Effect of age on methylphenidate-induced conditioned taste avoidance and related BDNF/TrkB signaling in the insular cortex of the rat.

RATIONALE: Drug use and abuse is thought to be a function of the balance between its rewarding and aversive effects, such that the rewarding effects increase the likelihood of use while the drug's dissociable aversive effects limit it. Adolescents exhibit a shift in this balance toward reward, which may ultimately lead to increased use. Importantly, recent work shows that adolescents are also protected from the aversive effects of many abusable drugs as measured by conditioned taste avoidance (CTA). However, such effects of methylphenidate (MPH, widely prescribed to adolescents with ADHD) have not been characterized. OBJECTIVES: The effect of age on MPH-induced CTA was assessed. In addition, MPH-induced changes in brain-derived neurotrophic factor (BDNF) activity in the insular cortex (IC) and central nucleus of the amygdala (CeA), known to be important to CTA, were examined and related to CTAs in adolescents and adults. METHODS: CTAs induced by MPH (0, 10, 18, and 32 mg/kg) were assessed in adolescent (n = 34) and adult (n = 33) male Sprague Dawley rats. Following MPH CTA, IC and CeA tissue was probed for differences in BDNF and tropomyosin-related kinase receptor-B (TrkB) using Western blots. RESULTS: Blunted expression of MPH CTA was observed in the adolescents versus adults, which correlated with generally attenuated adolescent BDNF/TrkB activity in the IC, but the drug effects ran contrary to the expression of CTA. CONCLUSIONS: Adolescents are protected from the aversive effects of MPH versus adults, but further work is needed to characterize the possible involvement of BDNF/TrkB.

Age-dependent MDPV-induced taste aversions and thermoregulation in adolescent and adult rats.

Adolescent rats are more sensitive to the rewarding and less sensitive to the aversive properties of various drugs of abuse than their adult counterparts. Given a nationwide increase in use of "bath salts," the present experiment employed the conditioned taste aversion procedure to assess the aversive effects of 3,4-methylenedioxypyrovalerone (MDPV; 0, 1.0, 1.8, or 3.2 mg/kg), a common constituent in "bath salts," in adult and adolescent rats. As similar drugs induce thermoregulatory changes in rats, temperature was recorded following MDPV administration to assess if thermoregulatory changes were related to taste aversion conditioning. Both age groups acquired taste aversions, although these aversions were weaker and developed at a slower rate in the adolescent subjects. Adolescents increased and adults decreased body temperature following MDPV administration with no correlation to aversions. The relative insensitivity of adolescents to the aversive effects of MDPV suggests that MDPV may confer an increased risk in this population.

Age differences in (±) 3,4-methylenedioxymethamphetamine (MDMA)-induced conditioned taste aversions and monoaminergic levels.

Preclinical work indicates that adolescent rats appear more sensitive to the rewarding effects and less sensitive to the aversive effects of abused drugs. The present investigation utilized the conditioned taste aversion (CTA) design to measure the relative aversive effects of (±)3,4-methylenedioxymethamphetamine (MDMA; 0, 1.0, 1.8, or 3.2 mg/kg) in adolescent and adult Sprague-Dawley rats. After behavioral testing was complete, monoamine and associated metabolite levels in discrete brain regions were quantified using high-performance liquid chromatography coupled to electrochemical detection (HPLC-ECD) to determine if adolescent animals displayed a different neurochemical profile than did adult animals after being exposed to subcutaneous low doses of MDMA. Adolescent rats displayed less robust MDMA-induced taste aversions than adults during acquisition and on a final two-bottle aversion test. MDMA at these doses had no consistent effect on monoamine levels in either age group, although levels did vary with age. The relative insensitivity of adolescents to MDMA's aversive effects may engender an increased vulnerability to MDMA abuse in this specific population.

Prepubertal Fischer 344 rats display stronger morphine-induced taste avoidance than prepubertal Lewis rats.

The present report asked if the previously reported differences in morphine-induced conditioned taste avoidance between adult F344 and LEW rats (F344 > LEW) are also evident in prepubescence (early adolescence). To assess this possibility, adult (Experiment 1) and prepubertal (Experiment 2) F344 and LEW rats were assessed for their ability to acquire morphine-induced taste avoidance (0, 3.2, 10, or 18 mg/kg) in a modified taste avoidance procedure. In each experiment, rats of both strains were given repeated pairings of saccharin and morphine followed by a final two-bottle avoidance test. Adult and prepubertal F344 subjects displayed a more rapid acquisition of the avoidance response as well as stronger suppression of consumption than their LEW counterparts. These data suggest the strains differ in their sensitivity to the aversive effects of morphine and that this differential sensitivity is evident early in development and is developmentally stable. The basis for these strain differences in morphine-induced avoidance was discussed.

