Search

Antagonistic allosteric A2AR-D2R receptor-receptor interactions in heteroreceptor complexes counteract cocaine self-administration and cocaine seeking in rats as seen in biochemical and behavioral experiments. It was shown that the human A2AR transmembrane five (TM5) was part of the interface of the human A2AR-D2R receptor heteromer. In the current paper, the rat A2AR synthetic TM5 (synthTM5) peptide disrupts the A2AR-D2R heteroreceptor complex in HEK293 cells as shown by the bioluminescence resonance energy transfer method. Rat A2AR synthTM5 peptide, microinjected into the nucleus accumbens, produced a complete counteraction of the inhibitory effects of the A2AR agonist CGS21680 on cocaine self-administration. It was linked to a disappearance of the accumbal A2AR-D2R heteroreceptor complexes and the A2AR agonist induced inhibition of D2R recognition using proximity ligation assay and biochemical binding techniques. However, possible effects of the A2AR synthTM5 peptide on accumbal A2AR-D3R and A2AR-D4R heteroreceptor complexes remain to be excluded. Evidence is provided that accumbal A2AR-D2R-like heteroreceptor complexes with their antagonistic receptor-receptor interactions can be major targets for treatment of cocaine use disorder.

HIV infection and drugs of abuse induce oxidative stress and redox imbalance, which cause neurodegeneration. The mechanisms by which HIV infection and cocaine consumption affect astrocyte energy metabolism, and how this leads to neurodegenerative dysfunction, remain poorly understood. Presently, we investigated how oxidative injury causes the depletion of energy resources and glutathione synthetase (GSS), which in turn activates 5' AMP-activated protein kinase (AMPK), glycolytic enzymes, and mitochondrial biogenesis, finally resulting in nuclear factor erythroid (NRF) transcription in astrocytes. Both human primary astrocytes incubated with HIV-1 Tat protein in vitro and HIV-inducible Tat (iTat) mice exposed to cocaine showed decreased levels of GSS and increased superoxide dismutase (SOD) levels. These changes, in turn, significantly activated AMPK and raised the concentrations of several glycolytic enzymes, along with oxidative phosphorylation, the mitochondrial biogenesis of peroxisome proliferator-activated receptor-γ coactivator (PGC-1α) and mitochondrial transcription factor (TFAM), and Nrf1 and Nrf2 gene transcription and protein expression. Moreover, neurons exposed to HIV-1Tat/cocaine-conditioned media showed reductions in dendritic formation, spine density, and neuroplasticity compared with control neurons. These results suggest that redox inhibition of GSS altered AMPK activation and mitochondrial biogenesis to influence Nrf transcription. These processes are important components of the astrocyte signaling network regulating brain energy metabolism in HIV-positive cocaine users. In conclusion, HIV-1 Tat alters redox inhibition, thus increasing glycolytic metabolic profiles and mitochondrial biogenesis, leading to Nrf transcription, and ultimately impacting astrocyte energy resource and metabolism. Cocaine exacerbated these effects, leading to a worsening of neurodegeneration. [ABSTRACT FROM AUTHOR]

Behavioral sensitization to psychostimulants hyperlocomotor effect is a useful model of addiction and craving. Particularly, cocaine sensitization in rats enhanced synaptic plasticity within the hippocampus, an important brain region for the associative learning processes underlying drug addiction. Nitric oxide (NO) is a neurotransmitter involved in both, hippocampal synaptic plasticity and cocaine sensitization. It has been previously demonstrated a key role of NOS-1/NO/sGC/cGMP signaling pathway in the development of cocaine sensitization and in the associated enhancement of hippocampal synaptic plasticity. The aim of the present investigation was to determine whether NOS-1 inhibition after development of cocaine sensitization was able to reverse it, and to characterize the involvement of the hippocampus in this phenomenon. Male Wistar rats were administered only with cocaine (15 mg/kg/day i.p.) for 5 days. Then, animals received 7-nitroindazole (NOS-1 inhibitor) either systemically for the next 5 days or a single intra-hippocampal administration. Development of sensitization and its expression after withdrawal were tested, as well as threshold for long-term potentiation in hippocampus, NOS-1, and CREB protein levels and gene expression. The results showed that NOS-1 protein levels and gene expression were increased only in sensitized animals as well as CREB gene expression. NOS-1 inhibition after sensitization reversed behavioral expression and the highest level of hippocampal synaptic plasticity. In conclusion, NO signaling within the hippocampus is critical for the development and expression of cocaine sensitization. Therefore, NOS-1 inhibition or NO signaling pathways interferences during short-term withdrawal after repeated cocaine administration may represent plausible pharmacological targets to prevent or reduce susceptibility to relapse. [ABSTRACT FROM AUTHOR]

