calculated between nicotine and saline administration conditions within subjects and changes in reinforcement value were assessed as differences in Q0, Pmax, Omax, and essential value. Nicotine administration increased operant responding across the entire range of reinforcement schedules tested, and uniformly affected model parameter estimates in a manner suggesting increased reinforcement value of the visual stimulus.
doi:10.1097/FBP.0b013e32835a38d9
PMCID: PMC3896977  PMID: 23080311
nicotine; rat; reinforcer demand; reward
7.  Subacute fluoxetine enhances conditioned responding and conditioning-specific reflex modification of the rabbit nictitating membrane response: implications for drug treatment with selective serotonin reuptake inhibitors 
Behavioural pharmacology  2013;24(1):55-64.
Extensive research on the rabbit nictitating membrane response (NMR) has shown that the NMR reflex can become exaggerated following classical fear conditioning. This learning-related change is referred to as conditioning-specific reflex modification (CRM) and is observed in the absence of the conditioned stimulus. The aim of the current study was to examine the sensitivity of the CRM paradigm to serotonergic manipulation with fluoxetine, a commonly prescribed selective serotonin reuptake inhibitor for anxiety disorders. To assess the effect of fluoxetine on exaggerated reflexive responding indicative of CRM and on conditioned cued fear, rabbits underwent delay NMR conditioning (pairings of tone and periorbital shock) and were tested for CRM, followed by 5 days of daily fluoxetine (0.03, 0.3, or 3.0 mg/kg) or saline injections. CRM was reassessed 1 day and 1 week later, followed by a retention test of conditioned responses (CRs) to the tone. Fluoxetine (3.0 mg/kg) enhanced CRM and retention of conditioned responses, a week after treatment ceased, and this is in agreement with the reports on increased anxiety-like behaviors in other animal models and humans. The CRM paradigm, therefore, may provide important insight into the mechanisms underlying the paradoxical selective serotonin reuptake inhibitor effects.
doi:10.1097/FBP.0b013e32835d528e
PMCID: PMC3896078  PMID: 23263485
classical conditioning; eyeblink; fear conditioning; fluoxetine; nictitating membrane response; post-traumatic stress disorder; rabbit; selective serotonin reuptake inhibitor
8.  GABAERGIC MODULATION OF THE DISCRIMINATIVE STIMULUS EFFECTS OF METHAMPHETAMINE 
Behavioural pharmacology  2005;16(4):261-266.
To assess whether GABA modulation of dopamine is important in mediation of the discriminative stimulus effects of methamphetamine, the GABA compounds chlordiazepoxide (benzodiazepine site agonist), pentobarbital (barbiturate site agonist), bicuculline and pentylenetetrazol (GABAA receptor antagonists) were tested in Sprague-Dawley rats trained to discriminate methamphetamine (1 mg/kg, i.p.) from saline. Each of the compounds produced modest amounts of methamphetamine-appropriate responding (20–35%) when tested alone. When tested in combination with methamphetamine, the antagonists (bicuculline and pentylenetetrazol) failed to shift the methamphetamine dose-effect curve. In contrast, chlordiazepoxide (25 mg/kg, i.p.) reduced methamphetamine-appropriate responding at each dose of methamphetamine tested, and pentobarbital (10 mg/kg, i.p.) dose-dependently decreased the discriminative stimulus effects of 1 mg/kg methamphetamine. In conclusion, GABAA antagonists and positive modulators likely do not produce methamphetamine-like stimulus effects. However, activation of GABAA receptors can interfere with the discriminative stimulus effects of methamphetamine.
PMCID: PMC3878065  PMID: 15961966
Methamphetamine; GABAA receptor; drug discrimination; rat
9.  Self-Administration of Agonists Selective for Dopamine D2, D3, and D4 Receptors by Rhesus Monkeys 
Behavioural pharmacology  2012;23(4):10.1097/FBP.0b013e3283564dbb.
