The Journal of pharmacology and experimental therapeutics, 1992
Several novel cocaine analogs, previously shown to be very potent in in vitro binding studies, ha... more Several novel cocaine analogs, previously shown to be very potent in in vitro binding studies, have been examined for their stimulatory effects on locomotor activity and for their ability to displace [3H]WIN 35,428 binding in vivo in mice. These compounds, like WIN 35,428, lack an ester link between the phenyl group and the tropane ring and have para-substitutions on the phenyl ring. They were much more potent than (-)-cocaine in producing increases in locomotor activity. In addition, they were more potent than (-)-cocaine in inhibiting [3H]WIN 35,428 binding in vivo in mouse striatum. Thus, these compounds demonstrate similar high potency in behavioral tests and in receptor binding assays, both in vivo and in vitro. Results support the hypothesis of a relationship between binding at the dopamine transporter and the behavioral effects of cocaine-like drugs. Further, assuming that maximal occupancy occurs with total displacement of [3H]WIN 35,428 binding in vivo, the data suggest tha...
Journal of the Experimental Analysis of Behavior, 1991
Reinforcer magnitude and fixed‐ratio requirement were varied under two second‐order schedules. Un... more Reinforcer magnitude and fixed‐ratio requirement were varied under two second‐order schedules. Under one, the first sequence of a fixed number of responses completed after the lapse of a 10‐min fixed interval produced reinforcement. Under the second, a second‐order progressive‐ratio schedule, the fixed number of responses increased after each reinforcement. Either cocaine (0 to 300 μg/kg/inj) or food (0 to 5,700 mg/delivery) reinforcers were delivered. Under some conditions, a 2‐s illumination of stimulus lights occurred on completion of each ratio sequence. Under the second‐order schedule, as cocaine dose or amount of food increased, rates of responding increased; at the highest values, rates of responding decreased. Increases in the ratio requirement from 10 to 170 responses minimally decreased overall response rates. Under the second‐order progressive‐ratio schedule, increases in dose of cocaine or amount of food increased rates of responding; at the highest amounts of food, rate...
The Journal of pharmacology and experimental therapeutics, 1992
The effects of corticotropin-releasing factor (CRF), a benzodiazepine inverse agonist (methyl-6,7... more The effects of corticotropin-releasing factor (CRF), a benzodiazepine inverse agonist (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; DMCM) and electric foot-shock on rat conflict behavior were characterized and compared. Rats were trained to lever press under a multiple fixed-ratio schedule (FR 20) of food reinforcement in which responses during the first component were not punished, and the first response of each FR during the second component produced electric shock of an intensity sufficient to suppress responding by 10% to 15%. Intracerebroventricular injection of CRF (0.1-5.6 micrograms) caused a dose-dependent decrease in the rate of responding in both components of the schedule. However, CRF was more potent in decreasing rates of punished responding (proconflict effect). DMCM (10-100 micrograms; i.c.v.) also decreased rates of punished and nonpunished responding and was more potent during the punishment component. The suppression of punished and nonpunished respo...
Journal of the Experimental Analysis of Behavior, 1991
Three pigeons were studied under a multiple schedule in which pecks in each component were reinfo... more Three pigeons were studied under a multiple schedule in which pecks in each component were reinforced according to a variable‐interval 120‐s second‐order schedule with fixed‐interval 60‐s units. In the first component of the multiple schedule, the completion of a fixed interval produced either food or a 4‐s change in key color plus houselight illumination. In the second component an identical schedule was in effect, but the stimulus was a 0.3‐s change in key color. Both long and short brief stimuli were not paired with food presentations in Conditions 1 and 3 and were paired with food in Condition 2. There were no consistent differences in response patterns under paired and nonpaired brief‐stimulus conditions when the stimulus was a 4‐s change in key color accompanied by houselight illumination. However, pairing the 0.3‐s key‐color change with food presentations resulted in higher indices of curvature and lower response rates in the early segments of the fixed interval than when the...
Molecular medicine (Cambridge, Mass.), Jan 18, 2016
The cadherin 13 (CDH13) gene encodes a cell adhesion molecule likely to influence development and... more The cadherin 13 (CDH13) gene encodes a cell adhesion molecule likely to influence development and connections of brain circuits that modulate addiction, locomotion and cognition, including those that involve midbrain dopamine neurons. Human CDH13 mRNA expression differs by more than 80% in postmortem cerebral cortical samples from individuals with different CDH13 genotypes, supporting examination of mice with altered Cdh13 expression as models for common human variation at this locus. Constitutive cdh13 knockout mice display evidence for changed cocaine reward: shifted dose response relationship in tests of cocaine-conditioned place preference using doses that do not alter cocaine conditioned taste aversion. Reduced adult Cdh13 expression in conditional knockouts also alters cocaine reward in ways that correlate with individual differences in cortical Cdh13 mRNA levels. In control and comparison behavioral assessments, knockout mice display modestly-quicker acquisition of rotarod an...
The Journal of pharmacology and experimental therapeutics, 1991
The reinforcing and subjective effects of morphine were determined in five human volunteers with ... more The reinforcing and subjective effects of morphine were determined in five human volunteers with histories of i.v. heroin abuse. Subjects responded under a second-order schedule of i.m. injection. Under this schedule, every 100 lever presses produced a brief stimulus light [fixed ratio (FR) 100:s]; the 30th completion of the FR 100 requirement turned on the light for 15 min and the subject received an i.m. injection of morphine [FR 30 (FR 100:s)]. Once each weekday morphine or placebo was available under this schedule. Each drug dose was available for 1 week. Under these conditions placebo did not maintain responding; 3.75 mg of morphine maintained responding in four of five subjects, and higher morphine doses (7.5, 15 and 30 mg) maintained responding in all five subjects. Subjective effects were measured concurrently: these included measures of drug liking, the Morphine Benzedrine Group scale of the Addiction Research Center Inventory, drug detection and identification. Subjects di...
