The effects of cocaine on the rate independent brain stimulation reward threshold in the mouse
Laboratory of Behavioral Pharmacology, Boston University School of Medicine, 715 Albany Street, L-620, Boston, MA 02118, USA. Pharmacology Biochemistry and Behavior
(Impact Factor: 2.78).
10/2004; 79(1):165-70. DOI: 10.1016/j.pbb.2004.07.001
Interest in the development of mouse models of drug abuse liability has increased with the introduction of selective gene expression. In the rat, the ability of drugs to lower brain stimulation reward (BSR) thresholds often correlates with high abuse liability. Measurement of BSR thresholds using rate-independent methods decreases the influence of impaired motor performance on threshold determination that may confound studies of mutant mice. In the present experiment, the effects of cocaine on mouse BSR thresholds were assessed using a modification of the rate-independent psychophysical method of limits as current intensity was systematically varied in a series of descending and ascending discrete trials. Bipolar electrodes were implanted into the medial forebrain bundle of male C57Bl/6N mice and the effects of intraperitoneal saline and cocaine (5.0-30.0 mg/kg) on BSR thresholds were assessed using a within-subject crossover design. Threshold was defined as the intensity at which the mouse would respond in 50% of the trials. Threshold levels were significantly lowered below levels of control following cocaine administration with the maximum lowering following a 20.0-mg/kg dose. These findings indicate that cocaine increases the sensitivity of the mouse to BSR, and that BSR thresholds can be determined using rate-independent methods in this species.
Available from: Astrid Stoker
- "The stimulation parameters, data collection, and all test session functions were controlled by a computer. ICSS procedure—The ICSS procedure was described previously for mice (Gill et al. 2004; Stoker et al. 2008) and adapted from a discrete-trial current-intensity threshold procedure originally used in rats (Kornetsky and Esposito 1979; Markou and Koob 1992). "
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ABSTRACT: To assess which nicotinic acetylcholine receptors (nAChRs) are involved in the aversive aspects of nicotine withdrawal, brain reward function and the somatic signs of nicotine withdrawal were assessed in mice that lack α7 and β4 nAChR subunits. Brain reward function was assessed with the intracranial self-stimulation (ICSS) procedure, in which elevations in ICSS thresholds reflect an anhedonic mood state. At 3-6 h of spontaneous nicotine/saline withdrawal, thresholds were elevated in nicotine-withdrawing α7(+/+) and β4(+/+), but not α7(-/-) or β4(-/-), mice compared with saline-withdrawing mice, indicating a delay in the onset of withdrawal in the knockout mice. From 8 to 100 h of withdrawal, thresholds in α7(+/+) and α7(-/-) mice were equally elevated, whereas thresholds in β4(+/+) and β4(-/-) mice returned to baseline levels. Somatic signs were attenuated in nicotine-withdrawing β4(-/-), but not α7(-/-), mice. Administration of a low dose of the nAChR antagonist mecamylamine induced threshold elevations in α7(-/-), but not α7(+/+), mice, whereas the highest dose tested only elevated thresholds in α7(+/+) mice. Mecamylamine-induced threshold elevations were similar in β4(-/-) and β4(+/+) mice. In conclusion, null mutation of the α7 and β4 nAChR subunits resulted in a delayed onset of the anhedonic aspects of the spontaneous nicotine withdrawal syndrome. Previous findings of attenuated somatic signs of nicotine withdrawal in β4(-/-), but not α7(-/-), mice were confirmed in the present study, indicating an important role for β4-containing nAChRs in the somatic signs of nicotine withdrawal. The mecamylamine-precipitated withdrawal data suggest that compensatory adaptations may occur in constitutive α7(-/-) mice or that mecamylamine may interact with other receptors besides nAChRs in these mice. In summary, the present results indicate an important role for α7 and β4-containing nAChRs in the anhedonic or somatic signs of nicotine withdrawal.