Dopamine receptor mechanisms are thought to play a role in the reinforcing effects of cocaine and other abused drugs. The lack of receptor-selective agonists has made it difficult to determine the role of the individual dopamine receptors in mediating these reinforcing effects. In this study, rhesus monkeys with a history of intravenous cocaine self-administration were tested for the reinforcing effects of several D3-preferring agonists, a D2-preferring agonist, and a D4 agonist. The D2-preferring agonist did not maintain responding in any monkeys, and the D4 agonist was self-administered at low rates, just above those maintained by saline in one monkey. The D3-preferring agonists were self-administered by approximately half of the animals, although at lower rates than cocaine. These results indicate the apparent limited reinforcing effectiveness of D2-like agonists requires activity at D3 receptors. Previous data from this laboratory and others also suggest that these drugs may not serve as reinforcers directly; the behavior may be maintained by response-contingent delivery of stimuli previously paired with cocaine. The ability of drug-related stimuli to maintain responding apparently differs among monkeys and other organisms, and may be related to individual differences in drug-taking behavior in humans.
doi:10.1097/FBP.0b013e3283564dbb
PMCID: PMC3871179  PMID: 22785383
D2-like agonists; reinforcing effects; rhesus monkeys; self-administration
10.  Effects of Monoamine Oxidase Inhibitors on Cocaine Discrimination in Rats 
Behavioural pharmacology  2006;17(2):10.1097/01.fbp.0000197459.08892.b5.
This study tested the time course of the discriminative stimulus effects of inhibitors of monoamine oxidase (MAO) alone or in combination with cocaine. Male Sprague-Dawley rats were trained to discriminate cocaine (10 mg/kg, i.p.) from saline using a two-lever choice methodology. The non-selective MAO inhibitors tranylcypromine (0.01 to 5 mg/kg) and phenelzine (1 to 25 mg/kg), the MAO-A selective compound clorgyline (1 to 25 mg/kg), and the MAO-B selective compounds pargyline (0.005 to 50 mg/kg) and selegiline (1 to 25 mg/kg) were tested for substitution 15 min or 24 hr following administration, and in combination with 10 mg/kg of cocaine 24 and 48 hr after administration. At 15 min, selegiline fully substituted for the discriminative stimulus effects of cocaine, whereas all other compounds partially substituted. At 24 hr, substitution of cocaine was diminished for all compounds except phenelzine, which produced a greater amount of substitution at 24 hr than at 15 min. When cocaine was administered 24 hr following clorgyline, selegiline, pargyline, and phenelzine, cocaine-appropriate responding was attenuated at intermediate doses of these drugs, whereas the highest doses did not alter cocaine-lever responding. All compounds except selegiline substantially decreased response rate and produced various adverse effects. At 48 hr, the effects of all compounds except phenelzine were markedly reduced. Selectivity for MAO-A or B did not predict the ability to substitute for or attenuate the subjective effects of cocaine. These findings suggest that MAO inhibitors can modulate the discriminative stimulus effects of cocaine for at least 24 hr, and may be useful for treatment of cocaine abuse.
doi:10.1097/01.fbp.0000197459.08892.b5
PMCID: PMC3867205  PMID: 16495723
Cocaine; drug discrimination; dopamine receptors; monoamine oxidase inhibitors; rat
11.  The Effects of Chronic Cocaine Exposure on Impulsivity in Rats 
Behavioural pharmacology  2009;20(0):10.1097/FBP.0b013e328330ad89.
Chronic exposure to cocaine increases impulsive behavior, leading to a reduced preference for a larger, delayed reinforcer over a smaller, immediate reinforcer. The present study examined the development of impulsivity over multiple days of cocaine exposure and cessation of cocaine. Male Sprague-Dawley rats were trained on a discrete-trials delay-discounting task, during which they chose between a small reinforcer of 1 food pellet immediately and a large reinforcer of 3 food pellets after an adjusted delay (0, 10, 20, 40 60 s). When stable preferences were established, rats received daily injections of deionized water or cocaine (3, 7.5, 15 mg/kg) 5 min prior to the delay-discounting task for 9 days. All groups showed an increased preference for the smaller reinforcer as delay to the larger reinforcer increased. Repeated exposure to 7.5 or 15 mg/kg cocaine further decreased preference for the larger reinforcer over the 9 days. When cocaine administration was discontinued, preference for the larger reinforcer returned to baseline levels in the 7.5 mg/kg group, but remained depressed in the 15 mg/kg group. These findings indicate that continuing exposure to cocaine dose-dependently decreases choice for the large reinforcer over time, that the bias remains when cocaine is no longer administered, and that recovery after high doses of cocaine occurs slowly.
