Selective Inhibition of Phosphodiesterase 7 Enzymes Reduces Motivation for Nicotine Use through Modulation of Mesolimbic Dopaminergic Transmission.

Approximately 5 million people die from diseases related to nicotine addiction and tobacco use each year. The nicotine-induced increase of corticomesolimbic dopaminergic (DAergic) transmission and hypodopaminergic conditions occurring during abstinence are important for maintaining drug-use habits. We examined the notion of reequilibrating DAergic transmission by inhibiting phosphodiesterase 7 (PDE7), an intracellular enzyme highly expressed in the corticomesolimbic circuitry and responsible for the degradation of cyclic adenosine monophosphate (cAMP), the main second messenger modulated by DA receptor activation.

Andrographis paniculata and Its Main Bioactive Ingredient Andrographolide Decrease Alcohol Drinking and Seeking in Rats Through Activation of Nuclear PPARγ Pathway.

Background And Aims: Andrographis paniculata is an annual herbaceous plant which belongs to the Acanthaceae family. Extracts from this plant have shown hepatoprotective, anti-inflammatory and antidiabetic properties, at least in part, through activation of the nuclear receptor Peroxisome Proliferator-Activated Receptor-gamma (PPAR γ). Recent evidence has demonstrated that activation of PPARγ reduces alcohol drinking and seeking in Marchigian Sardinian (msP) alcohol-preferring rats.

Further evidence for the involvement of the PPARγ system on alcohol intake and sensitivity in rodents.

Rationale: Peroxisome Proliferator Activator receptors (PPARs) are intracellular receptors that function as transcription factors, which regulate specific metabolic and inflammatory processes. PPARs are broadly distributed in the body and are also expressed in the central nervous system, especially in areas involved in addiction-related behavioral responses. Recent studies support a role of PPARs in alcoholism and pioglitazone: a PPARγ agonist used for treatment of type 2 diabetes showed efficacy in reducing alcohol drinking, stress-induced relapse, and alcohol withdrawal syndrome in rats.

Activation of peroxisome proliferator-activated receptor γ reduces alcohol drinking and seeking by modulating multiple mesocorticolimbic regions in rats.

Peroxisome proliferator-activated receptor γ (PPARγ) is an intracellular transcription factor whose signaling activation by the selective agonist pioglitazone reduces alcohol drinking and alcohol-seeking behavior in rats. The present study utilized the two-bottle choice and operant self-administration procedures to investigate neuroanatomical substrates that mediate the effects of PPARγ agonism on alcohol drinking and seeking in msP rats. Bilateral infusions of pioglitazone (0, 5, and 10 μg/μl) in the rostromedial tegmental nucleus (RMTg) decreased voluntary alcohol drinking and alcohol self-administration.

Activation of PPARγ Attenuates the Expression of Physical and Affective Nicotine Withdrawal Symptoms through Mechanisms Involving Amygdala and Hippocampus Neurotransmission.

An isoform of peroxisome proliferator-activated receptors (PPARs), PPARγ, is the receptor for the thiazolidinedione class of anti-diabetic medications including pioglitazone. Neuroanatomical data indicate PPARγ localization in brain areas involved in drug addiction. Preclinical and clinical data have shown that pioglitazone reduces alcohol and opioid self-administration, relapse to drug seeking, and plays a role in emotional responses.

Protection against alcohol-induced neuronal and cognitive damage by the PPARγ receptor agonist pioglitazone.

Binge alcohol drinking has emerged as a typical phenomenon in young people. This pattern of drinking, repeatedly leading to extremely high blood and brain alcohol levels and intoxication is associated with severe risks of neurodegeneration and cognitive damage. Mechanisms involved in excitotoxicity and neuroinflammation are pivotal elements in alcohol-induced neurotoxicity.

Pioglitazone attenuates the opioid withdrawal and vulnerability to relapse to heroin seeking in rodents.

Rationale: Relapse to opioids is often driven by the avoidance of the aversive states of opioid withdrawal. We recently demonstrated that activation of peroxisome proliferator-activated receptor gamma (PPARγ) by pioglitazone reduces the motivation for heroin and attenuates its rewarding properties. However, the role of PPARγ in withdrawal and other forms of relapse to heroin is unknown.

PPARγ activation attenuates opioid consumption and modulates mesolimbic dopamine transmission.

