Methcathinone (MCAT) is a monoamine releaser and parent compound to a new class of designer drugs that includes the synthetic cathinones mephedrone and flephedrone. Using MCAT and a series of para-substituted (or 4-substituted) MCAT analogs, it has been previously shown that expression of abuserelated behavioral effects in rats correlates both with the volume of the para substituent and in vitro neurochemical selectivity to promote monoamine release via the dopamine (DA) versus serotonin (5-HT) transporters in rat brain synaptosomes. The present study used in vivo microdialysis to determine the relationship between these previous measures and the in vivo neurochemical selectivity of these compounds to alter nucleus accumbens (NAc) DA and 5-HT levels. Male Sprague-Dawley rats were implanted with bilateral guide cannulae targeting the NAc. MCAT and five para-substituted analogs (4-F, 4-Cl, 4-Br, 4-CH 3, and 4-OCH 3 ) produced dose-and time-dependent increases in NAc DA and/or 5-HT levels. Selectivity was determined as the dose required to increase peak 5-HT levels by 250% divided by the dose required to increase peak DA levels by 250%. This measure of in vivo neurochemical selectivity varied across compounds and correlated with 1) in vivo expression of abuse-related behavioral effects (r 5 0.89, P 5 0.02); 2) in vitro selectivity to promote monoamine release via DA and 5-HT transporters (r 5 0.95, P , 0.01); and 3) molecular volume of the para substituent (r 5 20.85, P 5 0.03). These results support a relationship between these molecular, neurochemical, and behavioral measures and support a role for molecular structure as a determinant of abuse-related neurochemical and behavioral effects of MCAT analogs.

Identification of molecular mechanisms responsible for brain metastatic breast cancer (BMBC) is imperative to develop novel therapies. However, current understanding of the molecular circuitry that governs BMBC dissemination remains fragmentary. Heparanase (HPSE) is the only functional mammalian endoglycosidase whose activity correlates with cancer metastasis, angiogenesis, and the reduced post-operative survival of cancer patients, making it an active target for anti-cancer therapeutics. We hypothesized that HER2/EGFR activation promotes heparanase function in human BMBC. To address this, we examined heparanase content, activity, and intracellular trafficking in a HER2/EGFR - expressing BMBC model system and show that HPSE is present, functional, and correlates with HER2 status. Further, we demonstrated that EGF induced nucleolar translocation of heparanase in these cells in a dose and time-dependent manner upon activation of HER2/EGFR. Knockdowns of HER2/EGFR by siRNA abolished EGF-induced heparanase nucleolar translocalization. It was also noted that nucleolar heparanase modulates DNA topoisomerase I (Topo I), an enzyme which is highly present in nucleoli, essential for DNA replication and transcription in a variety of tumors, and inhibited by heparan sulfate. Evidence is provided that heparanase can regulate Topo I activity which subsequently affects BMBC cell proliferation. Finally, we demonstrated that nucleolar presence of heparanase with Topo I co-localization is detected only in HER2 overexpressing BMBC patient specimens. Altogether, these findings support the notion that heparanase is a critical downstream target of HER2 mechanisms driving BMBC, and potentially relevant for BMBC therapeutic interventions.

Repeated exposure to mixed-action DAT≈SERT substrates such as mephedrone can result in increased abuse potential due to sustained expression of DAT-mediated abuse-related effects and tolerance to SERT-mediated abuse-limiting effects.

3,4-methylenedioxymethamphetamine (MDMA) is a substrate for the dopamine (DA), norepinephrine and serotonin (5HT) transporters that produces greater pharmacological effects on certain endpoints in females than males in both clinical and rodent preclinical studies. To evaluate potential for sex differences in abuse-related MDMA effects, the present study compared MDMA effects on intracranial self-stimulation (ICSS) and on in vivo microdialysis measurements of DA or 5HT in the nucleus accumbens (NAc) in female and male Sprague-Dawley rats. For ICSS studies, electrodes were implanted in the medial forebrain bundle and rats trained to press for electrical stimulation over a range of frequencies (56–158 Hz, 0.05 log increments) under a fixed-ratio 1 schedule, and the potency (0.32–3.2 mg/kg, 10 min pretreatment) and time course (3.2. mg/kg, 10–180 min pretreatment) of MDMA effects were determined. For in vivo microdialysis, rats were implanted with bilateral guide cannulae targeting the NAc, and the time course of MDMA effects (1.0–3.2 mg/kg, 0–180 min) on DA and 5HT was determined. MDMA produced qualitatively similar effects in both sexes on ICSS (both increases in low ICSS rates maintained by low brain-stimulation frequencies and decreases in high ICSS rates maintained by high brain-stimulation frequencies) and microdialysis (increases in both DA and 5HT). The duration and peak levels of both abuse-related ICSS facilitation and increases in NAc DA were longer in females. MDMA was also more potent to increase 5HT in females. These results provide evidence for heightened sensitivity of females to abuse-related behavioral and neurochemical effects of MDMA in rats.