doi:10.1097/FBP.0b013e328330ad89
PMCID: PMC3867254  PMID: 19675455
12.  Abuse-related effects of mu opioid analgesics in an assay of intracranial self-stimulation in rats: modulation by chronic morphine exposure 
Behavioural pharmacology  2013;24(0):10.1097/FBP.0b013e328364c0bd.
Intracranial self-stimulation (ICSS) is an operant procedure in which responding is maintained by electrical brain stimulation. Stimulation frequency can be rapidly varied to maintain a wide range of baseline response rates, and drugs effects can be simultaneously evaluated on both low ICSS rates maintained by low stimulation frequencies and high ICSS rates maintained by high stimulation frequencies. ICSS “facilitation” denotes drug-induced increases in low ICSS rates and is often interpreted as an abuse-related effect, whereas ICSS “depression” denotes decreases in high ICSS rates and may indicate abuse-limiting effects. This study examined the roles of drug efficacy and of prior mu agonist exposure as determinants of mu agonist effects on ICSS in rats with electrodes implanted in the medial forebrain bundle. The high-, intermediate- and low-efficacy mu agonists methadone, fentanyl and nalbuphine were tested during escalating regimens of morphine exposure (Vehicle, 3.2, 18 mg/kg/day). During vehicle treatment, methadone and fentanyl primarily depressed ICSS, whereas nalbuphine produced weak facilitation that was not dose-dependent. Chronic morphine produced tolerance to ICSS depression and increased expression of ICSS facilitation. These results suggest that mu agonist exposure increases expression of abuse-related ICSS facilitation by mu agonists with a broad range of efficacies at mu receptors.
doi:10.1097/FBP.0b013e328364c0bd
PMCID: PMC3864000  PMID: 23881045
Drug abuse; Methadone; Fentanyl; Nalbuphine; Chronic morphine; Tolerance; Intracranial self-stimulation; Rat
13.  Role of mu opioid receptor reserve and mu agonist efficacy as determinants of mu agonist effects on intracranial self-stimulation in rats 
Behavioural pharmacology  2012;23(7):10.1097/FBP.0b013e328358593c.
The net effect of mu opioid receptor agonists on intracranial self-stimulation (ICSS) in rats reflects an integration of rate-increasing and rate-decreasing effects. Prior opioid exposure is associated with tolerance to rate-decreasing effects and augmented expression of abuse-related rate-increasing effects. This finding was replicated here with morphine. Subsequent studies then tested the hypothesis that opioid agonist-induced rate-decreasing effects require activation of a larger relative fraction of mu receptors, and hence are more vulnerable to tolerance-associated reductions in receptor density, than rate-increasing effects. Two sets of experiments were conducted to test this hypothesis. First, morphine effects on ICSS were examined after pretreatment with the irreversible mu antagonist β-funaltrexamine (β-FNA) to reduce density of available mu receptors. Second, effects were examined for a range of mu opioids that varied in relative efficacy at mu receptors. The hypothesis predicted that (a) morphine after β-FNA treatment or (b) low-efficacy mu agonists would mimic effects of morphine tolerance to produce reduced expression of rate-decreasing effects and enhanced expression of rate-increasing effects. Neither of these predictions was supported. These results suggest that mu agonist-induced facilitation and depression of ICSS may be mediated by distinct populations of mu receptors that respond differently to regimens of opioid exposure.
doi:10.1097/FBP.0b013e328358593c
PMCID: PMC3864003  PMID: 22914074
Morphine; opioid; efficacy; intracranial self-stimulation; drug abuse; rats
14.  Δ9-Tetrahydrocannabinol acts as a partial agonist/antagonist in mice 
Behavioural pharmacology  2012;23(8):802-805.