Journal of Pharmacology and Experimental Therapeutics, 2007
Cholinergic muscarinic systems have been shown to influence dopaminergic function in the CNS. In ... more Cholinergic muscarinic systems have been shown to influence dopaminergic function in the CNS. In addition, previous studies of benztropine analogues that inhibit dopamine uptake and show antagonism at muscarinic receptors show these drugs to be less effective than cocaine in producing its various prototypic effects such as locomotor stimulation. Because previous pharmacological studies on these topics have used non-selective M 1 antagonists, we examined the interactions of preferential M 1 muscarinic antagonists and cocaine. Dose-dependent increases in extracellular levels of dopamine in selected brain areas, the NAc shell and core, and the prefrontal cortex, were produced by cocaine, but not by the preferential M 1 antagonists, telenzepine and trihexyphenidyl. When administered with cocaine, however, both M 1 antagonists dose-dependently increased the effects of cocaine on dopamine in the NAc shell, and these effects were selective in that they were not obtained in the NAc core or in the prefrontal cortex. Telenzepine also increased locomotor activity, although the effect was small compared to that of cocaine. The locomotor stimulant effects of trihexyphenidyl on the other hand, approached those of cocaine. Telenzepine attenuated whereas trihexyphenidyl enhanced the locomotor stimulant effects of cocaine, with neither drug facilitating cocaine-induced stereotypy. The present results indicate that preferential antagonist effects at muscarinic M 1 receptors do not uniformly alter all of the effects of cocaine, nor do they explain the differences in effects of cocaine and BZT analogues, and that the alterations in dopamine levels in the NAc shell do not predict the behavioral effects of the interactions with cocaine.
Several N‐substituted benztropine (BZT) analogs with high dopamine transporter (DAT) affinity dec... more Several N‐substituted benztropine (BZT) analogs with high dopamine transporter (DAT) affinity decreased cocaine (Coc) self‐administration (SA) relative to food‐maintained behavior in rats. Further these BZT analogs failed to increase rates of responding greater than saline injections, when substituted for Coc (JPET:329;677). The present study examined if BZT analogs enhance the stereotypy‐inducing effects of Coc, which in turn interferes with continued Coc SA. Standard DAT inhibitors (WIN35,428, methylphenidate) maintained responding greater than saline injections when substituted for Coc, whereas responding maintained by BZT analogs (AHN1‐055, AHN2‐005, JHW007, JHW013, GA1‐69, GA2‐50, GA2‐99) was not different from vehicle. Additionally the DAT inhibitors shifted the Coc SA dose‐effect curve leftward, whereas the BZT analogs dose‐dependently decreased maximum SA of Coc SA. Administered alone, standard DAT inhibitors like Coc dose‐dependently increased stereotypy and enhanced the st...
Rimcazole (RIM) is a sigma receptor (σR) antagonist that also has affinity for the dopamine (DA) ... more Rimcazole (RIM) is a sigma receptor (σR) antagonist that also has affinity for the dopamine (DA) transporter (DAT). Despite this DAT affinity, RIM lacks stimulant effects and dose‐dependently attenuates ambulatory effects of cocaine (COC). RIM and its analogs decrease COC self‐administration in rats (JPET 339: 662), an effect that is obtained neither with selective σR antagonists nor standard DAT blockers.Thus, we tested RIM (1–17 mg/kg i.p.) alone and in combination with increasing doses of COC that maintain self‐administration (0.1–1.0 mg/kg i.v.), on stimulation of mesolimbic DA in Sprague Dawley rats implanted with a microdialysis probes in the accumbens shell.RIM dose‐dependently attenuated COC‐induced stimulation of DA levels at doses that had no effects on DA levels when administered alone. Previous studies suggest that the attenuation of COC self‐administration produced by RIM is due to the combined actions at σRs and the DAT as combinations of selective DAT inhibitors and s...
Author contributions A.L. Northcutt: design, completion and statistical analyses of the condition... more Author contributions A.L. Northcutt: design, completion and statistical analyses of the conditioned place preference and follow-up control studies; oversight, design, completion and statistical analyses of in vivo microdialaysis and follow-up control studies; design, oversight , and analysis of neonatal microglial cell culture studies; oversight and completion of HPLC procedures, quantification, and analysis; design and completion of brain mRNA studies, oversight of RT-PCR procedures, statistical analysis of RT-PCR data, design and completion of pharmacodynamic study; data graphics and figure preparation; manuscript preparation and review M.R. Hutchinson: all aspects of in silico analyses and data presentation; data graphics; general project oversight; figure and manuscript preparation and review X. Wang: design, completion and analysis of biophysical ELISA binding assays, Bis-ANS displacement assay; figure design; manuscript review M.V. Barrata: oversight of design, completion, and statistical analysis of mouse self-administration studies; manuscript preparation and review T. Hiranita: design, completion, and analysis of rat self-administration studies; figure preparation; manuscript preparation and review T.A. Cochran: surgical preparation of the in vivo microdialysis animals, microdialysis sample collection, HPLC sample preparation, collection and processing of micropunches for RT-PCR procedures, completion of neonatal microglial cell studies. M.B. Pomrenze: design, completion, and statistical analysis of mouse self-administration studies, figure preparation, manuscript preparation and review E.L. Galer: surgical preparation of the in vivo microdialysis animals, microdialysis sample collection, HPLC sample preparation; assistance with tissue collection for HPLC analysis of brain cocaine concentration T.A. Kopajtic: design and completion of the sigma-1 binding study and striatal membrane transporter binding study; table preparation; manuscript preparation and review C.M. Li: design, completion, and analysis of pharmacokinetic profiling (+)-naltrexone J. Amat: training and oversight of HPLC analyses; manuscript review G.Larson: assistance and oversight of tissue collection; completion of HPLC analysis for brain cocaine concentration study; data analysis; manuscript review D.C. Cooper: training and oversight of mouse-self administration procedures Y. Huang: oversight of design and completion of pharmacokinetic profiling (+)-naltrexone C.E. O'neill: assistance with statistical analysis; figure and manuscript preparation and review H. Yin: oversight of design and analysis of biophysical ELISA binding assays; Bis-ANS displacement assay; and BV-2 cell culture studies; manuscript review N.R. Zahniser: oversight of design and analysis of studies assessing brain cocaine concentrations via HPLC; manuscript preparation and review J. L. Katz: design and oversight of sigma-1, sigma-2 and striatal membrane assays; design and oversight of rat self-administration studies and analysis; figure and table preparation; manuscript drafting and review K. C. Rice: design, synthesis, purification and verification of (+)-naloxone and (+)-naltrexone; manuscript preparation and review S.F. Maier: oversight of experimental designs, control studies, and statistics; manuscript drafting and review R.K. Bachtell: oversight of experimental designs and control studies; oversight of statistical analysis;
Sigma1 receptors (σ1Rs) are intracellularly‐mobile chaperone proteins implicated in several disea... more Sigma1 receptors (σ1Rs) are intracellularly‐mobile chaperone proteins implicated in several diseases, as well as psychiatric disorders and substance abuse. A previous study showed that cocaine self‐administration (SA) induced dopamine (DA)‐independent reinforcing effects of selective σ1R agonists. The present study assessed whether the induction was specific to SA of cocaine. Selective σ1R agonists (PRE‐084, (+)‐pentazocine) lacked reinforcing effects in drug‐naive rats. SA was not obtained with 28 experimental sessions with the opportunity to selfadminister either σ1R agonist. The same exposure to cocaine was sufficient for its SA, after which robust SA of σ1R agonists was obtained. As with cocaine, SA of the indirect‐acting DA receptor agonist d‐methamphetamine induced the reinforcing effects of PRE‐084. In contrast, experiences with food reinforcement, or SA of (−)‐heroin or (±)‐ketamine were ineffective as inducers of PRE‐084 reinforcement. The results indicate that experience with indirect‐acting DA receptor agonists induces reinforcing effects of previously inactive σ1R agonists whereas reinforcement through different modalities is ineffective. It is further suggested that induced σ1R mechanisms may play an essential role in treatment‐resistant stimulant abuse, suggesting new approaches for the development of effective medications for stimulant abuse. Supported by NIDA IRP.
