A novel paradigm to investigate regulation of drug intake in rats self-administering cocaine or heroin intravenously.

Lynch, Wendy J.; LaBounty, Lynda P.; Carroll, Marilyn E.

doi:10.1037/1064-1297.6.1.22

Cited by 45 publications

(57 citation statements)

References 8 publications

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“…2A). Although at first this may be surprising given reports in the literature of well trained animals' ability to regulate intake when cocaine dose is varied (Pickens and Thompson, 1968;Gerber and Wise, 1989;Lynch et al, 1998;Panlilio et al, 2003), our animals received minimal training before the switch in cocaine dose. Furthermore, there are now many paradigms that model an escalation of consumption, and they all demonstrate conditions that produce instability of intake (i.e., escalation) (Carroll et al, 1989;Fitch and Roberts, 1993;Ahmed and Koob, 1998;Tornatzky and Miczek, 2000).…”

Section: Discussionmentioning

confidence: 75%

Cocaine Dose and Self-Administration History, but Not Initial Cocaine Locomotor Responsiveness, Affects Sensitization to the Motivational Effects of Cocaine in Rats

Mandt

Gomez²,

Johnston³

et al. 2012

J Pharmacol Exp Ther

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Cocaine addiction is a significant and complex disease. Part of this complexity is caused by the variability of the drug experience early in drug use (initial responsiveness, amount of use, etc.). In rats, individual differences in initial cocaine responsiveness and cocaine self-administration history both predict the development of cocaine sensitization, a putative mechanism contributing to the development of cocaine addiction. Here, we sought to determine the role of these factors and cocaine dose on the development of sensitization to cocaine's motivational effects during the earliest stages of self-administration. Rats were classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on acute cocaine-induced locomotor activity (10 mg/kg i.p.) before learning to self-administer cocaine (0.6 mg/kg/infusion i.v.) under a fixed ratio 1 (FR1) schedule of reinforcement. After acquisition, rats self-administered cocaine (0.6 or 1.2 mg/kg/infusion) under a progressive ratio (PR) schedule of reinforcement either immediately or after an additional five FR1 sessions (0.6 or 1.2 mg/kg/infusion). No LCR/HCR differences in sensitization were observed. However, regardless of LCR/HCR classification, exposure to the higher dose of cocaine produced sensitization to cocaine's motivational effects on the PR schedule (i.e., increased break points) and an escalation of consumption on the FR schedule. Thus, our results reveal a novel model for studying escalation and sensitization very early after acquisition and suggest that sensitization may be important in the earliest stages of the cocaine addiction process.

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Section: Discussionmentioning

confidence: 75%

Cocaine Dose and Self-Administration History, but Not Initial Cocaine Locomotor Responsiveness, Affects Sensitization to the Motivational Effects of Cocaine in Rats

Mandt

Gomez²,

Johnston³

et al. 2012

J Pharmacol Exp Ther

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“…Animals typically self-administer drugs at regularly spaced intervals under FR1 schedules (Yokel and Pickens, 1974;Dougherty and Pickens, 1976;Pickens et al, 1981;Wise et al, 1995a, b;Lynch et al, 1998). However, under certain conditions (eg exposure to prolonged periods of drug availability), this pattern of intake may be dysregulated, leading to an escalation of drug use (Ahmed et al, 2000;Ahmed and Koob, 1998;Bozarth and Wise, 1985;Tornatzky and Miczek, 2000).…”

Section: Discussionmentioning

confidence: 99%

Exposure to Δ-9-Tetrahydrocannabinol (THC) Increases Subsequent Heroin Taking but not Heroin's Reinforcing Efficacy: A Self-Administration Study in Rats