Δ9-Tetrahydrocannabinol (THC) has been characterized as a partial agonist at cannabinoid CB1 receptors in vitro; however, it often produces the same maximum effects in vivo as other cannabinoid agonists. This study was carried out to determine whether THC would antagonize the hypothermic effects of another cannabinoid agonist, AM2389, in mice. Male mice were injected with 1–100 mg/kg THC, 0.01–0.1 mg/kg AM2389, or a combination of 30 mg/kg THC and 0.1–1.0 mg/kg AM2389, and rectal temperature was recorded for up to 12 h after injection. THC reduced the temperature by 5.6°C at a dose of 30 mg/kg; further increases in the dose did not produce larger effects, indicating a plateau in the THC dose–effect function. AM2389 reduced temperature by 9.0°C at a dose of 0.1 mg/kg. One hour pretreatment with 30 mg/kg THC attenuated the hypothermic effects of 0.1 mg/kg AM2389; a 10-fold higher dose, 1.0 mg/kg AM2389, was required to further decrease temperature, reflecting a five-fold rightward shift of the lower portion of the AM2389 dose–effect function following THC pretreatment. These results indicate that, in an assay of mouse hypothermia, THC exerts both agonist and antagonist effects following acute administration, and mark the first demonstration of partial agonist/antagonist effects of THC in vivo.
doi:10.1097/FBP.0b013e32835a7c4d
PMCID: PMC3697741  PMID: 23075707
AM2389; efficacy; mouse; partial agonist; Δ9-tetrahydrocannabinol
15.  Reinforcing Effects of d-Amphetamine: Influence of Novel Ratios on a Progressive-Ratio Schedule 
Behavioural pharmacology  2010;21(8):745-753.
Progressive-ratio schedules are useful for studying reinforcing effects of drugs. Previous human laboratory studies showed that d-amphetamine significantly increased break points relative to placebo levels. However, the magnitude of the increase was modest, which may be attributable to rather high levels of placebo responding. We utilized novel response requirements under the modified progressive-ratio schedule and hypothesized that the altered range of response requirements would decrease responding for placebo and increase responding for d-amphetamine. Eight participants completed the study. The participants first sampled oral doses of d-amphetamine (0, 8, 16 and 24 mg). In subsequent sessions, participants were offered the opportunity to work for the sampled dose on a modified progressive-ratio procedure with response requirements ranging from 400 to 1800 mouse clicks. A battery of participant-rated drug-effect questionnaires, a performance measure and cardiovascular measures were included in orderto characterize more fully the effects of d-amphetamine. Placebo maintained low levels of responding. The intermediate dose of d-amphetamine increased responding significantly above placebo levels. d-Amphetamine produced prototypical subject-rated effects that were an orderly function of dose. The present data suggest that the modified response requirements resulted in lower levels of placebo taking and a larger separation between number of placebo and d-amphetamine capsules earned.
doi:10.1097/FBP.0b013e32833fa7b3
PMCID: PMC3815487  PMID: 20944503
Drug Reinforcement; Drug Self-Administration; Progressive Ratio; Subjective Effects; Human; Amphetamine
16.  Ontogeny of Methamphetamine- and Cocaine-Induced One-Trial Behavioral Sensitization in Preweanling and Adolescent Rats 
Behavioural pharmacology  2012;23(4):367-379.