Previous studies indicate that benztropine (BZT) analogs bind to the dopamine transporter (DAT), ... more Previous studies indicate that benztropine (BZT) analogs bind to the dopamine transporter (DAT), inhibit DA uptake, are less effective than cocaine in a variety of procedures, and block cocaine self administration. Previously studied BZT analogs have a low apparent rate of association, which has been hypothesized to contribute to their lower cocaine‐like effectiveness. Recent studies have revealed BZT analogs with a relatively fast onset of action, but it is unclear if these actions were related to DAT binding. Therefore, the present study assessed the in vivo displacement of [125I]RTI‐121 binding to the DAT by the N‐substituted BZT analog JHW 013, its self administration, effects on cocaine self administration and effectiveness in stimulating DA levels in the nucleus accumbens shell. Maximal in vivo binding of JHW 013 was achieved at 30 min, compared to 45 min with cocaine, indicating a relatively fast rate of association. In addition, JHW 013 dose‐dependently increased DA in the nucleus accumbens shell. JHW 013 failed to maintain self‐administration at levels greater than saline and its pretreatment blocked cocaine self administration. The relatively fast onset of action of JHW 013 at the DAT indicates that a low rate of association is not necessary for the reduced cocaine‐like effects of BZT analogs and their potential as therapeutics for stimulant abuse. Supported by NIDA IRP
Chronic treatment with the monoamine releaser damphetamine has been consistently shown to decreas... more Chronic treatment with the monoamine releaser damphetamine has been consistently shown to decrease cocaine self-administration in laboratory studies and clinical trials. However, the abuse potential of d-amphetamine is an obstacle to widespread clinical use. Approaches are needed that exploit the efficacy of the agonist approach but avoid the abuse potential associated with dopamine releasers. The present study assessed the effectiveness of chronic oral administration of phendimetrazine (PDM), a pro-drug for the monoamine releaser phenmetrazine (PM), to decrease cocaine self-administration in four rhesus monkeys. Each day, monkeys pressed a lever to receive food pellets under a 50-response fixed-ratio (FR) schedule of reinforcement and self-administered cocaine (0.003-0.56 mg/kg per injection, i.v.) under a progressive-ratio (PR) schedule in the evening. After completing a cocaine self-administration dose-response curve, sessions were suspended and PDM was administered (1.0-9.0 mg/kg, p.o., b.i.d.). Cocaine selfadministration was assessed using the PR schedule once every 7 days while food-maintained responding was studied daily. When a persistent decrease in self-administration was observed, the cocaine dose-effect curve was re-determined. Daily PDM treatment decreased cocaine self-administration by 30-90% across monkeys for at least 4 weeks. In two monkeys, effects were completely selective for cocaine. Tolerance developed to initial decreases in food-maintained responding in the third monkey and in the fourth subject, fluctuations were observed that were lower in magnitude than effects on cocaine self-administration. Cocaine dose-effect curves were shifted down and/or rightward in three monkeys. These data provide further support for the use of agonist medications for cocaine abuse, and indicate that the promising effects of d-amphetamine extend to a more clinically viable pharmacotherapy.
