Relative potency of the opioid antagonists naloxone and 6-alpha-naloxol to precipitate withdrawal from acute morphine dependence varies with time post-antagonist.

The current study compared the potency of naloxone versus 6-alpha-naloxol to precipitate opioid withdrawal under varying conditions of morphine pretreatment history using suppression of operant responding for food reward as the index of withdrawal. Male Wistar rats trained to respond on a lever for food reward received pretreatment with either Vehicle (Morphine-Naïve), a single subcutaneous (SC) injection of 5.6 mg/kg morphine (Single Morphine), or two morphine injections at 24 h intervals (Repeat Morphine), with varying doses of naloxone or 6-alpha-naloxol injected SC 4 h post-morphine and 5 min prior to the 30 min test session. When responding over the entire 30 min operant session was examined, naloxone was only 5-fold more potent than 6-alpha-naloxol in suppressing operant responding under Morphine Naïve conditions, but this increased to a 65-fold potency difference after Single or Repeat Morphine pretreatment. Examination of the relative potency of these antagonists in the Early Phase of operant testing (5-15 min post-antagonist) revealed an even greater 100-fold potency difference between naloxone and 6-alpha-naloxol, but in the Late Phase of testing (25-35 min post-antagonist), this had declined to a 9-fold potency difference, comparable to the relative potency of naloxone to 6-alpha-naloxol under Morphine-Naïve conditions. The results confirm a differential potency of naloxone to its reduced conjugate 6-alpha-naloxol in vivo, and extend the observation of this phenomenon to an acute (single) pretreatment with a low dose of morphine and an additional sign of opioid withdrawal to those previously used. However, the results also indicate that delay in onset of action of 6-alpha-naloxol at opioid receptors in the central nervous system may contribute significantly to its reduced potency relative to naloxone under certain morphine pretreatment conditions.

Intermittent binge alcohol exposure during the periadolescent period induces spatial working memory deficits in young adult rats.

Human and animal studies suggest adolescence is a period of heightened sensitivity to adverse cognitive sequelae of alcohol exposure. The present study assessed the effects of intermittent binge ethanol intoxication during the periadolescent period of Wistar rats on subsequent performance in a Morris water maze spatial navigation task. On postnatal days 32-56, rats were exposed to ethanol or air 3 days/week via vapor inhalation chambers. Acquisition of spatial navigation was assessed beginning 5 days after the final day of exposure, with 3 days of training in the Morris Water maze (four trials per day spaced at 90-s intertrial intervals [ITIs]). Rats were placed into the water maze at one of four positions along the perimeter, with a different release position to begin each trial. A probe trial assessed retention of platform location on the day after the final set of training trials. Four days after this probe trial, rats entered a working memory phase in which the platform was in a new location each day and a variable ITI of 1, 2, or 4 h was inserted between Trials 1 and 2; Trials 3 and 4 followed at 90-s intervals after Trial 2 on each day. The "savings" in latency to find the platform and distance traveled before finding it from Trial 1 to Trial 2 on each day served as an index of working memory. Ethanol-exposed rats showed similar acquisition of spatial navigation as control rats during training, as well as similar retention of platform location during the probe trial. However, rats exposed to average blood alcohol level (BAL) >200 mg% showed accelerated forgetting, with decreased retention of platform location at the 2-h ITI (P < .05), compared to control rats. Therefore, a 4-week history of intermittent ethanol exposure at BAL in excess of 200 mg% during periadolescence led to a working memory deficit in young adult rats, demonstrated by accelerated forgetting of novel information. These behavioral data are consistent with findings from adolescent human studies, indicating that binge-style alcohol exposure during the periadolescent stage of development is associated with deficits in retention of information.