Biomedical subjects

Jeffrey W Grimm

Publications and source records attributed to Jeffrey W Grimm.

10 recordsLinked to original sources

PubMed2006

Intraventricular insulin and leptin decrease sucrose self-administration in rats.

Data from our laboratory and others have demonstrated an effect of the candidate adiposity signals insulin and leptin to decrease brain reward function, as assessed by lateral hypothalamic self-stimulation and food-conditioned place preference. In this study, we evaluated the effect of centrally administrated insulin or leptin to acutely decrease motivated performance for 5% sucrose, i.e., progressive ratio (PR) sucrose self-administration. Consistent with findings using other behavioral assays, both insulin and leptin significantly decreased the number of bar presses (62+/-7 and 76+/-8% of paired controls respectively), and the number of sucrose rewards obtained (87+/-4 and 91+/-4% of paired controls respectively), relative to within-subjects' control day performance on PR sucrose self-administration, whereas acute intraventricular cerebrospinal fluid had no effect. Rats fed a higher fat diet for 5 weeks were resistant to the effects of the intraventricular insulin or leptin, suggesting a central resistance to their action. Thus the findings of this study extend and support previous observations which suggest that neuroendocrine signals which regulate energy homeostasis in the CNS may also play a role in modulating reward circuitry, and specifically, food reward.

Analysis of Variance↗

PubMed2006

Time-dependent dissociation of cocaine dose-response effects on sucrose craving and locomotion.

In the present study, rats self-administered sucrose 6 h/day for 10 days. Separate groups of rats were then tested on day 1 or day 30 of forced abstinence. After they had responded to near extinction, rats were injected with either saline or cocaine (2.5, 5, 10, or 20 mg/kg intraperitoneal) and then allowed to respond to a sucrose-paired stimulus. Locomotor activity was assessed during testing. Rats pressed more during the extinction responding phase of testing on day 30 than on day 1 of forced abstinence, and this incubation of craving was accompanied by a time-dependent increase in locomotor activity. Compared with saline, cocaine increased responding for the sucrose-paired cue on day 1 of forced abstinence at the 5 mg/kg dose only. In contrast, responding on day 30 was increased at the 10 and 20 mg/kg doses. Locomotor activity increased dose-dependently at both forced-abstinence time points, suggesting a dissociation between cocaine-induced locomotion and cocaine-elevated responding for a sucrose-paired stimulus. These results also indicate that there are time-dependent changes in how cocaine affects sucrose craving.

Animals↗

PubMed2004

Incubation of sucrose craving: effects of reduced training and sucrose pre-loading.

Time-dependent increases in cue-induced reward seeking after forced abstinence were described in rats with a history of cocaine or sucrose self-administration, suggesting reward craving incubates over time. In the present study, we examined the effects of reduced training experience, or sucrose pre-loading just prior to testing, on the incubation of sucrose craving. Sucrose seeking (responding in extinction and then for a sucrose-paired cue) increased over time in groups of rats that self-administered sucrose 6 h/day for 10 days and were tested at 1, 7, or 30 days of forced abstinence. We found that groups of rats that had self-administered 2 instead of 6 h/day showed a similar profile of responding. Incubation of sucrose craving was attenuated by free access to sucrose in home cages for 17 h immediately prior to testing assessed as extinction responding on days 1 and 30. However, this sucrose pre-loading had no effect on the time-dependent increase in responding for the sucrose-paired cue. In summary, reducing the training experience had no effect on the incubation of sucrose craving and free access to sucrose had only a limited effect-attenuating extinction responding. These results illustrate the strength of the incubation of craving and further suggest long-term changes in brain motivational circuitry following sucrose self-administration.

Analysis of Variance↗

PubMed2004

Cocaine seeking over extended withdrawal periods in rats: different time courses of responding induced by cocaine cues versus cocaine priming over the first 6 months.