Benztropine (BZT) analogs inhibit dopamine uptake but are less effective than cocaine in producin... more Benztropine (BZT) analogs inhibit dopamine uptake but are less effective than cocaine in producing behavioral effects predicting abuse liability. The present study compared reinforcing effects of intravenous BZT analogs with those of standard monoamine uptake inhibitors and the effects of their oral pretreatment on cocaine self-administration. Responding of rats was maintained by cocaine [0.032–1.0 mg/kg/injection (inj)] or food reinforcement under fixed-ratio five-response schedules. Maximal rates of responding were maintained by 0.32 mg/kg/inj cocaine or substituted methylphenidate, with lower rates maintained at lower and higher doses. The N-methyl BZT analog, AHN 1-055 (3 -[bis(4 -fluorophenyl)methoxy]-tropane), also maintained responding (0.1 mg/kg/inj), although maximal rates were less than those with cocaine. Responding was not maintained above vehicle levels by the N-allyl, AHN 2-005 (N-allyl3 -[bis(4 -fluorophenyl)methoxy]-tropane), and N-butyl, JHW 007 [N-(n-butyl)-3 -[bis(4 -fluorophenyl)methoxy]-tropane], BZT analogs, and it was not maintained with nisoxetine or citalopram. Presession treatment with methylphenidate (3.2–32 mg/kg) dose-dependently shifted the cocaine self-administration dose-effect curve leftward, whereas nisoxetine and citalopram effects were not significant. An intermediate dose of AHN 1-055 (32 mg/kg) increased responding maintained by low cocaine doses and decreased responding maintained by higher doses. A higher dose of AHN 1-055 completely suppressed cocaine-maintained responding. Both AHN 2-005 and JHW 007 dose-dependently (10–32 mg/kg) decreased cocaine selfadministration, shifting its dose-effect curve down. Decreases in cocaine-maintained responding occurred at doses of methylphenidate and BZT analogs that left food-maintained responding unchanged. During a component in which injections were not available, methylphenidate and AHN 1-055, but not AHN 2-005 or JHW 007, increased response rates. These findings further support the low abuse liability of BZT analogs and their potential development as medications for cocaine abuse. Drug abuse is a problem worldwide, with concomitant medical, social, and economic burdens at the individual and societal level. Drug self-administration procedures using laboratory animals have been used to assess the liability for abuse of drugs, to understand the behavioral and neurobiological mechanisms underlying drug reinforcement, and to discover potential medical treatments for drug abusers. Such treatments have been difficult to obtain with cocaine and other psychomotor stimulants (Vocci and Ling, 2005). Cocaine inhibits the uptake of monoamine neurotransmitters (Taylor and Ho, 1978), although most studies support actions at the DAT as the primary biological mechanism underlying its abuse-related effects. For example, DAT affinities of various monoamine uptake inhibitors are correlated with their potencies in drug self-administration procedures, whereas there is no such correlation for the SERT or NET (Ritz et al., 1987; Bergman et al., 1989). These and other results suggesting the DAT as the primary target for coThis work was supported by the Intramural Research program of the National Institutes of Health National Institute on Drug Abuse. Parts of this work were previously presented at the following conference: Hiranita T, Newman AH, and Katz JL (2008) Assessment of reinforcing effects of benztropine analogs and their effects on cocaine self-administration in rats: comparisons with monoamine uptake inhibitors; 2008 Annual Meeting of the American Society for Pharmacology and Experimental Therapeutics; 2008 Apr 5–9; San Diego, CA. American Society for Pharmacology and Experimental Therapeutics, Bethesda, MD. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.108.145813. ABBREVIATIONS: DAT, dopamine transporter; SERT, serotonin transporter; NET, norepinephrine transporter; BZT, benztropine; AHN 1-055, 3 -[bis(4 -fluorophenyl)methoxy]-tropane; AHN 2-005, N-allyl-3 -[bis(4 -fluorophenyl)methoxy]-tropane; JHW 007, N-(n-butyl)-3 -[bis(4 -fluorophenyl)methoxy]-tropane; LED, light-emitting diode; FR, fixed ratio; inj, injection; ANOVA, analysis of variance; GBR 12909, 1-{2-[bis-(4fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine; WIN 35,428, ( )-carbomethoxy-3 -(4-fluorophenyl)tropane. 0022-3565/09/3292-677–686 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 329, No. 2 U.S. Government work not protected by U.S. copyright 145813/3464891 JPET 329:677–686, 2009 Printed in U.S.A.
Sigma 1 receptors (σ 1 Rs) represent a structurally unique class of intracellular proteins that f... more Sigma 1 receptors (σ 1 Rs) represent a structurally unique class of intracellular proteins that function as chaperones. σ 1 Rs translocate from the mitochondria-associated membrane to the cell nucleus or cell membrane, and through protein-protein interactions influence several targets, including ion channels, G-protein-coupled receptors, lipids, and other signaling proteins. Several studies have demonstrated that σR antagonists block stimulant-induced behavioral effects, including ambulatory activity, sensitization, and acute toxicities. Curiously, the effects of stimulants have been blocked by σR antagonists tested under place-conditioning but not self-administration procedures, indicating fundamental differences in the mechanisms underlying these two effects. The self administration of σR agonists has been found in subjects previously trained to self administer cocaine. The reinforcing effects of the σR agonists were blocked by σR antagonists. Additionally, σR agonists were found to increase dopamine concentrations in the nucleus accumbens shell, a brain region considered important for the reinforcing effects of abused drugs. Although the effects of the σR agonist, DTG, on dopamine were obtained at doses that approximated those that maintained self administration behavior those of another agonist, PRE-084 required higher doses. The effects of DTG were antagonized by non-selective or a preferential σ 2 R antagonist but not by a preferential σ 1 R antagonist. The effects of PRE-084 on dopamine were insensitive to σR antagonists. The data suggest that the self administration of σR agonists is independent of dopamine and the findings are discussed in light of a hypothesis that cocaine has both intracellular actions mediated by σRs, as well as extracellular actions mediated through conventionally studied mechanisms.
Serotonin-selective reuptake inhibitors (SSRIs) have been shown to enhance the locomotor stimulat... more Serotonin-selective reuptake inhibitors (SSRIs) have been shown to enhance the locomotor stimulatory, discriminative-stimulus, and convulsive effects of cocaine in rodents. A pharmacokinetic mechanism for the interaction is supported by increases in the brain levels of cocaine by fluoxetine treatment. Furthermore, the locomotor-stimulant effects of cocaine in rodents are enhanced by fluoxetine and fluvoxamine, SSRIs known to inhibit cocainemetabolizing cytochrome P450 enzymes, whereas citalopram, an SSRI that does not inhibit P450 enzymes, does not enhance cocaine's locomotor-stimulant effects. Citalopram, however, attenuated the discriminative-stimulus effects of cocaine in squirrel monkeys trained to discriminate cocaine from saline, though it enhanced the discriminative-stimulus effects of a low dose of cocaine in rats trained to discriminate high and low doses of the drug. This study investigated the effects of citalopram on cocaine's discriminative-stimulus effects in rats trained more simply to discriminate cocaine from saline. Citalopram alone produced predominantly saline-appropriate responding, but when administered before cocaine, citalopram dosedependently shifted the cocaine dose-response curve leftward. The present findings suggest that enhancement of cocaine's discriminative-stimulus effects may occur through a mechanism different from that underlying enhancement of cocaine's locomotor effects or that another action of citalopram selectively blocks locomotor enhancement.
