No abstract

Thyrotropin releasing hormone (TRH) is released from the median eminence in response to neural stimuli evoked by different physiologic conditions (i.e. cold stress or suckling). The paraventricular nucleus (PVN) synthesizes pro-TRH and responds to negative thyroid hormone feedback. With the aim of determining if TRH biosynthesis is regulated in coordination with its release, we quantified TRH mRNA levels in PVN and in preoptic area-anterior hypothalamus (POA-AH) of rats sacrificed at different times during cold (0.5, 1,2 or 6 h) or suckling (15, 30 and 60 min) stimulus; TRH-like immunoreactivity (TRH-LI) in medial basal hypothalamus (MBH) and in POA-AH as well as corticosterone, triiodothyronine and prolactin levels in serum were also measured. Increases of serum hormones were observed in both paradigms as has been reported. MBH TRH-LI content decreased during suckling by 33% (p < 0.01) after 1 h, but did not change after cold stimulation. At short stimulation times, PVN TRH mRNA levels were 85% (30 min of suckling) and 97% (1 h in the cold) higher than their respective controls, decreasing to normal after 1-2 h. In the POA-AH, another TRH synthesizing region not involved in TRH hypophysiotropic function, a similar transient enhancement of TRH mRNA (146%) was observed only in cold stimulated animals after 30 min, consistent with its suggested role in thermogenesis. These results show a fast and transient response of TRH mRNA in PVN evoked by a neural stimulus.

Background New pharmacotherapies to treat Alcohol Use Disorders (AUD) are needed. Given the complex nature of AUD, there likely exist multiple novel drug targets. We, and others, have shown that the tetracycline drugs, minocycline and doxycycline, reduced ethanol drinking in mice. To test the hypothesis that suppression of high ethanol consumption is a general property of tetracyclines, we screened several derivatives for anti-drinking activity using the Drinking-In-the-Dark (DID) paradigm. Active drugs were studied further using the dose-response relationship. Methods Adult female and male C57BL/6J mice were singly housed and the DID paradigm was performed using 20% ethanol over a 4-day period. Mice were administered a tetracycline or its vehicle 20 h prior to drinking. Water and ethanol consumption was measured daily. Body weight was measured at the start of drug injections and after the final day of the experiment. Blood was collected for ethanol content measurement immediately following the final bout of drinking. Results Seven tetracyclines were tested at a 50 mg/kg dose. Only minocycline and tigecycline significantly reduced ethanol drinking, and doxycycline showed a strong effect-size trend towards reduced drinking. Subsequent studies with these three drugs revealed a dose-dependent decrease in ethanol consumption for both female and male mice, with sex differences in efficacy. Minocycline and doxycycline reduced water intake at higher doses, although to a lesser degree than their effects on ethanol drinking. Tigecycline did not negatively affect water intake. The rank order of potency for reduction in ethanol consumption was minocycline > doxycycline > tigecycline, indicating efficacy was not strictly related to their partition-coefficients (LogP) or distribution constants (LogD). Conclusions Due to its effectiveness in reducing high ethanol consumption coupled without an effect on water intake, tigecycline was found to be the most promising lead tetracycline compound for further study toward the development of a new pharmacotherapy for the treatment of AUD.