RATIONALE AND OBJECTIVES: We previously found time dependent increases, or incubation, of cocaine seeking induced by re-exposure to cocaine cues over withdrawal periods of up to 3 months. Here, we studied cocaine seeking induced by re-exposure to cocaine cues or cocaine itself over an extended withdrawal period of 6 months. METHODS: Rats were trained to self-administer intravenous cocaine for 6 h/day for 10 days. Cocaine seeking induced by re-exposure to cocaine cues or cocaine itself, as measured in extinction or drug-induced reinstatement tests, respectively, was then assessed 1 day, or 1, 3 or 6 months after withdrawal. Rats were first given six 1-h extinction sessions wherein lever presses resulted in contingent presentations of cues previously paired with cocaine infusions. Subsequently, reinstatement of drug seeking induced by cocaine injections (expt 1: 0, 5, and 15 mg/kg, i.p.; expt 2: 0, 2.5, and 5 mg/kg) was assessed during three 1-h sessions. RESULTS: Profound time dependent changes in responsiveness to cocaine cues in the extinction tests were observed, with low responding after 1 day, high responding after 1 and 3 months, and intermediate responding after 6 months of withdrawal. In contrast, no significant time dependent changes in cocaine-induced drug seeking were found; acute re-exposure to cocaine effectively reinstated responding at all withdrawal periods. CONCLUSIONS: Results indicate that the withdrawal period is a critical modulator of drug seeking provoked by re-exposure to cocaine cues, but not cocaine itself. Results also indicate that while the incubation of responsiveness to cocaine cues is a long lasting phenomenon, it is not permanent.

Animals↗

PubMed2004

Incubation of cocaine craving after withdrawal: a review of preclinical data.

Using a rat model of drug craving and relapse, we recently found that cocaine seeking induced by re-exposure to drug-associated cues progressively increases over the first 2 months after withdrawal from cocaine self-administration, suggesting that drug craving incubates over time [Nature 412 (2001) 141]. Here, we summarize data from studies that further characterized this incubation phenomenon and briefly discuss its implications for drug addiction. The main findings of our ongoing research are: 1. Incubation of cocaine craving is long-lasting, but not permanent: cocaine seeking induced by exposure to cocaine cues remains elevated for up to 3 months of withdrawal, but decreases after 6 months. 2. Incubation of reward craving is not drug specific: sucrose seeking induced by re-exposure to the reward cues also increases after withdrawal, but for a time period that is shorter than that of cocaine. 3. Incubation of cocaine craving is not evident after acute re-exposure to cocaine itself: cocaine seeking induced by cocaine priming injections remains essentially unchanged over the first 6 months of withdrawal. 4. Incubation of cocaine craving after withdrawal is associated with increases in the levels of brain-derived neurotrophic factor (BDNF) in mesolimbic dopamine areas.

Amphetamine-Related Disorders↗

PubMed2004

Enhanced wet deposition estimates using modeled precipitation inputs.

Effective assessments of linkages between atmospheric deposition and sensitive aquatic and terrestrial ecosystems require a knowledge of spatial patterns in deposition of greater resolution than currently available using point estimates and two-dimensional surface algorithms. A high resolution wet deposition model was developed for the Eastern U.S.A. by incorporating daily precipitation measurements from National Oceanic and Atmospheric Administration (NOAA) monitoring sites located within the Eastern U.S.A.; topographic variables, including elevation, slope, and aspect that affect the amount and distribution of precipitation across the region; and precipitation chemistry data from National Atmospheric Deposition Program (NADP) sites within and adjacent to the region. Model performance, which was tested against independent measurements from three physiographic regions of the eastern U.S.A., revealed a statistically significant reduction in interpolation error compared to traditional two-dimensional surface algorithms.

Air Pollutants↗

PubMed2003

Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: implications for incubation of cocaine craving.

Using a rat model of drug craving, we found that the responsiveness to cocaine cues progressively increases or incubates over the first 60 d of cocaine withdrawal. Here we studied whether alterations in brain-derived neurotrophic factor (BDNF) protein levels within the mesolimbic dopamine system are associated with this incubation phenomenon. BDNF is involved in synaptic plasticity and was found to enhance responding for cues associated with natural rewards. Rats were trained to press a lever to receive intravenous cocaine or oral sucrose for 6 hr/d for 10 d; each earned reward was paired with a tone-light cue. Resumption of lever-pressing behavior was then assessed on days 1, 30, or 90 of reward withdrawal. First, resistance to extinction was assessed during 6 hr in which lever presses were not reinforced and the cue was absent. Second, cue-induced reinstatement was assessed after extinction during 1 hr in which responding led to cue presentations. Other rats were killed without testing on days 1, 30, and 90 of reward withdrawal, and BDNF and nerve growth factor (NGF) protein levels were measured in the ventral tegmental area (VTA), accumbens, and amygdala. Lever pressing during extinction and cue-induced reinstatement tests of cocaine craving progressively increased after cocaine withdrawal. Time-dependent changes also were observed during the tests for sucrose craving, with maximal responding on day 30. BDNF, but not NGF, levels in the VTA, accumbens, and amygdala progressively increased after cocaine, but not sucrose, withdrawal. Time-dependent increases in BDNF levels may lead to synaptic modifications that underlie enhanced responsiveness to cocaine cues after prolonged withdrawal periods.