The Journal of pharmacology and experimental therapeutics, 1992
Several novel cocaine analogs, previously shown to be very potent in in vitro binding studies, ha... more Several novel cocaine analogs, previously shown to be very potent in in vitro binding studies, have been examined for their stimulatory effects on locomotor activity and for their ability to displace [3H]WIN 35,428 binding in vivo in mice. These compounds, like WIN 35,428, lack an ester link between the phenyl group and the tropane ring and have para-substitutions on the phenyl ring. They were much more potent than (-)-cocaine in producing increases in locomotor activity. In addition, they were more potent than (-)-cocaine in inhibiting [3H]WIN 35,428 binding in vivo in mouse striatum. Thus, these compounds demonstrate similar high potency in behavioral tests and in receptor binding assays, both in vivo and in vitro. Results support the hypothesis of a relationship between binding at the dopamine transporter and the behavioral effects of cocaine-like drugs. Further, assuming that maximal occupancy occurs with total displacement of [3H]WIN 35,428 binding in vivo, the data suggest tha...
Journal of the Experimental Analysis of Behavior, 1991
Reinforcer magnitude and fixed‐ratio requirement were varied under two second‐order schedules. Un... more Reinforcer magnitude and fixed‐ratio requirement were varied under two second‐order schedules. Under one, the first sequence of a fixed number of responses completed after the lapse of a 10‐min fixed interval produced reinforcement. Under the second, a second‐order progressive‐ratio schedule, the fixed number of responses increased after each reinforcement. Either cocaine (0 to 300 μg/kg/inj) or food (0 to 5,700 mg/delivery) reinforcers were delivered. Under some conditions, a 2‐s illumination of stimulus lights occurred on completion of each ratio sequence. Under the second‐order schedule, as cocaine dose or amount of food increased, rates of responding increased; at the highest values, rates of responding decreased. Increases in the ratio requirement from 10 to 170 responses minimally decreased overall response rates. Under the second‐order progressive‐ratio schedule, increases in dose of cocaine or amount of food increased rates of responding; at the highest amounts of food, rate...
The Journal of pharmacology and experimental therapeutics, 1992
The effects of corticotropin-releasing factor (CRF), a benzodiazepine inverse agonist (methyl-6,7... more The effects of corticotropin-releasing factor (CRF), a benzodiazepine inverse agonist (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; DMCM) and electric foot-shock on rat conflict behavior were characterized and compared. Rats were trained to lever press under a multiple fixed-ratio schedule (FR 20) of food reinforcement in which responses during the first component were not punished, and the first response of each FR during the second component produced electric shock of an intensity sufficient to suppress responding by 10% to 15%. Intracerebroventricular injection of CRF (0.1-5.6 micrograms) caused a dose-dependent decrease in the rate of responding in both components of the schedule. However, CRF was more potent in decreasing rates of punished responding (proconflict effect). DMCM (10-100 micrograms; i.c.v.) also decreased rates of punished and nonpunished responding and was more potent during the punishment component. The suppression of punished and nonpunished respo...
Journal of the Experimental Analysis of Behavior, 1991
Three pigeons were studied under a multiple schedule in which pecks in each component were reinfo... more Three pigeons were studied under a multiple schedule in which pecks in each component were reinforced according to a variable‐interval 120‐s second‐order schedule with fixed‐interval 60‐s units. In the first component of the multiple schedule, the completion of a fixed interval produced either food or a 4‐s change in key color plus houselight illumination. In the second component an identical schedule was in effect, but the stimulus was a 0.3‐s change in key color. Both long and short brief stimuli were not paired with food presentations in Conditions 1 and 3 and were paired with food in Condition 2. There were no consistent differences in response patterns under paired and nonpaired brief‐stimulus conditions when the stimulus was a 4‐s change in key color accompanied by houselight illumination. However, pairing the 0.3‐s key‐color change with food presentations resulted in higher indices of curvature and lower response rates in the early segments of the fixed interval than when the...
Molecular medicine (Cambridge, Mass.), Jan 18, 2016
The cadherin 13 (CDH13) gene encodes a cell adhesion molecule likely to influence development and... more The cadherin 13 (CDH13) gene encodes a cell adhesion molecule likely to influence development and connections of brain circuits that modulate addiction, locomotion and cognition, including those that involve midbrain dopamine neurons. Human CDH13 mRNA expression differs by more than 80% in postmortem cerebral cortical samples from individuals with different CDH13 genotypes, supporting examination of mice with altered Cdh13 expression as models for common human variation at this locus. Constitutive cdh13 knockout mice display evidence for changed cocaine reward: shifted dose response relationship in tests of cocaine-conditioned place preference using doses that do not alter cocaine conditioned taste aversion. Reduced adult Cdh13 expression in conditional knockouts also alters cocaine reward in ways that correlate with individual differences in cortical Cdh13 mRNA levels. In control and comparison behavioral assessments, knockout mice display modestly-quicker acquisition of rotarod an...
The Journal of pharmacology and experimental therapeutics, 1991
The reinforcing and subjective effects of morphine were determined in five human volunteers with ... more The reinforcing and subjective effects of morphine were determined in five human volunteers with histories of i.v. heroin abuse. Subjects responded under a second-order schedule of i.m. injection. Under this schedule, every 100 lever presses produced a brief stimulus light [fixed ratio (FR) 100:s]; the 30th completion of the FR 100 requirement turned on the light for 15 min and the subject received an i.m. injection of morphine [FR 30 (FR 100:s)]. Once each weekday morphine or placebo was available under this schedule. Each drug dose was available for 1 week. Under these conditions placebo did not maintain responding; 3.75 mg of morphine maintained responding in four of five subjects, and higher morphine doses (7.5, 15 and 30 mg) maintained responding in all five subjects. Subjective effects were measured concurrently: these included measures of drug liking, the Morphine Benzedrine Group scale of the Addiction Research Center Inventory, drug detection and identification. Subjects di...