The ontogenetic profile of psychostimulant-induced one-trial behavioral sensitization has not been determined. The purpose of this study was to systematically assess the ontogeny of methamphetamine- and cocaine-induced behavioral sensitization across the preweanling and adolescent periods. To this end, rats were injected with methamphetamine, cocaine, or saline in either an activity chamber or home cage during the preweanling (PD 12, PD 16, or PD 20), preadolescent (PD 24), or adolescent (PD 34) periods. One day later, rats were challenged with the same psychostimulant and locomotion was measured in an activity chamber. Results showed that methamphetamine produced one-trial locomotor sensitization on PD 13 and PD 17; whereas, cocaine-induced behavioral sensitization was only evident on PD 21. The sensitized responding of preweanling rats was not influenced by environmental context. Interestingly, preadolescent and adolescent rats did not exhibit locomotor sensitization. The latter result is generally consistent with past studies showing that rats from the middle and late adolescent periods do not exhibit cocaine-induced one-trial behavioral sensitization. The present results show that methamphetamine, as well as cocaine, can produce one-trial context-independent behavioral sensitization during early ontogeny, but sensitized responding is only apparent within a narrow developmental window.
doi:10.1097/FBP.0b013e32835651c9
PMCID: PMC3789585  PMID: 22732208
behavioral sensitization; ontogeny; methamphetamine; cocaine
17.  Reinforcement magnitude modulation of rate-dependent effects of fluvoxamine and desipramine in the rat 
Behavioural pharmacology  2008;19(8):829-835.
Reinforcement magnitude modulates the effects of the antidepressants fluvoxamine and desipramine in the pigeon. Increasing reinforcement magnitude diminishes the rate-dependent effects of these drugs. Whether this is also the case in other species is unknown. Rats were trained to respond under a multiple fixed-interval (FI 300-s) schedule of reinforcement. In one FI component, rats earned 2 food pellets, and in the other component they earned 10 food pellets when they completed the FI requirement. The effects of fluvoxamine (3, 5.6, 10, and 17.8 mg/kg) or desipramine (1, 3, 5.6, 10, 30 mg/kg) given 30-min, presession (i.p.) on overall response rate were examined. Local rates of responding (during each tenth of the component) increased throughout the FI as is typical, and were higher during the component reinforced with 10-pellets. Fluvoxamine and desipramine decreased overall response rates similarly in both components. Both drugs exerted limited rate dependent effects, demonstrated by a negative slope for the regression of LOG[drug rate/control rate] on LOG[control rate] using data from each tenth of the FI. However, the slope for the 2-pellet condition was significantly steeper than the slope for the 10-pellet condition following 3 and 10 mg/kg fluvoxamine and following 30 mg/kg desipramine. This result is consistent with those obtained in pigeons and demonstrates that reinforcement magnitude can modulate rate-dependent effects of fluvoxamine and perhaps desipramine in rats.
doi:10.1097/FBP.0b013e32831d9667
PMCID: PMC3769992  PMID: 19020418
behavioral momentum; rate-dependent; antidpressant
18.  Peer Influences on Drug Self-Administration: An Econometric Analysis in Socially Housed Rats 
Behavioural pharmacology  2013;24(2):114-123.
Social-learning theories of substance use propose that members of peer groups influence the drug use of other members by selectively modeling, reinforcing, and punishing either abstinence-related or drug-related behaviors. The objective of the present study was to examine social influences on cocaine self-administration in isolated and socially housed rats, with the caveat that the socially housed rats were tested simultaneously with their partner in the same chamber. To this end, male rats were obtained at weaning and housed in isolated or pair-housed conditions for 6 weeks. Rats were then implanted with intravenous catheters and cocaine self-administration was examined in custom-built operant conditioning chambers that allowed two rats to be tested simultaneously. For some socially housed subjects, both rats had simultaneous access to cocaine; for others, only one rat of the pair had access to cocaine. An econometric analysis was applied to the data, and the reinforcing strength of cocaine was measured by examining consumption (i.e., quantity demanded) and elasticity of demand as a function of price, which was manipulated by varying the dose and ratio requirements on a fixed ratio schedule of reinforcement. Cocaine consumption decreased as a function of price in all groups. Elasticity of demand did not vary across groups, but consumption was significantly lower in socially housed rats paired with a rat without access to cocaine. These data suggest that the presence of an abstaining peer decreases the reinforcing strength of cocaine, thus supporting the development of social interventions in drug abuse prevention and treatment programs.
doi:10.1097/FBP.0b013e32835f1719
PMCID: PMC3749306  PMID: 23412112
cocaine; consumption; demand; elasticity; rat; reinforcing strength; self-administration; social; social learning; unit price
19.  An inhibitor of casein kinase 1 ε/δ partially normalizes the manic-like behaviors of the ClockΔ19 mouse 
Behavioural pharmacology  2012;23(4):392-396.