The current study was performed to establish the actions of nanomolar concentrations of cocaine, not blocking the dopamine transporter, on dopamine D2 receptor (D2R)-sigma 1 receptor (δ1R) heteroreceptor complexes and the D2R protomer recognition, signaling and internalization in cellular models. We report the existence of D2R-δ1R heteroreceptor complexes in subcortical limbic areas as well as the dorsal striatum, with different distribution patterns using the in situ proximity ligation assay. Also, through BRET, these heteromers were demonstrated in HEK293 cells. Furthermore, saturation binding assay demonstrated that in membrane preparations of HEK293 cells coexpressing D2R and δ1R, cocaine (1 nM) significantly increased the D2R Bmax values over cells singly expressing D2R. CREB reporter luc-gene assay indicated that coexpressed δ1R significantly reduced the potency of the D2R-like agonist quinpirole to inhibit via D2R activation the forskolin induced increase of the CREB signal. In contrast, the addition of 100 nM cocaine was found to markedly increase the quinpirole potency to inhibit the forskolin-induced increase of the CREB signal in the D2R-δ1R cells. These events were associated with a marked reduction of cocaine-induced internalization of D2R protomers in D2R-δ1R heteromer-containing cells vs D2R singly expressing cells as studied by means of confocal analysis of D2R-δ1R trafficking and internalization. Overall, the formation of D2R-δ1R heteromers enhanced the ability of cocaine to increase the D2R protomer function associated with a marked reduction of its internalization. The existence of D2R-δ1R heteromers opens up a new understanding of the acute actions of cocaine. [ABSTRACT FROM AUTHOR]

Two efflux transporters, ATP-binding cassettes B1 (ABCB1) and G2 (ABCG2), are highly expressed in the endothelial cells of the brain, where they regulate the bioavailability and distribution of several endogenous and xenobiotic compounds. However, whether ABCB1 or ABCG2 has any link with drug dependence, drug withdrawal effects, or the incidence of adverse effects in drug abuser is not known. In this study, we determined the effects of voluntary ethanol consumption following repeated exposure to cocaine or vehicle on the relative mRNA and protein expression of Abcg2/ABCG2 and Abcb1/ABCB1 in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) of male alcohol-preferring (P) rats. Male P rats were allowed free choice access to ethanol (15 and 30% v/v) and water for 5 weeks to establish baseline drinking behavior. The following week, rats were either injected with 20 mg/kg i.p. of cocaine or saline, once a day, for 7 days. The relative mRNA and protein expression of Abcb1/ABCB1 and Abcg2/ABCG2 in the NAc and mPFC were significantly decreased in ethanol-saline- and ethanol-cocaine-exposed rats compared to control rats that received neither ethanol nor cocaine. Thus, prolonged exposure to commonly abused drugs, ethanol and cocaine, alters the expression of Abcb1/ABCB1 and Abcg2/ABCG2 mRNA and protein levels in brain areas that play a role in drug dependence. [ABSTRACT FROM AUTHOR]

Substance use disorders (SUDs) are highly prevalent. SUDs involve vicious cycles of binges followed by occasional periods of abstinence with recurrent relapses despite treatment and adverse medical and psychosocial consequences. There is convincing evidence that early and adult stressful life events are risks factors for the development of addiction and serve as cues that trigger relapses. Nevertheless, the fact that not all individuals who face traumatic events develop addiction to licit or illicit drugs suggests the existence of individual and/or familial resilient factors that protect these mentally healthy individuals. Here, I give a brief overview of the epigenetic bases of responses to stressful events and of epigenetic changes associated with the administration of drugs of abuse. I also discuss the psychobiology of resilience and alterations in epigenetic markers that have been observed in models of resilience. Finally, I suggest the possibility that treatment of addiction should involve cognitive and pharmacological approaches that enhance resilience in at risk individuals. Similar approaches should also be used with patients who have already succumbed to the nefarious effects of addictive substances. [ABSTRACT FROM AUTHOR]