Journal of Pharmacology and Experimental Therapeutics, 2007
Cholinergic muscarinic systems have been shown to influence dopaminergic function in the CNS. In ... more Cholinergic muscarinic systems have been shown to influence dopaminergic function in the CNS. In addition, previous studies of benztropine analogues that inhibit dopamine uptake and show antagonism at muscarinic receptors show these drugs to be less effective than cocaine in producing its various prototypic effects such as locomotor stimulation. Because previous pharmacological studies on these topics have used non-selective M 1 antagonists, we examined the interactions of preferential M 1 muscarinic antagonists and cocaine. Dose-dependent increases in extracellular levels of dopamine in selected brain areas, the NAc shell and core, and the prefrontal cortex, were produced by cocaine, but not by the preferential M 1 antagonists, telenzepine and trihexyphenidyl. When administered with cocaine, however, both M 1 antagonists dose-dependently increased the effects of cocaine on dopamine in the NAc shell, and these effects were selective in that they were not obtained in the NAc core or in the prefrontal cortex. Telenzepine also increased locomotor activity, although the effect was small compared to that of cocaine. The locomotor stimulant effects of trihexyphenidyl on the other hand, approached those of cocaine. Telenzepine attenuated whereas trihexyphenidyl enhanced the locomotor stimulant effects of cocaine, with neither drug facilitating cocaine-induced stereotypy. The present results indicate that preferential antagonist effects at muscarinic M 1 receptors do not uniformly alter all of the effects of cocaine, nor do they explain the differences in effects of cocaine and BZT analogues, and that the alterations in dopamine levels in the NAc shell do not predict the behavioral effects of the interactions with cocaine.
Several N‐substituted benztropine (BZT) analogs with high dopamine transporter (DAT) affinity dec... more Several N‐substituted benztropine (BZT) analogs with high dopamine transporter (DAT) affinity decreased cocaine (Coc) self‐administration (SA) relative to food‐maintained behavior in rats. Further these BZT analogs failed to increase rates of responding greater than saline injections, when substituted for Coc (JPET:329;677). The present study examined if BZT analogs enhance the stereotypy‐inducing effects of Coc, which in turn interferes with continued Coc SA. Standard DAT inhibitors (WIN35,428, methylphenidate) maintained responding greater than saline injections when substituted for Coc, whereas responding maintained by BZT analogs (AHN1‐055, AHN2‐005, JHW007, JHW013, GA1‐69, GA2‐50, GA2‐99) was not different from vehicle. Additionally the DAT inhibitors shifted the Coc SA dose‐effect curve leftward, whereas the BZT analogs dose‐dependently decreased maximum SA of Coc SA. Administered alone, standard DAT inhibitors like Coc dose‐dependently increased stereotypy and enhanced the st...
Rimcazole (RIM) is a sigma receptor (σR) antagonist that also has affinity for the dopamine (DA) ... more Rimcazole (RIM) is a sigma receptor (σR) antagonist that also has affinity for the dopamine (DA) transporter (DAT). Despite this DAT affinity, RIM lacks stimulant effects and dose‐dependently attenuates ambulatory effects of cocaine (COC). RIM and its analogs decrease COC self‐administration in rats (JPET 339: 662), an effect that is obtained neither with selective σR antagonists nor standard DAT blockers.Thus, we tested RIM (1–17 mg/kg i.p.) alone and in combination with increasing doses of COC that maintain self‐administration (0.1–1.0 mg/kg i.v.), on stimulation of mesolimbic DA in Sprague Dawley rats implanted with a microdialysis probes in the accumbens shell.RIM dose‐dependently attenuated COC‐induced stimulation of DA levels at doses that had no effects on DA levels when administered alone. Previous studies suggest that the attenuation of COC self‐administration produced by RIM is due to the combined actions at σRs and the DAT as combinations of selective DAT inhibitors and s...
Author contributions A.L. Northcutt: design, completion and statistical analyses of the condition... more Author contributions A.L. Northcutt: design, completion and statistical analyses of the conditioned place preference and follow-up control studies; oversight, design, completion and statistical analyses of in vivo microdialaysis and follow-up control studies; design, oversight , and analysis of neonatal microglial cell culture studies; oversight and completion of HPLC procedures, quantification, and analysis; design and completion of brain mRNA studies, oversight of RT-PCR procedures, statistical analysis of RT-PCR data, design and completion of pharmacodynamic study; data graphics and figure preparation; manuscript preparation and review M.R. Hutchinson: all aspects of in silico analyses and data presentation; data graphics; general project oversight; figure and manuscript preparation and review X. Wang: design, completion and analysis of biophysical ELISA binding assays, Bis-ANS displacement assay; figure design; manuscript review M.V. Barrata: oversight of design, completion, and statistical analysis of mouse self-administration studies; manuscript preparation and review T. Hiranita: design, completion, and analysis of rat self-administration studies; figure preparation; manuscript preparation and review T.A. Cochran: surgical preparation of the in vivo microdialysis animals, microdialysis sample collection, HPLC sample preparation, collection and processing of micropunches for RT-PCR procedures, completion of neonatal microglial cell studies. M.B. Pomrenze: design, completion, and statistical analysis of mouse self-administration studies, figure preparation, manuscript preparation and review E.L. Galer: surgical preparation of the in vivo microdialysis animals, microdialysis sample collection, HPLC sample preparation; assistance with tissue collection for HPLC analysis of brain cocaine concentration T.A. Kopajtic: design and completion of the sigma-1 binding study and striatal membrane transporter binding study; table preparation; manuscript preparation and review C.M. Li: design, completion, and analysis of pharmacokinetic profiling (+)-naltrexone J. Amat: training and oversight of HPLC analyses; manuscript review G.Larson: assistance and oversight of tissue collection; completion of HPLC analysis for brain cocaine concentration study; data analysis; manuscript review D.C. Cooper: training and oversight of mouse-self administration procedures Y. Huang: oversight of design and completion of pharmacokinetic profiling (+)-naltrexone C.E. O'neill: assistance with statistical analysis; figure and manuscript preparation and review H. Yin: oversight of design and analysis of biophysical ELISA binding assays; Bis-ANS displacement assay; and BV-2 cell culture studies; manuscript review N.R. Zahniser: oversight of design and analysis of studies assessing brain cocaine concentrations via HPLC; manuscript preparation and review J. L. Katz: design and oversight of sigma-1, sigma-2 and striatal membrane assays; design and oversight of rat self-administration studies and analysis; figure and table preparation; manuscript drafting and review K. C. Rice: design, synthesis, purification and verification of (+)-naloxone and (+)-naltrexone; manuscript preparation and review S.F. Maier: oversight of experimental designs, control studies, and statistics; manuscript drafting and review R.K. Bachtell: oversight of experimental designs and control studies; oversight of statistical analysis;
Sigma1 receptors (σ1Rs) are intracellularly‐mobile chaperone proteins implicated in several disea... more Sigma1 receptors (σ1Rs) are intracellularly‐mobile chaperone proteins implicated in several diseases, as well as psychiatric disorders and substance abuse. A previous study showed that cocaine self‐administration (SA) induced dopamine (DA)‐independent reinforcing effects of selective σ1R agonists. The present study assessed whether the induction was specific to SA of cocaine. Selective σ1R agonists (PRE‐084, (+)‐pentazocine) lacked reinforcing effects in drug‐naive rats. SA was not obtained with 28 experimental sessions with the opportunity to selfadminister either σ1R agonist. The same exposure to cocaine was sufficient for its SA, after which robust SA of σ1R agonists was obtained. As with cocaine, SA of the indirect‐acting DA receptor agonist d‐methamphetamine induced the reinforcing effects of PRE‐084. In contrast, experiences with food reinforcement, or SA of (−)‐heroin or (±)‐ketamine were ineffective as inducers of PRE‐084 reinforcement. The results indicate that experience with indirect‐acting DA receptor agonists induces reinforcing effects of previously inactive σ1R agonists whereas reinforcement through different modalities is ineffective. It is further suggested that induced σ1R mechanisms may play an essential role in treatment‐resistant stimulant abuse, suggesting new approaches for the development of effective medications for stimulant abuse. Supported by NIDA IRP.