Bipolar disorder is a terrible and debilitating disease with limited treatment options. Circadian rhythm disruptions are prominent in bipolar subjects, and studies have shown that rhythm stabilization through psychosocial interventions can improve their symptoms. Furthermore, mice with a mutation in one of the central circadian proteins, CLOCK, have severely disrupted rhythms along with a behavioral profile that closely resembles human mania. A compound has been developed (CK01, similar to PF-670462) that inhibits the activity of casein kinase 1 (CK1), a critical protein involved in the timing of the molecular clock. Previous studies have shown that PF-670462 and other similar compounds are capable of entraining and stabilizing rhythms in arrhythmic animals. Here we show that chronic administration of CK01 leads to a reversal of the anxiety-related behavior, and partial reversal of the depression-related phenotypes of the Clock mutant mouse. This drug had no significant effects on the behavior of wild-type mice at the doses tested. These results suggest that CK1ε/δ inhibitors could be viable drugs for the treatment of bipolar disorder.
doi:10.1097/FBP.0b013e32835651fd
PMCID: PMC3673712  PMID: 22743604
anxiety; bipolar disorder; circadian rhythms; depression; mouse
20.  Novel Approach to Data Analysis in Cocaine Conditioned Place Preference 
Behavioural pharmacology  2009;20(8):720-730.
Only a sub-group of human drug users progress from initial drug-taking to drug addiction. An important aspect of this progression is the influence of the learned association between the effects of the drug and the environment in which it is experienced on continued drug-taking and-seeking. These associations can be modeled using the conditioned place preference (CPP) paradigm, although no current method of CPP analysis allows for identification of within-group variability among subjects. In the present study, we adapted a “criterion” method of analysis to separate “CPP expressing” from “non-CPP expressing” rats, in order to study more directly within-group variability in the CPP paradigm. Male Sprague-Dawley rats were conditioned with cocaine (5, 10, 20 mg/kg) or saline in an unbiased three-chamber CPP apparatus in either a single- or four-trial CPP procedure. A classification and regression tree analysis of time spent in the cocaine-paired chamber established a time of 324 s spent in the cocaine-paired chamber as the criterion for cocaine CPP expression. This criterion effectively discriminated control from cocaine-conditioned rats and was reliable for rats trained in both a single- and four-trial CPP procedure. The criterion method showed an enhanced ability to detect effective doses of cocaine in the single trial procedure and a blockade of CPP expression by MK 212 (0.125 mg/kg) treatment in a sub-group of rats. These data support the utility of the criterion analysis as an adjunct to traditional methods that compare group averages in CPP.
doi:10.1097/FBP.0b013e328333b266
PMCID: PMC3725613  PMID: 19901823
classical conditioning; statistical analysis; classification and regression tree analysis; serotonin 2C receptor; animal model; rat
21.  Evaluation of the endogenous cannabinoid system in mediating the behavioral effects of dipyrone (metamizol) in mice 
Behavioural pharmacology  2012;23(7):722-726.
Dipyrone is a common nonopioid analgesic and antipyretic, which, in many countries, is available over the counter and is more widely used than paracetamol or aspirin. However, the exact mechanisms by which dipyrone acts remain inconclusive. Two novel arachidonoyl-conjugated metabolites are formed in mice following the administration of dipyrone that are dependent on the activity of fatty acid amide hydrolase (FAAH), which also represents the major catabolic enzyme of the endogenous cannabinoid ligand anandamide. These arachidonoyl metabolites not only inhibit cyclooxygenase (COX-1/COX-2) but also bind to cannabinoid receptors at low micromolar concentrations. The relative contributions of cannabinoid receptors and FAAH in the overall behavioral response to dipyrone remain untested. Accordingly, the two primary objectives of the present study were to determine whether the behavioral effects of dipyrone would (a) be blocked by cannabinoid receptor antagonists and (b) occur in FAAH−/− mice. Here, we report that thermal antinociceptive, hypothermic, and locomotor suppressive actions of dipyrone are mediated by a noncannabinoid receptor mechanism of action and occurred after acute or repeated administration irrespective of FAAH. These findings indicate that FAAH-dependent arachidonoyl metabolites and cannabinoid receptors are not requisites by which dipyrone exerts these pharmacological effects under noninflammatory conditions.
