Pharmacological activation of kappa opioid receptors: aversive effects in adolescent and adult male rats

Abstract

Rationale: The dynorphin (DYN)/kappa opioid receptor (KOR) system is involved in the dysphoric properties of drugs of abuse. Given that adolescents show reduced sensitivity to aversive effects of many drugs, alterations in the DYN/KOR system may contribute to the prevalence of drug use during adolescence.

Objectives: The present study was designed to assess dysphoric properties of a selective kappa agonist, U62,066, in adolescent and adult rats using both conditioned taste aversion (CTA) and conditioned place aversion (CPA) paradigms.

Methods: For CTA, water-restricted rats were administered U62,066 following 30 min access to a saccharin solution, with subsequent saccharin consumption used to index aversion. For CPA, animals were allowed access to both compartments of a two-compartment chamber for a 15-min pre- and post-conditioning test. For conditioning, subjects were administered U62,066 prior to confinement to one side of the chamber and saline prior to confinement to the other side for a total of four pairings.

Results: Overall, adolescents displayed reduced sensitivity to the kappa agonist relative to adults. Adults demonstrated taste aversions to the 0.2 and 0.3 mg/kg doses of U62,066, whereas adolescents did not display aversions to any tested doses. Adults demonstrated a place aversion to the 0.1 and 0.2 mg/kg dose of U62,066 when paired with the preferred side of the conditioning chamber. Adolescents did not display aversions to any of the doses tested.

Conclusions: Reduced sensitivity to DYN/KOR system activation during adolescence may be a contributing factor to the age-typical insensitivity to aversive properties of drugs commonly abused by adolescents.

Fig. 1. Conditioned taste aversion

(A) Adolescents (striped bars) and adults (solid bars) consumed similar amounts of saccharin on the conditioning day (B) On the test days, adult rats administered the 0.2 and 0.3 mg/kg doses of U62,066 consumed less saccharin (indicated by asterisks) relative to saline controls, whereas no differences were seen in adolescents (data shown are collapsed across four test days)

Fig. 2. Conditioned place aversion: Percent of time spent on the drug-paired side

No differences between pre- and post-conditioning values were seen among adolescents (left panel), whereas adults (right panel) demonstrated reduced post-test (black bars) relative to pre-test (gray bars) values following conditioning with the 0.1 and 0.2 mg/kg doses of U62,066 (indicated by asterisks)