Oxycodone withdrawal is associated with increased cocaine self-administration and aberrant accumbens glutamate plasticity in rats.

Individuals with opioid use disorder (OUD) frequently use other substances, including cocaine. Opioid withdrawal is associated with increased likelihood of cocaine use, which may represent an attempt to ameliorate opioid withdrawal effects. Clinically, 30% of co-using individuals take opioids and cocaine exclusively in a sequential manner. Preclinical studies evaluating mechanisms of drug use typically study drugs in isolation. However, polysubstance use is a highly prevalent clinical issue and thus, we established a novel preclinical model of sequential oxycodone and cocaine self-administration (SA) whereby rats acquired oxycodone and cocaine SA in an A-B-A-B design. Somatic signs of withdrawal were evaluated at 0, 22, and 24h following oxycodone SA, with the 24h timepoint representing somatic signs immediately following cocaine SA. Preclinically, aberrant glutamate signaling within the nucleus accumbens core (NAcore) occurs following use of cocaine or opioids, whereby medium spiny neurons (MSNs) rest in a potentiated or depotentiated state, respectively. Further, NAcore glial glutamate transport via GLT-1 is downregulated following SA of either drug alone. However, it is not clear if cocaine can exacerbate opioid-induced changes in glutamate signaling. In this study, NAcore GLT-1 protein and glutamate plasticity were measured (via AMPA/NMDA ratio) following SA. Rats acquired SA of both oxycodone and cocaine regardless of sex, and the acute oxycodone-induced increase in somatic signs at 22h was positively correlated with cocaine consumption during the cocaine testing phase. Cocaine use following oxycodone SA downregulated GLT-1 and reduced AMPA/NMDA ratios compared to cocaine use following food SA. Further, oxycodone SA alone was associated with reduced AMPA/NMDA ratio. Together, behavioral signs of oxycodone withdrawal may drive cocaine use and further dysregulate NAcore glutamate signaling.

Current and future therapies to treat impaired awareness of hypoglycemia.

In order to achieve optimal glycemic control, intensive insulin regimes are needed for individuals with Type 1 Diabetes (T1D) and insulin-dependent Type 2 Diabetes (T2D). Unfortunately, intensive glycemic control often results in insulin-induced hypoglycemia. Moreover, recurrent episodes of hypoglycemia result in both the loss of the characteristic warning symptoms associated with hypoglycemia and an attenuated counterregulatory hormone responses. The blunting of warning symptoms is known as impaired awareness of hypoglycemia (IAH). Together, IAH and the loss of the hormonal response is termed hypoglycemia associated autonomic failure (HAAF). IAH is prevalent in up to 25% in people with T1D and up to 10% in people with T2D. IAH and HAAF increase the risk of severe hypoglycemia 6-fold and 25-fold, respectively. To reduce this risk for severe hypoglycemia, multiple different therapeutic approaches are being explored that could improve awareness of hypoglycemia. Current therapies to improve awareness of hypoglycemia include patient education and psychoeducation, the use of novel glycemic control technology, pancreas/islet transplantation, and drug therapy. This review examines both existing therapies and potential therapies that are in pre-clinical testing. Novel treatments that improve awareness of hypoglycemia, via improving the counterregulatory hormone responses or improving hypoglycemic symptom recognition, would also shed light on the possible neurological mechanisms that lead to the development of IAH. To reduce the risk of severe hypoglycemia in people with diabetes, elucidating the mechanism behind IAH, as well as developing targeted therapies is currently an unmet need for those that suffer from IAH.