Solinas¹,

Panlilio²,

Goldberg³

2004

Neuropsychopharmacol

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One concern about the widespread use of cannabis is that exposure to its active ingredient, D-9-tetrahydrocannabinol (THC), might increase future reinforcing effects of other abused drugs such as heroin. In this study, we investigated the effects of pre-exposure to THC on subsequent intravenous self-administration of heroin by Sprague-Dawley rats. In one group of rats, we studied (1) acquisition of heroin self-administration behavior using a continuous-reinforcement (fixed-ratio (FR) 1) schedule, (2) heroin dose-response relationships using an FR1/variable-dose schedule, and (3) reinforcing efficacy of heroin using a progressive-ratio schedule. The number of rats pre-exposed to THC that subsequently learned to self-administer 50 mg/kg injections of heroin within 10 daily sessions did not differ from vehicle-pretreated controls. In contrast, rats pre-exposed to THC subsequently self-administered significantly more heroin injections per session and showed significantly shorter post-injection pauses over a range of heroin doses (12.5-100 mg/kg/injection) using the variable-dose schedule. Interestingly, the maximum effort rats would exert to receive an injection of the different doses of heroin under the progressive-ratio schedule was not altered by THC pre-exposure. In a second group of rats, we varied the 'price' of heroin (responses required/dose), by manipulating FR response requirements at different doses of heroin across sessions, to calculate demand and response output curves. Again, consumption was significantly higher in the THC-treated rats at the lowest prices of heroin (FR1/ 100 mg/kg and FR1/50 mg/kg) but there were no differences in the reinforcing efficacy of heroin between THC-and vehicle-pretreated rats. Altogether, these results demonstrate that pre-exposure to THC alters some pharmacological effects of heroin that determine frequency of heroin taking, but offer no support for the hypothesis that pre-exposure to THC alters heroin's efficacy as a reinforcer.

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“…These procedures have shown that the reinforcing effects of cocaine can be described by an ascending dose-response curve. The peak of the progressive ratio dose-response curve is typically in the range of 1.5 mg/ kg (for review, see Arnold and Roberts, 1997;Stafford et al, 1998), and studies offering a choice between different doses of cocaine (Johanson and Schuster, 1975;Llewellyn et al, 1976;Lynch et al, 1998;Ward et al, 2005) have shown that larger doses on the ascending limb are generally preferred.…”

Section: Introductionmentioning

confidence: 99%

Brain-Cocaine Concentrations Determine the Dose Self-Administered by Rats on a Novel Behaviorally Dependent Dosing Schedule

Zimmer

Dobrin

Roberts

2011

Neuropsychopharmacol

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A novel behaviorally dependent dosing (BDD) schedule was used to examine the relationship between doses of cocaine selfadministered by rats and brain drug levels within a session. The BDD schedule used a hold-down response to activate a syringe pump. The length of time the lever was held down determined the duration that the syringe pump was activated. In the first experiment, rats self-administered cocaine for daily 3 h sessions and brain levels of cocaine were modeled using well-established parameters. Although analysis revealed that rats self-administered doses within a predicted range, one extremely large dose was consistently observed at the beginning of each session when brain levels of cocaine were low. In the second experiment, we introduced a range of timeout periods (10-25 min) in order to produce variability in brain-cocaine concentrations. Animals self-administered larger doses immediately following each timeout period and the dose size was inversely correlated with the length of the timeout. These results show that the dose of cocaine that rats self-administer within a session is inversely related to the amount of drug on board.

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A novel paradigm to investigate regulation of drug intake in rats self-administering cocaine or heroin intravenously.

Cited by 45 publications

References 8 publications

Cocaine Dose and Self-Administration History, but Not Initial Cocaine Locomotor Responsiveness, Affects Sensitization to the Motivational Effects of Cocaine in Rats

Cocaine Dose and Self-Administration History, but Not Initial Cocaine Locomotor Responsiveness, Affects Sensitization to the Motivational Effects of Cocaine in Rats

Exposure to Δ-9-Tetrahydrocannabinol (THC) Increases Subsequent Heroin Taking but not Heroin's Reinforcing Efficacy: A Self-Administration Study in Rats

Brain-Cocaine Concentrations Determine the Dose Self-Administered by Rats on a Novel Behaviorally Dependent Dosing Schedule

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