Opioid overdose deaths have been on the rise in the United States since 1999. Naloxone is a competitive opioid antagonist that rapidly reverses opioid overdose. The implementation of naloxone access laws and development of naloxone formulations that can be administered by laypersons have coincided with changes in the landscape of naloxone availability in the United States. Using data from IQVIA's National Prescription Audit we present the number of naloxone prescriptions dispensed quarterly from 2011 through the second quarter of 2017. The data demonstrate that nationwide naloxone dispensing increased nearly eight-fold from the fourth quarter of 2015 to the second quarter of 2017. Narcan was the most commonly prescribed naloxone formulation as of the second quarter of 2017, accounting for 68% of prescriptions during that quarter followed by Evzio (20%). There was considerable variability in the extent to which states experienced increases in naloxone dispensing, which may represent a general state-specific response to the opioid crisis, rather than direct association with opioid overdose death rates in a particular state. Although naloxone access laws continue to increase the amount of naloxone dispensed, cost remains a concern in terms of wide distribution of the life-saving medication.

Drug use typically begins during adolescence, which is a period of ongoing neurobiological development that may confer heightened vulnerability to develop drug dependence. Previously, our lab has shown that amphetamine (AMPH)-induced deficits in a medial prefrontal cortex (mPFC)-sensitive working memory task are greater in rats exposed to the drug during adolescence compared to adulthood. Here, we examine potential age-dependent effects of AMPH exposure on behavioral flexibility tasks that are sensitive to disruptions in mPFC and orbitofrontal cortex (OFC) function. Male Sprague-Dawley rats were injected (i.p.) with saline or 3 mg/kg AMPH every other day between postnatal days (PNDs) 27–45 and PNDs 85–103. Starting around PND 125, rats were tested in an attentional set-shifting task and a subset of those was then tested in an operant strategy shifting task. Following completion of the operant task, rats were challenged with 3 mg/kg AMPH and monitored in open field chambers. Our results demonstrate that AMPH-exposed rats were faster to acquire simple and compound discriminations, but were impaired during the first stimulus-reward reversal when compared to controls. In the operant strategy shifting task, adolescent-exposed rats shifted more rapidly between strategies and completed reversals faster than adult-exposed and control rats, respectively. The final AMPH challenge revealed evidence for sensitization in drug pre-exposed rats, with adult-exposed animals exhibiting the most significant effects. Together, these results suggest that AMPH induces long-lasting changes in behavioral flexibility that are at least partially dependent on age of exposure and may be due to adaptations in OFC function.

Amphetamine (AMPH) exposure leads to changes in behavior and dopamine receptor function in the prefrontal cortex (PFC). Since dopamine plays an important role in regulating GABAergic transmission in the PFC, we investigated if AMPH exposure induces long-lasting changes in dopamine’s ability to modulate inhibitory transmission in the PFC as well as whether the effects of AMPH differed depending on the age of exposure. Male Sprague–Dawley rats were given saline or 3 mg/kg AMPH (i.p.) repeatedly during adolescence or adulthood and following a withdrawal period of up to 5 weeks (Experiment 1) or up to 14 weeks (Experiment 2), they were sacrificed for in vitro whole-cell recordings in layer V/VI of the medial PFC. We found that in brain slices from either adolescent- or adult-exposed rats, there was an attenuation of dopamine-induced increases in inhibitory synaptic currents in pyramidal cells. These effects did not depend on age of exposure, were mediated at least partially by a reduced sensitivity of D1 receptors in AMPH-treated rats, and were associated with an enhanced behavioral response to the drug in a separate group of rats given an AMPH challenge following the longest withdrawal period. Together, these data reveal a prolonged effect of AMPH exposure on medial PFC function that persisted for up to 14 weeks in adolescent-exposed animals. These long-lasting neurophysiological changes may be a contributing mechanism to the behavioral consequences that have been observed in those with a history of amphetamine abuse.

Repeated stress impacts emotion, and can induce mood and anxiety disorders. These disorders are characterized by imbalance of emotional responses. The amygdala is fundamental in expression of emotion, and is hyperactive in many patients with mood or anxiety disorders. Stress also leads to hyperactivity of the amygdala in humans. In rodent studies, repeated stress causes hyperactivity of the amygdala, and increases fear conditioning behavior that is mediated by the basolateral amygdala (BLA). Calcium-activated potassium (KCa) channels regulate BLA neuronal activity, and evidence suggests reduced small conductance KCa (SK) channel function in male rats exposed to repeated stress. Pharmacological enhancement of SK channels reverses the BLA neuronal hyperexcitability caused by repeated stress. However, it is not known if pharmacological targeting of SK channels can repair the effects of repeated stress on amygdala-dependent behaviors. The purpose of this study was to test whether enhancement of SK channel function reverses the effects of repeated restraint on BLA-dependent auditory fear conditioning. We found that repeated restraint stress increased the expression of cued conditioned fear in male rats. However, 1-EBIO (1 or 10 mg/kg) or CyPPA (5 mg/kg) administered 30 minutes prior to testing of fear expression brought conditioned freezing to control levels, with little impact on fear expression in control handled rats. These results demonstrate that enhancement of SK channel function can reduce the abnormalities of BLA-dependent fear memory caused by repeated stress. Furthermore, this indicates that pharmacological targeting of SK channels may provide a novel target for alleviation of psychiatric symptoms associated with amygdala hyperactivity.

Repeated exposure to psychostimulant drugs is associated with long-lasting changes in cognition, particularly in behavioral tasks that are sensitive to prefrontal cortex function. Adolescents may be especially vulnerable to these drug-induced cognitive changes because of the widespread adaptations in brain anatomy and function that are characteristic of normal development during this period. Here, we used a differential reinforcement of low rates of responding task in rats to determine if amphetamine exposure during adolescence would alter behavioral inhibition in adulthood. Between postnatal day 27 and 45, rats received every other day injections of saline or amphetamine (3 mg/kg). At postnatal day 125, rats were trained progressively through a series of four reinforcement schedules (DRL 5, 10, 15 and 30 sec) that required them to withhold responding for the appropriate amount of time before a lever press was reinforced. Relative to controls, amphetamine-treated rats displayed transient deficits in behavioral inhibition (i.e., decreases in efficiency ratio) that were only evident at DRL 5. In addition, they had increased responding during non-reinforced periods, which suggested increased perseveration and propensity to attribute incentive salience to reward-paired cues. Following challenge injections with amphetamine (0.25–1 mg/kg, i.p.), which were given 10 min before the start of DRL 30 test sessions, both groups exhibited dose-dependent decreases in efficiency. These results suggest that amphetamine-induced alterations in incentive-motivation and perseveration are more robust and longer-lasting than its effects on impulse control.