Effective medications for drug abuse remain a largely unmet goal in biomedical science. Recently, the (+)-enantiomers of naloxone and naltrexone, TLR4 antagonists, have been reported to attenuate preclinical indicators of both opioid and stimulant abuse. To further examine the potential of these compounds as drug-abuse treatments, we extended the previous assessments to include a wider range of doses and procedures. We report the assessment of (+)-naloxone and (+)-naltrexone on the acute dopaminergic effects of cocaine and heroin determined by in vivo microdialysis, on the reinforcing effects of cocaine and the opioid agonist, remifentanil, tested under intravenous self-administration procedures, as well as the subjective effects of cocaine determined by discriminative-stimulus effects in rats. Pretreatments with (+)-naloxone or (+)-naltrexone did not attenuate, and under certain conditions enhanced the stimulation of dopamine levels produced by cocaine or heroin in the nucleus accumbens shell. Furthermore, although an attenuation of either cocaine or remifentanil self-administration was obtained at the highest doses of (+)-naloxone and (+)-naltrexone, those doses also attenuated rates of food-maintained behaviors, indicating a lack of selectivity of TLR4 antagonist effects for behaviors reinforced with drug injections. Drug-discrimination studies failed to demonstrate a significant interaction of (+)-naloxone with subjective effects of cocaine. The present studies demonstrate that under a wide range of doses and experimental conditions, the TLR4 antagonists, (+)-naloxone and (+)-naltrexone, did not specifically block neurochemical or behavioral abuse-related effects of cocaine or opioid agonists.

Recent discoveries have improved our understanding of the physiological and pathological roles of the dopamine transporter (DAT); however, only a few drugs are clinically available for DATimplicated disorders. Among those drugs, modafinil (MOD) and its (R)enantiomer (R-MOD) have been used off-label as therapies for psychostimulant use disorders, but they have shown limited effectiveness in clinical trials. Recent preclinical studies on MOD and R-MOD have led to chemically modified structures aimed toward improving their neurobiological properties that might lead to more effective therapeutics for stimulant use disorders. This study examines three MOD analogues (JJC8-016, JJC8-088, and JJC8-091) with improved DAT affinities compared to their parent compound. These compounds were investigated for their effects on the neurochemistry (brain microdialysis and FSCV) and behavior (ambulatory activity) of male Swiss-Webster mice. Our data indicate that these compounds have dissimilar effects on tonic and phasic dopamine in the nucleus accumbens shell and variability in producing ambulatory activity. These results suggest that small changes in the chemical structure of a DAT inhibitor can cause compounds such as JJC8-088 to produce effects similar to abused psychostimulants like cocaine. In contrast, other compounds like JJC8-091 do not share cocaine-like effects and have a more atypical DAT-inhibitor profile, which may prove to be an advancement in the treatment of psychostimulant use disorders.

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ADP -ammonium dihydrogen phosphate, antiPSA -monoclonal antibodies specific for PSA, APTES -(3 aminopropyl) triethoxysilane, BSF -back surface field, BSA -bovine serum albumin, DNAdeoxyribonucleic acid, EDC -1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, ELISA -Enzyme Linked Immunosorbent Assay, EQE -external quantum efficiency, FET-field effect transistors, MACEmetal assisted chemical etching, , NW -nanowire, PBS -Phosphate Buffered Saline, PC -Prostate cancer, PCR -polymerase chain reaction, pI-Isoelectric point, PSA-prostate specific antigen, SiNW -Silicon nanowire, SiNW-FET -silicon nanowire field effect transistors, SiNW-SC -Silicon nanowire based solar cells, sNHS -N-hydroxysulfosuccinimide, VLS CVD-vapor liquid solid chemical vapor deposition.