Background Allopregnanolone (ALLO) is a potent positive modulator of γ-aminobutyric acidA receptors (GABAARs) that affects ethanol withdrawal. Finasteride (FIN), a 5α-reductase inhibitor that blocks the formation of ALLO and other GABAergic neurosteroids, alters ethanol sensitivity. Recently, we found that Withdrawal Seizure-Prone mice from the first genetic replicate (WSP-1) exhibited behavioral tolerance to the anticonvulsant effect of intra-hippocampal ALLO during ethanol withdrawal and that intra-hippocampal FIN significantly increased ethanol withdrawal severity. The purpose of the present study was to determine whether neurosteroid manipulations in the substantia nigra reticulata (SNR) and ventral tegmental area (VTA) produced effects during ethanol withdrawal comparable to those seen with intra-hippocampal ALLO and FIN. Methods Male WSP-1 mice were surgically implanted with bilateral guide cannulae aimed at the SNR or VTA at two weeks prior to ethanol vapor or air exposure for 72 hrs. Initial studies examined the anticonvulsant effect of a single ALLO infusion (0, 100 or 400 ng/side) at a time corresponding to peak withdrawal in the air- and ethanol-exposed mice. Separate studies examined the effect of four FIN infusions (0 or 10 µg/side/day) during the development of physical dependence on the expression of ethanol withdrawal. Results ALLO infusion exerted a potent anticonvulsant effect in ethanol-naïve mice, but a diminished anticonvulsant effect during ethanol withdrawal. Administration of FIN into the SNR exerted a delayed proconvulsant effect in ethanol-naïve mice, whereas infusion into the VTA increased ethanol withdrawal duration. Conclusions Activation of local GABAARs in the SNR and VTA via ALLO infusion is sufficient to exert an anticonvulsant effect in naïve mice and to produce behavioral tolerance to the anticonvulsant effect of ALLO infusion during ethanol withdrawal. Thus, ethanol withdrawal reduced sensitivity of GABAARs to GABAergic neurosteroids in two neuroanatomical substrates within the basal ganglia in WSP-1 male mice.

Purpose Bone metastases are reported in 10% to 12% of patients with neuroendocrine neoplasms (NENs) and can lead to pain and skeletal-related events (SREs), resulting in diminished quality of life and functional status. In other solid tumors with bone metastases, radiation therapy (RT) is an established treatment approach for SREs, yet few data are available in NENs historically considered to be radioresistant. We hypothesize that RT is effective for pain and other SREs in NENs and aimed to delineate any differences in pain palliation and time until progression of pain between different fractionation and dosing schedules of RT. Methods and Materials We retrospectively reviewed 686 records of patients with NENs treated at the institution between 2011 and 2018 and identified 28 (4.1%) patients treated with RT for 61 cases of SREs. The primary endpoint was change in patient reported pain scores after RT. Results All 28 patients experienced bone pain. Nineteen sites were treated with a single fraction (doses of 800-1800 cGy) and 42 sites with fractionated regimens (doses of 900-3750 cGy over 3-15 fractions). In 55 of 61 cases (90%), patients experienced improvement in pain after RT. The median time to recurrence or progression of pain was 3.5 months. Significant differences were found between primary site and change in performance status ( P = .024), sex, and reported magnitude of pain score decrease after RT ( P = .025). There were no differences in the time to the progression of pain, change in performance status, and degree of improvement in pain based on age, chemotherapy received during RT, or radiation site. Outcomes were similar for patients who received single-fraction versus fractionated regimens ( P = .545) and between those receiving palliative versus ablative RT regimens ( P = .812). Conclusions Although the majority of cases in this NEN cohort benefited from RT, additional studies on the use of RT in the treatment of painful bone metastases are warranted.

Trichomonas vaginalis, a sexually transmitted parasitic flagellate of the human urogenital tract, requires the polyamine spermine, which is present in high concentrations in the vagina and the epididymus. We investigated the possibility that these parasites might use spermine or other polyamines as chemical signals in migrating to sites of infection, which in turn would suggest a possible class of chemotherapeutic targets. We tested this possibility with a novel assay method. Log‐phase cells were placed in one of two 2‐ml tubes connected by a glass capillary; the other tube contained a test chemical. Numbers of cells migrating through the capillary into the second chamber were monitored over time by sampling the second tube. Significant migration responses were found to be 0.02 mM for spermine, putrescine, and citrulline. Lesser responses were found to spermidine, arginine and ornithine. Other amino acids did not differ from buffered salt solution controls. Cell behavior and motility were studied by videomicrosopy. A larger percentage of motile cells was observed in the presence of the active polyamines than in controls, where more cells attached to surfaces. These results suggest that this parasite does have chemosensory responses to polyamines specifically, and that the behavioral mechanism may involve a simple kinesis, though the latter possibility needs to be tested further.

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