We have recently shown that upregulation of glutamate transporter 1 (GLT1) in the brain is associated in part with reduction in ethanol intake in alcohol-preferring (P) male rats. In this study, we investigated the effects of a synthetic compound, (R)-(−)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153), known to activate GLT1 on ethanol consumption as well as GLT1 expression and certain signaling pathways in P rats. P rats were given 24-h concurrent access to 15 and 30% ethanol, water and food for 5 weeks. On week 6, P rats received MS-153 at a dose of 50 mg/kg (i.p.) or a vehicle (i.p.) for 5 consecutive days. We also tested the effect of MS-153 on daily sucrose (10%) intake. Our studies revealed a significant decrease in ethanol intake at the dose of 50 mg/kg MS-153 from Day 1 through 14. In addition, MS-153 at dose of 50 mg/kg did not induce any significant effect on sucrose intake. Importantly, we found that MS-153 upregulated the GLT1 level in the nucleus accumbens (NAc) but not in the prefrontal cortex (PFC). In accordance, we found upregulation of nuclear NFkB-65 level in NAc in MS-153-treated group, however, IkBα was downregulated in MS-153-treated group in NAc. We did not find any changes in NFkB-65 and IkBα levels in PFC. Interestingly, we revealed that p-Akt was downregulated in ethanol vehicle treated groups in the NAc; this downregulation was reversed by MS-153 treatment. We did not observe any significant differences in glutamate aspartate transporter (GLAST) expression among all groups. These findings reveal MS-153 as a GLT1 modulator that may have potential as a therapeutic drug for the treatment of alcohol dependence.

Current research to find effective anticancer treatments is being performed on photodynamic therapy (PDT) with increasing attention. PDT is a very promising therapeutic way to combine a photosensitive drug with visible light to manage different intense malignancies. PDT has several benefits, including better safety and lower toxicity in the treatment of malignant tumors over traditional cancer therapy. This reasonably simple approach utilizes three integral elements: a photosensitizer (PS), a source of light, and oxygen. Upon light irradiation of a particular wavelength, the PS generates reactive oxygen species (ROS), beginning a cascade of cellular death transformations. The positive therapeutic impact of PDT may be limited because several factors of this therapy include low solubilities of PSs, restricting their effective administration, blood circulation, and poor tumor specificity. Therefore, utilizing nanocarrier systems that modulate PS pharmacokinetics (PK) and pharmacodynamics (PD) is a promising approach to bypassing these challenges. In the present paper, we review the latest clinical studies and preclinical in vivo studies on the use of PDT and progress made in the use of nanotherapeutics as delivery tools for PSs to improve their cancer cellular uptake and their toxic properties and, therefore, the therapeutic impact of PDT. We also discuss the effects that photoimmunotherapy (PIT) might have on solid tumor therapeutic strategies.

The glutamatergic system has an important role in cocaine-seeking behavior. Studies have reported that chronic exposure to cocaine induces downregulation of glutamate transporter-1 (GLT-1) and cystine/glutamate exchanger (xCT) in the central reward brain regions. Ceftriaxone, a β-lactam antibiotic, restored GLT-1 expression and consequently reduced cue-induced reinstatement of cocaine-seeking behavior. In this study, we investigated the reinstatement to cocaine (20 mg/kg, i.p.) seeking behavior using a conditioned place preference (CPP) paradigm in male alcohol-preferring (P) rats. In addition, we investigated the effects of Ampicillin/Sulbactam (AMP/SUL) (200 mg/kg, i.p.), a β-lactam antibiotic, on cocaine-induced reinstatement. We also investigated the effects of AMP/SUL on the expression of glial glutamate transporters and metabotropic glutamate receptor 1 (mGluR1) in the nucleus accumbens (NAc) core and shell and the dorsomedial prefrontal cortex (dmPFC). We found that AMP/SUL treatment reduced cocaine-triggered reinstatement. This effect was associated with a decrease in locomotor activity. Moreover, GLT-1 and xCT were downregulated in the NAc core and shell, but not in the dmPFC, following cocaine-primed reinstatement. However, cocaine exposure increased the expression of mGluR1 in the NAc core, but not in the NAc shell or dmPFC. Importantly, AMP/SUL treatment normalized GLT-1 and xCT expression in the NAc core and shell; however, the drug normalized mGluR1 expression in the NAc core only. Additionally, AMP/SUL increased the expression of GLT-1 and xCT in the dmPFC as compared to the water naïve group. These findings demonstrated that glial glutamate transporters and mGluR1 in the mesocorticolimbic area could be potential therapeutic targets for the attenuation of reinstatement to cocaine-seeking behavior.

Alcohol consumption with psychostimulants is very common among drug addicts. There is little known about the possible pharmacological interactions between alcohol and psychostimulants. Among most commonly co-abused psychostimulants with alcohol are methamphetamine, cocaine, 3,4-methylenedioxymethamphetaminen, and nicotine. Co-abuse of alcohol with psychostimulants can lead to several neurophysiological dysfunctions such as decrease in brain antioxidant enzymes, disruption of learning and memory processes, cerebral hypo-perfusion, neurotransmitters depletion as well as potentiation of drug seeking behaviour. Moreover, co-abuse of alcohol and psychostimulants can lead to increase in heart rate, blood pressure, myocardial oxygen consumption and cellular stress, and the risk of developing different types of cancer. Co-abuse of alcohol with psychostimulants during pregnancy can lead to fetal brain abnormalities. Further studies are needed to investigate the pharmacokinetics, pharmacodynamics, and neurochemical changes on co-abuse of alcohol and psychostimulants.

Drug addiction remains a prevalent and fatal disease worldwide that carries significant social and economic impacts. Recent reports suggest illicit pregabalin (Lyrica) use may be increasing among youth, however the addictive potential of pregabalin has not been well established. Drug seeking behavior and chronic drug use are associated with deficits in glutamate clearance and activation of postsynaptic glutamatergic receptors. In the current study, we investigated the abuse potential of pregabalin using conditioned place preference (CPP) paradigm. Different doses of pregabalin (30, 60, 90, and 120 mg/kg) were used to assess the seeking behavior in mice. Glutamate homeostasis is maintained by glutamate transporter type-1 (GLT-1), which plays a vital role in clearing the released glutamate from synapses and drug seeking behavior. Therefore, we investigated the role of glutamate in pregabalin-seeking behavior with ceftriaxone (CEF), a potent GLT-1 upregulator. Mice treated with pregabalin 60 and 90 mg/kg doses demonstrated drug seeking-like behavior, which was significantly blocked by CEF pretreatment. These results suggest that pregabalin-induced CPP was successfully modulated by CEF which could serve as a lead compound for developing treatment for pregabalin abuse.