PPARγ Activation Attenuates Opioid Consumption and Modulates Mesolimbic Dopamine Transmission

Guglielmo, Giordano de; Melis, Miriam; Luca, Maria Antonietta De; Kallupi, Marsida; Li, Hong Wu; Niswender, Kevin D.; Giordano, Antonio; Senzacqua, Martina; Somaini, Lorenzo; Cippitelli, Andrea; Gaitanaris, George A.; Demopulos, Gregory; Damadzic, Ruslan; Tapocik, Jenica D.; Heilig, Markus; Ciccocioppo, Roberto

doi:10.1038/npp.2014.268

Cited by 66 publications

(89 citation statements)

References 53 publications

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“…PPARγ is expressed primarily in microglia and PPARγ agonists inhibit the expression of proinflammatory cytokines (Kielian and Drew, 2003). Recent studies show that stimulation of PPARγ reduces heroin self-administration and reinstatement of heroin seeking (de Guglielmo et al, 2016, 2015). …”

Section: Drugs Of Abuse and Glial Cell Activitymentioning

confidence: 99%

“…Interest in PPARγ agonists has grown in many neuroinflammatory disorders due to the expression of PPARγ primarily in microglia and the ability of PPARγ agonists to inhibit the expression of cytokines by monocytes/macrophages and microglia (Kielian and Drew, 2003). In response to the promising preclinical research (de Guglielmo et al, 2016, 2015), researchers sought to test the ability of PIO to alter the abuse potential of opioids in human subjects. One of these trials maintained non-dependent prescription opioid abusers (n=17 completers) on an ascending daily dose of PIO (0 mg, 15 mg, 45 mg) for 2–3 weeks per dose.…”

Section: Drugs Of Abuse and Glial Cell Activitymentioning

confidence: 99%

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Glial and neuroinflammatory targets for treating substance use disorders

Bachtell

Jones

Heinzerling

et al. 2017

Drug and Alcohol Dependence

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Background The plenary session at the 2016 Behavior, Biology and Chemistry: Translational Research in Addiction Conference focused on glia as potential players in the development, persistence and treatment of substance use disorders. Glia partake in various functions that are important for healthy brain activity. Drugs of abuse alter glial cell activity producing several perturbations in brain function that are thought to contribute to behavioral changes associated with substance use disorders. Consequently, drug-induced changes in glia-driven processes in the brain represent potential targets for pharmacotherapeutics treating substance use disorders. Methods Four speakers presented preclinical and clinical research illustrating the effects that glial modulators have on abuse-related behavioral effects of psychostimulants and opioids. This review highlights some of these findings and expands its focus to include other research focused on drug-induced glia abnormalities and glia-focused treatment approaches in substance use disorders. Results Preclinical findings show that drugs of abuse induce neuroinflammatory signals and disrupt glutamate homeostasis through their interaction with microglia and astrocytes. Preclinical and clinical studies testing the effects of glial modulators show general effectiveness in reducing behaviors associated with substance use disorders. Conclusions The contribution of drug-induced glial activity continues to emerge as an intriguing target for substance use disorder treatments. Clinical investigations of glial modulators have yielded promising results on substance use measures and indicate that they are generally safe and well-tolerated. However, results have not been entirely positive and more questions remain for continued exploration in the development and testing of glial-directed treatments for substance use disorders.

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Section: Drugs Of Abuse and Glial Cell Activitymentioning

confidence: 99%

Section: Drugs Of Abuse and Glial Cell Activitymentioning

confidence: 99%

Glial and neuroinflammatory targets for treating substance use disorders

Bachtell

Jones

Heinzerling

et al. 2017

Drug and Alcohol Dependence

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“…PPARγ agonists, like PIO, inhibit the expression of cytokines by monocytes/macrophages and microglia (Kielian and Drew, 2003). Preclinical research has also shown that PIO attenuates drug-induced dopamine release in the nucleus accumbens, which is an important system in the development and maintenance of addiction (Di Chiara and Bassareo, 2007; Diana, 2011; de Guglielmo et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