Previous studies indicate that benztropine (BZT) analogs bind to the dopamine transporter (DAT), ... more Previous studies indicate that benztropine (BZT) analogs bind to the dopamine transporter (DAT), inhibit DA uptake, are less effective than cocaine in a variety of procedures, and block cocaine self administration. Previously studied BZT analogs have a low apparent rate of association, which has been hypothesized to contribute to their lower cocaine‐like effectiveness. Recent studies have revealed BZT analogs with a relatively fast onset of action, but it is unclear if these actions were related to DAT binding. Therefore, the present study assessed the in vivo displacement of [125I]RTI‐121 binding to the DAT by the N‐substituted BZT analog JHW 013, its self administration, effects on cocaine self administration and effectiveness in stimulating DA levels in the nucleus accumbens shell. Maximal in vivo binding of JHW 013 was achieved at 30 min, compared to 45 min with cocaine, indicating a relatively fast rate of association. In addition, JHW 013 dose‐dependently increased DA in the nucleus accumbens shell. JHW 013 failed to maintain self‐administration at levels greater than saline and its pretreatment blocked cocaine self administration. The relatively fast onset of action of JHW 013 at the DAT indicates that a low rate of association is not necessary for the reduced cocaine‐like effects of BZT analogs and their potential as therapeutics for stimulant abuse. Supported by NIDA IRP
Chronic treatment with the monoamine releaser damphetamine has been consistently shown to decreas... more Chronic treatment with the monoamine releaser damphetamine has been consistently shown to decrease cocaine self-administration in laboratory studies and clinical trials. However, the abuse potential of d-amphetamine is an obstacle to widespread clinical use. Approaches are needed that exploit the efficacy of the agonist approach but avoid the abuse potential associated with dopamine releasers. The present study assessed the effectiveness of chronic oral administration of phendimetrazine (PDM), a pro-drug for the monoamine releaser phenmetrazine (PM), to decrease cocaine self-administration in four rhesus monkeys. Each day, monkeys pressed a lever to receive food pellets under a 50-response fixed-ratio (FR) schedule of reinforcement and self-administered cocaine (0.003-0.56 mg/kg per injection, i.v.) under a progressive-ratio (PR) schedule in the evening. After completing a cocaine self-administration dose-response curve, sessions were suspended and PDM was administered (1.0-9.0 mg/kg, p.o., b.i.d.). Cocaine selfadministration was assessed using the PR schedule once every 7 days while food-maintained responding was studied daily. When a persistent decrease in self-administration was observed, the cocaine dose-effect curve was re-determined. Daily PDM treatment decreased cocaine self-administration by 30-90% across monkeys for at least 4 weeks. In two monkeys, effects were completely selective for cocaine. Tolerance developed to initial decreases in food-maintained responding in the third monkey and in the fourth subject, fluctuations were observed that were lower in magnitude than effects on cocaine self-administration. Cocaine dose-effect curves were shifted down and/or rightward in three monkeys. These data provide further support for the use of agonist medications for cocaine abuse, and indicate that the promising effects of d-amphetamine extend to a more clinically viable pharmacotherapy.
