Carlezon Jr WA, Chartoff EH. Intracranial self-stimulation (ICSS) in rodents to study the neurobiology of motivation. Nat Prot 2: 2987-2995
Behavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02478, USA.Nature Protocol (Impact Factor: 9.67). 02/2007; 2(11):2987-95. DOI: 10.1038/nprot.2007.441
It has become increasingly important to assess mood states in laboratory animals. Tests that reflect reward, reduced ability to experience reward (anhedonia) and aversion (dysphoria) are in high demand because many psychiatric conditions that are currently intractable in humans (e.g., major depression, bipolar disorder, addiction) are characterized by dysregulated motivation. Intracranial self-stimulation (ICSS) can be utilized in rodents (rats, mice) to understand how pharmacological or molecular manipulations affect the function of brain reward systems. Although many different methodologies are possible, we will describe in this protocol the use of medial forebrain bundle (MFB) stimulation together with the 'curve-shift' variant of analysis. This combination is particularly powerful because it produces a highly reliable behavioral output that enables clear distinctions between the treatment effects on motivation and the treatment effects on the capability to perform the task.
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- "Drugs of abuse usually increase (facilitate) the low rates of ICSS maintained by low frequencies of electrical stimulation. This effect is related to the selectivity of a drug to induce DA release, its reinforcing effects in the drug SA paradigm, and abuse in humans (Carlezon and Chartoff, 2007). It has been proposed that the selectivity to promote DA versus 5-HT release influences the expression of abuse-related effects in the ICSS paradigm (Bauer et al., 2013). "
ABSTRACT: In recent years, studies with animal models of reward, such as the intracranial self-stimulation, self-administration, and conditioned place preference paradigms, have increased our knowledge on the neurochemical substrates of the rewarding effects of 3,4-methylenedioxymetamphetamine (MDMA) in rodents. However, pharmacological and neuroimaging studies with human participants are scarce. Serotonin [5-hydroxytryptamine (5-HT)], dopamine (DA), endocannabinoids, and endogenous opiates are the main neurotransmitter systems involved in the rewarding effects of MDMA in rodents, but other neurotransmitters such as glutamate, acetylcholine, adenosine, and neurotensin are also involved. The most important finding of recent research is the demonstration of differential involvement of specific neurotransmitter receptor subtypes (5-HT2, 5-HT3, DA D1, DA D2, CB1, μ and δ opioid, etc.) and extracellular proteins (DA and 5-HT transporters) in the acquisition, expression, extinction, and reinstatement of MDMA self-administration and conditioned place preference. It is important to extend the research on the effects of different compounds acting on these receptors/transporters in animal models of reward, especially in priming-induced, cue-induced, and stress-induced reinstatement. Increase in knowledge of the neurochemical substrates of the rewarding effects of MDMA may contribute to the design of new pharmacological treatments for individuals who develop MDMA dependence.
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- "Data from the first 10-min response component were discarded as they have been shown to exhibit greater variability than data from subsequent components (Carlezon and Chartoff 2007). Stimulations earned during each 1-min trial of the second and third air/vehicle exposure control components were averaged and used as the baseline for comparison with the fourth treatment component. "
ABSTRACT: Rationale: There is an emerging body of evidence that implicates a crucial role of γ-aminobutyric acid subtype A (GABAA) receptors in modulating the rewarding effects of a number of abused drugs. Modulation of GABAA receptors may therefore represent a novel drug-class independent mechanism for the development of abuse treatment pharmacotherapeutics. Objectives: We tested the hypothesis that the GABAA receptor benzodiazepine-site (BDZ) negative modulator Ro15-4513 would reduce the reward-related effects of three pharmacologically dissimilar drugs; toluene vapor, d-methamphetamine, and diazepam using intracranial self-stimulation (ICSS) in mice. We also examined whether Ro15-4513 attenuated dopamine release produced by d-methamphetamine in an in vivo microdialysis procedure. Results: Ro15-4513 abolished ICSS reward facilitation produced by all three abused drugs at Ro15-4513 doses which had no effect on ICSS when administered alone. In contrast, the BDZ antagonist flumazenil only attenuated the ICSS-facilitating effects of diazepam. Administration of the same dose of Ro15-4513 which abolished drug-facilitated ICSS produced a 58 % decrease in d-methamphetamine-stimulated dopamine in the nucleus accumbens of mice relative to d-methamphetamine alone. Conclusions: These results demonstrate that negative modulation of GABAA receptors can produce profound reductions in reward-related effects of a diverse group of drugs that activate the mesolimbic reward pathway through different mechanisms. These data suggest that pharmacological modulation of GABAA receptors may represent a viable pathway for the development of drug abuse pharmacotherapies.
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- "Surgical procedures for implanting electrodes in mice for ICSS studies were similar to those previously reported (Carlezon and Chartoff, 2007). Mice were anesthetized with isoflurane and received constant isoflurane delivery during surgical procedures. "
ABSTRACT: A growing body of evidence implicates endogenous cannabinoids as modulators of the mesolimbic dopamine system and motivated behavior. Paradoxically, the reinforcing effects of Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, have been difficult to detect in preclinical rodent models. In this study, we investigated the impact of THC and inhibitors of the endocannabinoid hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on operant responding for electrical stimulation of the medial forebrain bundle (intracranial self-stimulation, ICSS), which is known to activate the mesolimbic dopamine system. These drugs were also tested in assays of operant responding for food reinforcement and spontaneous locomotor activity. THC and the MAGL inhibitor JZL184 attenuated operant responding for ICSS and food, and also reduced spontaneous locomotor activity. In contrast, the FAAH inhibitor PF-3845 was largely without effect in these assays. Consistent with previous studies showing that combined inhibition of FAAH and MAGL produces a substantially greater cannabimimetic profile than single enzyme inhibition, the dual FAAH-MAGL inhibitor SA-57 produced a similar magnitude of ICSS depression as that produced by THC. ICSS attenuation by JZL184 was associated with increased brain levels of 2-arachidonoylglycerol (2-AG), while peak effects of SA-57 were associated with increased levels of both N-arachidonoylethanolamine (anandamide; AEA) and 2-AG. The CB1 receptor antagonist rimonabant, but not the CB2 receptor antagonist SR144528, blocked the attenuating effects of THC, JZL184, and SA-57 on ICSS. Thus, THC, MAGL inhibition, and dual FAAH-MAGL inhibition not only reduce ICSS, but also decrease other reinforced and non-reinforced behaviors.
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