Pioglitazone, a PPARγ agonist, reduces nicotine craving in humans, with marginal effects on abuse potential

Jones

Comer

Metz

et al. 2017

Pharmacology Biochemistry and Behavior

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Possibly through their actions upon glia, peroxisome proliferator-activated receptor agonists (PPAR) have been shown to alter the abuse potential of addictive drugs in several preclinical models. The current study extends this research into the human laboratory as the first clinical study into the effects of the PPAR gamma agonist, pioglitazone, on the abuse potential of nicotine. Heavy smokers were recruited for this 3-week study. Upon admission, participants were randomized to either active (45 mg, n = 14) or placebo (0 mg, n = 13) PIO maintenance conditions for the duration of the study. After 5–7 days of stabilization on a 7 mg nicotine patch, participants began laboratory testing. On the 1st–4th test days, participants could self-administer cigarettes or receive money by making verbal choices for either option. On the 5th day, participants were administered 10 puffs of their usual brand of cigarette in the morning and later chose between smoking and money by making finger presses on a computer mouse in a progressive ratio self-administration task. Later on the 5th day participants also underwent a smoking cue exposure session. The 8th–11th test days were identical to the 1st–4th test days with the exception that during one of the test weeks de-nicotinized cigarettes were available, and during the other nicotinized cigarettes were available. Nicotinized cigarettes were always administered on the 5th and 12th days. On some measures PIO increased indicators of abuse potential, though this effect was typically not statistically significant. However, PIO did significantly reduce measures of craving.

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“…For instance, PPARα and PPARγ are expressed in addiction-related brain areas, such as the lateral hypothalamus and the ventral tegmental area (VTA), from which dopamine (DA) release into the NAc can be modulated (Moreno et al, 2004; Sarruf et al, 2009; Melis et al, 2010; de Guglielmo et al, 2015b). In fact, electrophysiological experiments have shown that the activation of PPARα by fibrates decreased the ability of nicotine to enhance the firing rate of VTA DA neurons.…”

Section: Peroxisome Proliferating Activator Receptors (Ppars)mentioning

confidence: 99%

Emerging targets for addiction neuropharmacology

Ubaldi

Cannella

Ciccocioppo

2016

Progress in Brain Research

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Drug abuse represents a considerable burden of disease and has enormous economic impacts on societies. Over the years, few medications have been developed for clinical use. Their utilization is endowed with several limitations, including partial efficacy or significant side effects. On the other hand, the successful advancement of these compounds provides an important proof-of-concept for the feasibility of drug development programs in addiction. In recent years, a wealth of information has been generated on the psychological mechanisms, genetic or epigenetic predisposing factors, and neurobiological adaptations induced by drug consumption that interact with each other to contribute to disease progression. It is now clear that addiction develops through phases, from initial recreational use to excessive consumption and compulsive drug seeking, with a shift from positive to negative reinforcement driving motivated behaviors. A greater understanding of these mechanisms has opened new vistas in drug development programs. Researchers’ attention has been shifted from investigation of classical targets associated with reward to biological substrates responsible for negative reinforcement, impulse loss of control and maladaptive mechanisms resulting from protracted drug use. From this research, several new biological targets for the development of innovative therapies have started to emerge. The present article offers an overview of targets currently under scrutiny for the development of new medications for addiction. This work is not exhaustive but rather it provides a few examples of how this research has advanced in recent years by virtue of studies carried out in our laboratory.

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PPARγ Activation Attenuates Opioid Consumption and Modulates Mesolimbic Dopamine Transmission

Cited by 66 publications

References 53 publications

Glial and neuroinflammatory targets for treating substance use disorders

Glial and neuroinflammatory targets for treating substance use disorders

Pioglitazone, a PPARγ agonist, reduces nicotine craving in humans, with marginal effects on abuse potential

Emerging targets for addiction neuropharmacology

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