Assessment of the aversive effects of peripheral mu opioid receptor agonism in Fischer 344 and Lewis rats.

The Fischer 344 (F344) and Lewis (LEW) inbred rat strains differ on a host of biochemical, neuroanatomical, immunological and behavioral endpoints. One behavioral difference of interest is their differential reactivity to the aversive effects of morphine as indexed by the conditioned taste aversion preparation (aversions acquired by F344 rats are significantly greater than those acquired by the LEW strain). This differential effect appears to be specific to opioids that work primarily on the mu opioid receptor. Given that morphine works systemically, it is unknown whether these differential effects in F344 and LEW animals are centrally or peripherally mediated. To address this issue, the present study investigated the ability of the peripherally acting mu preferring opioid agonist loperamide to induce differential taste aversions in F344 and LEW animals. Both F344 and LEW animals acquired dose-dependent taste aversions to the loperamide-associated solution with no difference between them. Additionally, control animals initially injected with vehicle during aversion training with loperamide and subsequently conditioned with morphine displayed the typical aversive profile to morphine (F344>LEW). Although the basis for the present data is unknown, their relation to morphine-induced taste aversions and the role of the interaction of stimulus effects of drugs that produce differential abuse liability were discussed.

Naloxone-induced taste aversions in opiate-naïve Lewis and Fischer 344 rat strains.

BACKGROUND: The Lewis (LEW) and Fischer (F344) rat strains appear differentially sensitive to the aversive effects of several used and abused drugs. Naloxone, a mu opioid receptor antagonist that induces aversions in outbred rats but has no abuse potential, was assessed to determine the characteristics of compounds for which the strains differ. METHODS: Opioid-naïve male LEW and F344 rats were given access to saccharin followed by low (Experiment 1) and high (Experiment 2) doses of naloxone every 4th day for five pairings. Aversions were assessed in both one-bottle and two-bottle tests. RESULTS: In Experiment 1, aversions were evident at 10mg/kg (one-bottle) and at 5.6 and 10mg/kg (two-bottle) with no apparent strain difference for either assessment. In Experiment 2, aversions were evident for LEW animals (but not F344) at 18 and 32 mg/kg (one-bottle). LEW animals injected with 32 mg/kg displayed greater aversions than F344 animals receiving the same dose. Both strains displayed aversions at all doses in the two-bottle test with no strain difference. CONCLUSIONS: Naloxone induced aversions that were strain dependent only at specific doses and under the one-bottle testing condition. These results parallel those of several other used and abused drugs but differ dramatically from those seen with morphine in the two strains (F344>LEW). Further assessments utilizing the LEW-F344 model should investigate other drugs to establish the set of compounds for which the strains differ and to characterize the mechanism underlying the observed differences.

Spontaneous withdrawal in opiate-dependent Fischer 344, Lewis and Sprague-Dawley rats.

The Lewis (LEW) and Fischer 344 (F344) inbred rat strains react differentially to acute morphine administration for a variety of behavioral and neurochemical measures. Investigations into effects of chronic morphine are less common, and investigations assessing dependence have been limited to those utilizing antagonist-precipitated withdrawal. The present experiment extended these assessments by examining spontaneous withdrawal in the LEW and F344 strains. In this preparation, males of the LEW, F344 and the outbred Sprague-Dawley (SD) strain were made dependent on morphine. Following this, opiate administration was terminated and animals were examined for spontaneous withdrawal by the acquisition of a withdrawal-associated taste aversion, changes in body weight loss and the display of several behaviors characteristic of opiate withdrawal. Although all morphine-treated subjects decreased body weight and avoided consumption of the withdrawal-associated solution, indicating successful induction of dependence, no difference between the strains emerged in these indices of withdrawal severity. The only strain difference to appear in the behavioral indicators of withdrawal was with diarrhea (LEW>F344). That the strains differ in acute reactivity to opioids, but not in the overall severity of withdrawal, was discussed in relation to the need to examine the relationship between neurochemical and behavioral data in a variety of neural systems and behavioral endpoints.