Intracranial self-stimulation (ICSS) in rodents to study the neurobiology of motivation

Behavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02478, USA.
Nature Protocol (Impact Factor: 8.36). 02/2007; 2(11):2987-95. DOI: 10.1038/nprot.2007.441
Source: PubMed

ABSTRACT 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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    • "The KOR agonists are well known to induce dysphoria and an anhedonic-like response in humans and mice (Potter et al., 2011; Ranganathan et al., 2012). For these studies, the anhedonia-like effects of sal A, RB-64, or U69593 were tested in C57BL/6J mice using the curve-shift method of ICSS (Carlezon and Chartoff, 2007). The mice responded in a frequency-dependent manner for BSR, as shown by the average baseline rate-frequency curves (Fig. 6A). "
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    ABSTRACT: The hypothesis that functionally selective GPCR agonists may have enhanced therapeutic benefits has revitalized interest for many GPCR targets. In particular, although κ-opioid receptor (KOR) agonists are analgesic with a low risk of dependence and abuse, their utility is limited by a propensity to induce sedation, motor incoordination, hallucinations and dysphoria-like states. Several labs have produced a body of work implying that G-protein biased KOR agonists might be analgesic with fewer side-effects. Although this has been an intriguing hypothesis, suitably KOR selective and G-protein biased agonists have not been available to test this idea. Here we provide data using a G-protein biased agonist RB-64 which suggests that KOR-mediated G protein signaling induces analgesia and aversion, whereas β-arrestin 2 signaling may be associated with motor incoordination. Additionally, unlike unbiased KOR agonists, the G protein-biased ligand RB 64 does not induce sedation and does not have anhedonia-like actions, suggesting that a mechanism other than G protein signaling mediates these effects. Our findings provide the first evidence with a highly selective and G-protein biased tool compound that many, but not all, of the negative side effects of KOR agonists can be minimized by creating G protein biased KOR agonists.
    Journal of Pharmacology and Experimental Therapeutics 10/2014; 352(1). DOI:10.1124/jpet.114.216820 · 3.86 Impact Factor
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    • "In curveshift analysis, these data are then submitted to some form of regression analysis. Figure 6B shows linear regression through the ascending portions of the baseline and test frequency-rate curves, but both linear regression and different nonlinear regression equations have been used to fit ICSS data (Miliaressis et al., 1986; Coulombe and Miliaressis, 1987; Carlezon and Chartoff, 2007). Once the regression is established, it is used to calculate a measure of the lateral position of the curve along the X-axis. "
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    ABSTRACT: Intracranial self-stimulation (ICSS) is a behavioral procedure in which operant responding is maintained by pulses of electrical brain stimulation. In research to study abuse-related drug effects, ICSS relies on electrode placements that target the medial forebrain bundle at the level of the lateral hypothalamus, and experimental sessions manipulate frequency or amplitude of stimulation to engender a wide range of baseline response rates or response probabilities. Under these conditions, drug-induced increases in low rates/probabilities of responding maintained by low frequencies/amplitudes of stimulation are interpreted as an abuse-related effect. Conversely, drug-induced decreases in high rates/probabilities of responding maintained by high frequencies/amplitudes of stimulation can be interpreted as an abuse-limiting effect. Overall abuse potential can be inferred from the relative expression of abuse-related and abuse-limiting effects. The sensitivity and selectivity of ICSS to detect abuse potential of many classes of abused drugs is similar to the sensitivity and selectivity of drug self-administration procedures. Moreover, similar to progressive-ratio drug self-administration procedures, ICSS data can be used to rank the relative abuse potential of different drugs. Strengths of ICSS in comparison with drug self-administration include 1) potential for simultaneous evaluation of both abuse-related and abuse-limiting effects, 2) flexibility for use with various routes of drug administration or drug vehicles, 3) utility for studies in drug-naive subjects as well as in subjects with controlled levels of prior drug exposure, and 4) utility for studies of drug time course. Taken together, these considerations suggest that ICSS can make significant contributions to the practice of abuse potential testing.
    Pharmacological reviews 07/2014; 66(3):869-917. DOI:10.1124/pr.112.007419 · 18.55 Impact Factor
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    • "This method offers quantitative scaling of drug-induced changes in reward (see, (Campbell et al. 1985) which is useful when comparing the effects of different drugs. In other words, the rate-frequency method appears to have the reward selectivity required in psychopharmacological research (Carlezon and Chartoff 2007; Miliaressis et al. 1986; Vlachou and Markou 2011). "
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    ABSTRACT: Rationale Recent animal studies reported that curcumin, the active constituent of Curcuma longa, has several central actions and may attenuate morphine tolerance. Objectives In the present study, we utilized the intracranial self-stimulation (ICSS) paradigm to examine the effects of the commercially available curcuminoid mixture and each one of its components, individually, on brain stimulation reward and on the reward-facilitating effect of morphine. Methods Male Sprague-Dawley rats were implanted with an electrode into the medial forebrain bundle and trained to respond for electrical stimulation using a rate-frequency paradigm. In the first study, rats were injected with graded doses either of the curcuminoid mixture, or curcumin I, or II, or III. In the second study, we examined whether a low dose of the curcuminoid mixture or each individual curcumin analogue composing it could counteract the reward-facilitating effect of morphine. Results At low doses, both the curcuminoid mixture and curcumin I did not affect brain stimulation reward, whereas, higher doses increased ICSS thresholds. Curcumin II and curcumin III did not affect brain stimulation reward at any doses. Subthreshold doses of the curcuminoid mixture and curcumin I inhibited the reward-facilitating effect of morphine. Conclusion Both the curcuminoid mixture and curcumin I lack hedonic properties and moderate the reward-facilitating effect of morphine. Our data suggest that curcumin interferes with brain reward mechanisms responsible for the expression of the acute reinforcing properties of opioids and provide evidence that curcumin may be a promising adjuvant for attenuating morphine's rewarding effects in patients who are under long-term opioid therapy.
    Psychopharmacology 05/2014; 231(23). DOI:10.1007/s00213-014-3603-5 · 3.99 Impact Factor
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