PPARγ is one of the three isoforms identified for the peroxisome proliferator-activated receptors (PPARs) and is the receptor for the thiazolidinedione class of anti-diabetic medications including pioglitazone. PPARγ has been long studied for its role in adipogenesis and glucose metabolism, but the discovery of the localization in ventral tegmental area (VTA) neurons opens new vistas for a potential role in the regulation of reward processing and motivated behavior in drug addiction. Here, we demonstrate that activation of PPARγ by pioglitazone reduces the motivation for heroin and attenuates its rewarding properties.

Analgesic tolerance to morphine is regulated by PPARγ.

Background And Purpose: Opioid drugs are potent analgesics. However, their chronic use leads to the rapid development of tolerance to their analgesic effects and subsequent increase of significant side effects, including drug dependence and addiction. Here, we investigated the role of PPARγ in the development of analgesic tolerance to morphine in mice.

Activation of PPARγ by pioglitazone potentiates the effects of naltrexone on alcohol drinking and relapse in msP rats.

Background: Pioglitazone is a selective peroxisome proliferator-activated receptor γ (PPARγ) agonist used for the treatment of insulin resistance and type 2 diabetes. Previous studies conducted in our laboratory showed that activation of PPARγ by pioglitazone reduces alcohol drinking, stress-induced relapse, and alcohol withdrawal syndrome in rats. Pioglitazone was not able to prevent relapse elicited by alcohol cues.

Activation of nuclear PPARγ receptors by the antidiabetic agent pioglitazone suppresses alcohol drinking and relapse to alcohol seeking.

Background: Pioglitazone and rosiglitazone belong to the class of thiazolidinediones (TZDs). They were first developed as antioxidants and then approved for the clinical treatment of insulin resistance and Type 2 diabetes. TZDs bind with high affinity and activate peroxisome proliferator-activated receptor-gamma (PPARγ) receptors, which in the brain are expressed both in neurons and in glia.

Selection of targeted mutants from a library of randomly mutagenized ES cells.

A method for random relatively unbiased mutagenesis of ES cells with a mutagenic retroviral vector is described. An orderly assembly of mutant ES cells in multi-well plates is generated. 3D pooling of the wells of the assembly allows quick PCR search for insertions in genes of interest.

An inducible and reversible mouse genetic rescue system.

Inducible and reversible regulation of gene expression is a powerful approach for uncovering gene function. We have established a general method to efficiently produce reversible and inducible gene knockout and rescue in mice. In this system, which we named iKO, the target gene can be turned on and off at will by treating the mice with doxycycline.

Large-scale, saturating insertional mutagenesis of the mouse genome.

We describe the construction of a large-scale, orderly assembly of mutant ES cells, generated with retroviral insertions and having mutational coverage in >90% of mouse genes. We also describe a method for isolating ES cell clones with mutations in specific genes of interest from this library. This approach, which combines saturating random mutagenesis with targeted selection of mutations in the genes of interest, was successfully applied to the gene families of G protein-coupled receptors (GPCRs) and nuclear receptors.

Unequal contribution of Akt isoforms in the double-negative to double-positive thymocyte transition.

Pre-TCR signals regulate the transition of the double-negative (DN) 3 thymocytes to the DN4, and subsequently to the double-positive (DP) stage. In this study, we show that pre-TCR signals activate Akt and that pharmacological inhibition of the PI3K/Akt pathway, or combined ablation of Akt1 and Akt2, and to a lesser extent Akt1 and Akt3, interfere with the differentiation of DN3 and the accumulation of DP thymocytes. Combined ablation of Akt1 and Akt2 inhibits the proliferation of DN4 cells, while combined ablation of all Akt isoforms also inhibits the survival of all the DN thymocytes.

Neuromedin U receptor 2-deficient mice display differential responses in sensory perception, stress, and feeding.

Neuromedin U (NMU) is a highly conserved neuropeptide with a variety of physiological functions mediated by two receptors, peripheral NMUR1 and central nervous system NMUR2. Here we report the generation and phenotypic characterization of mice deficient in the central nervous system receptor NMUR2. We show that behavioral effects, such as suppression of food intake, enhanced pain response, and excessive grooming induced by intracerebroventricular NMU administration were abolished in the NMUR2 knockout (KO) mice, establishing a causal role for NMUR2 in mediating NMU's central effects on these behaviors.

The G protein-coupled receptor repertoires of human and mouse.

Diverse members of the G protein-coupled receptor (GPCR) superfamily participate in a variety of physiological functions and are major targets of pharmaceutical drugs. Here we report that the repertoire of GPCRs for endogenous ligands consists of 367 receptors in humans and 392 in mice. Included here are 26 human and 83 mouse GPCRs not previously identified.