doi:10.1097/FBP.0b013e3283584794
PMCID: PMC3696505  PMID: 22954646
analgesia; antinociception; CB1 and CB2 cannabinoid receptors; dipyrone; fatty acid amide hydrolase; mouse; thermal regulation
22.  The behavioral pharmacology of anorexigenic drugs in nonhuman primates: 30 years of progress 
Behavioural pharmacology  2012;23(0):461-477.
Comparatively few studies over the past 30 years have used pharmacological manipulations as a means of understanding processes underlying feeding behavior of nonhuman primates. In the 1970s and early 1980s, four laboratories provided data on the anorexigenic effects of a range of drugs on rhesus monkeys and baboons, and a fifth laboratory studied the effects of neuropeptides on feeding behavior of baboons. There were differences in the way anorexigenic drugs altered eating topography, and those that increased dopamine levels had greater abuse liability than those that increased serotonin levels. Studies in the 1980s and 1990s used foraging models and principles of behavioral economics to understand food–drug interactions. Experimenter-given anorexigenic drugs did not function as economic substitutes for food. Recent studies have examined the effects of a range of drugs on consumption of highly palatable food and model diet-induced obesity. Although some drugs, including stimulants, N-methyl-D-aspartate antagonists, and a cannabinoid antagonist increased the latency to standard food consumption, there was little evidence for a selective effect of any drug on highly palatable food consumption. Results obtained in nonhuman primates did not always confirm those observed in rodents. Future studies looking at sex differences and social factors may provide insight into factors related to human obesity.
doi:10.1097/FBP.0b013e3283566aa0
PMCID: PMC3680107  PMID: 22772334
amphetamine; anorectic; anorexigenic; baboon; binge eating; dexfenfluramine; diazepam; eating; nonhuman primate; rhesus monkey; topography
23.  Reinforcement Magnitude Modulates the Rate-Dependent Effects of Fluvoxamine and Desipramine on Fixed-Interval Responding in the Pigeon 
Behavioural pharmacology  2008;19(1):51-60.
Some doses of fluvoxamine can decrease ethanol-maintained behavior more than food-maintained behavior. This might be explained by differences in reinforcement magnitude. In a previous study, fluvoxamine’s effects on Fixed-Ratio responding did not depend upon reinforcement magnitude. However, response rates differed with reinforcement magnitude. These differences in response rate might explain the failure to observe differences in the potency of fluvoxamine with changes in reinforcement magnitude.
Methods
We examined if the effects of fluvoxamine and desipramine depend on reinforcement magnitude and response rate by administering these drugs to pigeons responding under a multiple Fixed-Interval schedule in which responding in three components was maintained by differing durations of food presentation (2-, 4-, & 8-sec).
Results
Fluvoxamine and desipramine’s effects depended jointly on control rate, reinforcement magnitude, and dose. Low fluvoxamine doses had rate-dependent effects in all three components, --increasing lower rates more than higher rates; as dose increased these rate-dependent effects became greater for components maintained by 2- or 4-sec of food presentation, while declining in the component maintained by 8-sec. Low desipramine doses had rate-dependent effects only in the component maintained by 2-sec; whereas higher doses had rate-dependent effects in components maintained by 2- or 4-sec. Still higher doses had rate-dependent effects in all three components.