Benztropine (BZT) analogs inhibit dopamine uptake but are less effective than cocaine in producin... more Benztropine (BZT) analogs inhibit dopamine uptake but are less effective than cocaine in producing behavioral effects predicting abuse liability. The present study compared reinforcing effects of intravenous BZT analogs with those of standard monoamine uptake inhibitors and the effects of their oral pretreatment on cocaine self-administration. Responding of rats was maintained by cocaine [0.032–1.0 mg/kg/injection (inj)] or food reinforcement under fixed-ratio five-response schedules. Maximal rates of responding were maintained by 0.32 mg/kg/inj cocaine or substituted methylphenidate, with lower rates maintained at lower and higher doses. The N-methyl BZT analog, AHN 1-055 (3 -[bis(4 -fluorophenyl)methoxy]-tropane), also maintained responding (0.1 mg/kg/inj), although maximal rates were less than those with cocaine. Responding was not maintained above vehicle levels by the N-allyl, AHN 2-005 (N-allyl3 -[bis(4 -fluorophenyl)methoxy]-tropane), and N-butyl, JHW 007 [N-(n-butyl)-3 -[bis(4 -fluorophenyl)methoxy]-tropane], BZT analogs, and it was not maintained with nisoxetine or citalopram. Presession treatment with methylphenidate (3.2–32 mg/kg) dose-dependently shifted the cocaine self-administration dose-effect curve leftward, whereas nisoxetine and citalopram effects were not significant. An intermediate dose of AHN 1-055 (32 mg/kg) increased responding maintained by low cocaine doses and decreased responding maintained by higher doses. A higher dose of AHN 1-055 completely suppressed cocaine-maintained responding. Both AHN 2-005 and JHW 007 dose-dependently (10–32 mg/kg) decreased cocaine selfadministration, shifting its dose-effect curve down. Decreases in cocaine-maintained responding occurred at doses of methylphenidate and BZT analogs that left food-maintained responding unchanged. During a component in which injections were not available, methylphenidate and AHN 1-055, but not AHN 2-005 or JHW 007, increased response rates. These findings further support the low abuse liability of BZT analogs and their potential development as medications for cocaine abuse. Drug abuse is a problem worldwide, with concomitant medical, social, and economic burdens at the individual and societal level. Drug self-administration procedures using laboratory animals have been used to assess the liability for abuse of drugs, to understand the behavioral and neurobiological mechanisms underlying drug reinforcement, and to discover potential medical treatments for drug abusers. Such treatments have been difficult to obtain with cocaine and other psychomotor stimulants (Vocci and Ling, 2005). Cocaine inhibits the uptake of monoamine neurotransmitters (Taylor and Ho, 1978), although most studies support actions at the DAT as the primary biological mechanism underlying its abuse-related effects. For example, DAT affinities of various monoamine uptake inhibitors are correlated with their potencies in drug self-administration procedures, whereas there is no such correlation for the SERT or NET (Ritz et al., 1987; Bergman et al., 1989). These and other results suggesting the DAT as the primary target for coThis work was supported by the Intramural Research program of the National Institutes of Health National Institute on Drug Abuse. Parts of this work were previously presented at the following conference: Hiranita T, Newman AH, and Katz JL (2008) Assessment of reinforcing effects of benztropine analogs and their effects on cocaine self-administration in rats: comparisons with monoamine uptake inhibitors; 2008 Annual Meeting of the American Society for Pharmacology and Experimental Therapeutics; 2008 Apr 5–9; San Diego, CA. American Society for Pharmacology and Experimental Therapeutics, Bethesda, MD. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.108.145813. ABBREVIATIONS: DAT, dopamine transporter; SERT, serotonin transporter; NET, norepinephrine transporter; BZT, benztropine; AHN 1-055, 3 -[bis(4 -fluorophenyl)methoxy]-tropane; AHN 2-005, N-allyl-3 -[bis(4 -fluorophenyl)methoxy]-tropane; JHW 007, N-(n-butyl)-3 -[bis(4 -fluorophenyl)methoxy]-tropane; LED, light-emitting diode; FR, fixed ratio; inj, injection; ANOVA, analysis of variance; GBR 12909, 1-{2-[bis-(4fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine; WIN 35,428, ( )-carbomethoxy-3 -(4-fluorophenyl)tropane. 0022-3565/09/3292-677–686 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 329, No. 2 U.S. Government work not protected by U.S. copyright 145813/3464891 JPET 329:677–686, 2009 Printed in U.S.A.
Sigma 1 receptors (σ 1 Rs) represent a structurally unique class of intracellular proteins that f... more Sigma 1 receptors (σ 1 Rs) represent a structurally unique class of intracellular proteins that function as chaperones. σ 1 Rs translocate from the mitochondria-associated membrane to the cell nucleus or cell membrane, and through protein-protein interactions influence several targets, including ion channels, G-protein-coupled receptors, lipids, and other signaling proteins. Several studies have demonstrated that σR antagonists block stimulant-induced behavioral effects, including ambulatory activity, sensitization, and acute toxicities. Curiously, the effects of stimulants have been blocked by σR antagonists tested under place-conditioning but not self-administration procedures, indicating fundamental differences in the mechanisms underlying these two effects. The self administration of σR agonists has been found in subjects previously trained to self administer cocaine. The reinforcing effects of the σR agonists were blocked by σR antagonists. Additionally, σR agonists were found to increase dopamine concentrations in the nucleus accumbens shell, a brain region considered important for the reinforcing effects of abused drugs. Although the effects of the σR agonist, DTG, on dopamine were obtained at doses that approximated those that maintained self administration behavior those of another agonist, PRE-084 required higher doses. The effects of DTG were antagonized by non-selective or a preferential σ 2 R antagonist but not by a preferential σ 1 R antagonist. The effects of PRE-084 on dopamine were insensitive to σR antagonists. The data suggest that the self administration of σR agonists is independent of dopamine and the findings are discussed in light of a hypothesis that cocaine has both intracellular actions mediated by σRs, as well as extracellular actions mediated through conventionally studied mechanisms.
Serotonin-selective reuptake inhibitors (SSRIs) have been shown to enhance the locomotor stimulat... more Serotonin-selective reuptake inhibitors (SSRIs) have been shown to enhance the locomotor stimulatory, discriminative-stimulus, and convulsive effects of cocaine in rodents. A pharmacokinetic mechanism for the interaction is supported by increases in the brain levels of cocaine by fluoxetine treatment. Furthermore, the locomotor-stimulant effects of cocaine in rodents are enhanced by fluoxetine and fluvoxamine, SSRIs known to inhibit cocainemetabolizing cytochrome P450 enzymes, whereas citalopram, an SSRI that does not inhibit P450 enzymes, does not enhance cocaine's locomotor-stimulant effects. Citalopram, however, attenuated the discriminative-stimulus effects of cocaine in squirrel monkeys trained to discriminate cocaine from saline, though it enhanced the discriminative-stimulus effects of a low dose of cocaine in rats trained to discriminate high and low doses of the drug. This study investigated the effects of citalopram on cocaine's discriminative-stimulus effects in rats trained more simply to discriminate cocaine from saline. Citalopram alone produced predominantly saline-appropriate responding, but when administered before cocaine, citalopram dosedependently shifted the cocaine dose-response curve leftward. The present findings suggest that enhancement of cocaine's discriminative-stimulus effects may occur through a mechanism different from that underlying enhancement of cocaine's locomotor effects or that another action of citalopram selectively blocks locomotor enhancement.
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