Available from: ncbi.nlm.nih.gov
- "Similar to rateintensity measures of ICSS thresholds, administration of drugs of abuse lowers ICSS thresholds in the discrete-trial procedure in rats (Harrison et al., 2002). Most recently, cocaine was shown to lower ICSS thresholds in mice using this discrete-trial current-threshold procedure (Gill et al., 2004). A major advantage of this rate-free threshold procedure is that it is less sensitive than rate-dependent measures to performance-altering effects of pharmacological or genetic manipulations, which may be a concern when testing genetically modified mouse strains in rate-dependent behavioral tasks. "
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ABSTRACT: Deficits in brain reward function during nicotine withdrawal may serve as an important substrate for negative reinforcement that contributes to the persistence of the tobacco habit in human smokers. The ability to assess withdrawal-associated reward deficits in genetically modified mice may facilitate understanding of the neurobiological mechanisms of nicotine dependence. Here, we assessed the effects of nicotine withdrawal on brain reward function in mice, as measured by intracranial self-stimulation (ICSS) thresholds. Male C57BL6 mice were trained in a discrete-trial current-threshold ICSS procedure until stable reward thresholds were obtained. Mice then received experimenter-administered saline or nicotine (2 mg/kg/injection salt; x4 daily) injections for 7 consecutive days, and ICSS thresholds assessed for 3 days after cessation of injections. Thresholds were unaltered in nicotine- and saline-treated mice after cessation of injections, indicating that this treatment regimen was not sufficient to induce withdrawal-associated reward deficits. Next, mice were implanted subcutaneously with osmotic minipumps delivering a constant daily amount of saline or nicotine (24 mg/kg/day; free-base), with pumps surgically removed 13 days later. The nicotinic receptor antagonist mecamylamine (2 mg/kg) elevated ICSS thresholds in nicotine- but not saline-treated mice when administered 8-10 days after pump implantation. Similarly, reward thresholds were elevated in nicotine-treated mice 12-72 h after minipump removal. These data demonstrate that antagonist-precipitated or spontaneous withdrawal from nicotine delivered via osmotic minipumps induced reward deficits in mice. Further, these findings highlight the potential utility of the ICSS procedure for assessing this important affective component of nicotine withdrawal in genetically modified mice.
Available from: Astrid Stoker
- "The ICSS procedure used here was described previously for mice (Gill et al., 2004) and is adapted from the discrete-trial current threshold procedure in rats (Kornetsky and Esposito, 1979; Markou and Koob, 1992). Initially, mice were trained to turn the wheel manipulandum on a fixed-ratio 1 schedule of reinforcement. "
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ABSTRACT: The aversive aspects of nicotine withdrawal are powerful motivational forces contributing to the tobacco smoking habit. We evaluated measures of affective and somatic aspects of nicotine withdrawal in C57BL/6J and BALB/cByJ mice. Nicotine withdrawal was induced by termination of chronic nicotine delivery through osmotic minipumps or precipitated with the nicotinic acetylcholine receptor (nAChR) antagonists mecamylamine or dihydro-beta-erythroidine (DHbetaE). A rate-independent discrete-trial intracranial self-stimulation threshold procedure was used to assess brain reward function. Anxiety-like behavior and sensorimotor gating were assessed in the light-dark box and prepulse inhibition (PPI) tests, respectively. Acoustic startle response and somatic signs of withdrawal were also evaluated. Spontaneous nicotine withdrawal after 14-day exposure to 10-40 mg/kg/day nicotine induced no alterations in anxiety-like behavior, startle reactivity, PPI, or somatic signs in either strain, and no changes in thresholds in C57BL/6J mice. Extended 28-day exposure to 40 mg/kg/day nicotine induced threshold elevations, increased somatic signs, and anxiety-like behavior 24 h post-nicotine in C57BL/6J mice; thresholds returned to baseline levels by day 4 in nicotine-exposed mice. Mecamylamine or DHbetaE administration induced threshold elevations in nicotine-exposed C57BL/6J mice compared with saline-exposed mice. In conclusion, administration of relatively high nicotine doses over prolonged periods of time induces both the affective and somatic aspects of spontaneous nicotine withdrawal in the mouse, while exposure to nicotine for shorter periods of time is sufficient for nAChR antagonist-precipitated nicotine withdrawal. The current study is one of the first to demonstrate reward deficits associated with both spontaneous and nAChR antagonist-precipitated nicotine withdrawal in C57BL/6J mice.
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