Acoustic Stimulation↗

PubMed2002

Reinstatement of cocaine seeking in 129X1/SvJ mice: effects of cocaine priming, cocaine cues and food deprivation.

RATIONALE AND OBJECTIVES: The mechanisms underlying relapse to cocaine seeking induced by exposure to priming cocaine injections, cues associated with cocaine self-administration and environmental stressors have been studied in rats. Here we describe a reinstatement method for studying relapse to cocaine seeking in mice, a suitable species for studying the effect of genetic manipulations such as gene knockout or gene over-expression on compulsive drug use. METHODS: Male mice of the 129X1/SvJ strain were trained for 14-16 days to self-administer cocaine (0.75 mg/kg/infusion; 4 h/day; fixed-ratio-1 schedule of reinforcement; infusions were paired with a light-tone compound cue). Next, the lever-pressing behavior was extinguished by removing the cocaine syringes in the presence (Exps. 1 and 3) or absence (Exp. 2) of the cocaine cue. Subsequently, tests for reinstatement were conducted after exposure to priming injections of cocaine (0, 1.5, 3.0 and 6.0 mg/kg, IV; Exp. 1), response-contingent presentations of the cocaine-associated cue (Exp. 2), or food deprivation stress (1 and 22 h; Exp. 3). RESULTS: The effect of cocaine priming on reinstatement was modest and was only observed at the highest dose tested. On the other hand, reinstatement of cocaine seeking was observed following exposure to the cocaine-associated cue and food deprivation stress. CONCLUSIONS: The present data suggest that factors contributing to relapse to drugs can be studied in the reinstatement model using the common 129X1/SvJ mouse inbred strain.

Animals↗

PubMed2002

Effect of dopamine receptor antagonists on renewal of cocaine seeking by reexposure to drug-associated contextual cues.

We recently found that in rats trained to self-administer a heroin-cocaine mixture, exposure to the drug self-administration environment, after extinction of the drug-reinforced behavior in a different context, leads to renewal of drug seeking. Here we further explored the role of contextual stimuli in drug seeking by characterizing the effect of drug-associated environmental stimuli on renewal of cocaine seeking. We also investigated whether activation of dopamine receptors contributes to context-induced renewal of cocaine seeking by testing the effects of selective D1-like (SCH 23390) and D2-like (raclopride) receptor antagonists. Rats were trained for 10 days to self-administer cocaine by pressing a lever. Next, lever pressing was extinguished in the presence of the discrete cues associated with cocaine infusions for 10 days in a context that was distinctively different from the drug-taking context. On the test days, rats were pretreated with SCH 23390 (0, 5 or 10 microg/kg) or raclopride (0, 50 or 100 microg/kg) and non-reinforced lever-pressing behavior was determined either in the extinction context (Control group) or the cocaine-associated context (Renewal group). Consistent with our previous report, cocaine seeking was renewed when rats were exposed to the drug-associated context after extinction in a different context. Furthermore, pretreatment with the D1-like or the D2-like receptor antagonists attenuated context-induced renewal of cocaine seeking. These data suggest that activation of dopamine receptors is involved in reinstatement of cocaine seeking induced by exposure to the drug self-administration context.

Animals↗

PubMed2002

Neurobiology of relapse to heroin and cocaine seeking: a review.

The objective of this article is to review data from studies that used a reinstatement model in rats to elucidate the neural mechanisms underlying relapse to heroin and cocaine seeking induced by exposure to the self-administered drug (drug priming), conditioned drug cues, and stressors. These factors were reported to contribute to relapse to drug use in humans following prolonged abstinence periods. In the reinstatement model, the ability of acute exposure to drug or nondrug stimuli to reinstate drug seeking is determined following training for drug self-administration and subsequent extinction of the drug-reinforced behavior. We will review studies in which pharmacological agents were injected systemically or intracranially to block (or mimic) reinstatement by drug priming, drug cues, and stressors. We also will review studies in which brain lesions, in vivo microdialysis and electrochemistry, and gene expression methods were used to map brain sites involved in relapse to drug seeking. Subsequently, we will discuss theoretical issues related to the processes underlying relapse to drugs and address methodological issues in studies on reinstatement of drug seeking. Finally, the implications of the findings from the studies reviewed for addiction theories and treatment will be discussed. The main conclusion of this review is that the neuronal mechanisms involved in relapse to heroin and cocaine seeking induced by drug priming, drug cues, and stressors are to a large degree dissociable. The data reviewed also suggest that the neuronal events mediating drug-induced reinstatement are to some degree dissociable from those mediating drug reinforcement.

Animals↗