Conclusions
While the effects of fluvoxamine and desipramine may not depend upon reinforcement magnitude when studied under Fixed-Ratio schedules, reinforcement magnitude can modulate their effects when studied over a wider range of control response rates.
doi:10.1097/FBP.0b013e3282f3d093
PMCID: PMC3677835  PMID: 18195594
fluvoxamine; desipramine; fixed-interval; rate-dependency; reinforcement magnitude
24.  Environmental enrichment during development decreases intravenous self-administration of methylphenidate at low unit doses in rats 
Behavioural pharmacology  2012;23(7):650-657.
Despite the efficacy and widespread use of methylphenidate (MPH) as a treatment for Attention Deficit Hyperactivity Disorder (ADHD), clinical and preclinical findings indicate it has abuse potential. Environmental enrichment reduces susceptibility to cocaine and amphetamine self-administration, and decreases impulsive behavior, but its effects on MPH self-administration are unknown. The present experiments sought to determine the influence of environmental enrichment on MPH self-administration. Male rats were raised in an enriched condition (EC) or isolated condition (IC). They were trained to self-administer MPH (0.3 mg/kg/infusion) and then exposed to varying doses of MPH on either a fixed ratio (FR; Experiment 1) or progressive ratio (PR; Experiment 2) schedule of reinforcement. EC rats earned significantly fewer infusions of MPH at low doses (0.03 and 0.056 mg/kg/infusion) than IC rats under both schedules; however, no differences were observed at high unit doses (0.1–1.0 mg/kg/infusion). During saline substitution at the end of MPH self-administration, EC rats also responded less for saline than IC rats, indicative of more rapid extinction. As with other stimulant drugs with different mechanisms of action, environmental enrichment during development protects against self-administration of MPH at low unit doses, but not at high unit doses.
doi:10.1097/FBP.0b013e3283584765
PMCID: PMC3674782  PMID: 22914073
Environmental enrichment; methylphenidate; self-administration; rat; progressive ratio
25.  Effects of repeated oxycodone administration on its analgesic and subjective effects in normal, healthy volunteers 
Behavioural Pharmacology  2012;23(3):271-279.
Tolerance to the analgesic effects of opioids has been demonstrated in laboratory animals after repeated drug administration, yet this effect has been studied less frequently under controlled laboratory conditions in humans. This within-subject, double-blind, placebo-controlled study was designed to determine if tolerance developed to the analgesic, subjective, and physiological effects of the commonly prescribed opioid oxycodone when it was administered daily for 5 days. The effects of oxycodone’s (0, 5, and 20 mg/70 kg, p.o.) were compared, using a within-session cumulative dosing procedure, on the 1st and 5th days of the ‘daily’ dosing phase to assess for tolerance; active oxycodone was administered on the 2nd-4th days of the daily dosing phase. Changes in the effects of oxycodone were also compared when the medication was only administered on the 1st and 5th day of a 5-day ‘intermittent’ dosing phase; placebo medication was administered on the 2nd–4th days of the intermittent dosing phase. A 9-day ‘washout’ period occurred between phases when no medication was administered. Healthy volunteers (N=10) with no history of drug dependence or current drug use participated in this outpatient study. Analgesia was assessed using the Cold-Pressor Test (CPT), pain and drug effects were measured using a variety of questionnaires, and pupil diameter was monitored as an index of physiological effects. When administered daily, no differences were observed in oxycodone-induced analgesia between the 1st and 5th days, but tolerance did develop to some of the positive subjective effects of oxycodone. In contrast, oxycodone-induced analgesia and participant ratings of some positive subjective drug effects were greater on the 5th day compared to the 1st day of the intermittent dosing phase. No differences in the miotic effects of oxycodone between the 1st and 5th days of either dosing phase were detected. Though obtained under limited experimental conditions, these findings suggest that tolerance may not develop to the analgesic effects of therapeutic doses of oxycodone under short-term daily dosing conditions, even though some of its subjective effects may decrease. These data also suggest that intermittent administration may enhance the analgesic effects of oxycodone, while also increasing some of the drug’s positive subjective effects related to abuse liability.
doi:10.1097/FBP.0b013e3283536d6f
PMCID: PMC3341961  PMID: 22495183
Analgesia; Tolerance; Opioid; Oxycodone; Abuse Liability; Subjective Effects; human

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