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.

Age-dependent differences in morphine-induced taste aversions.

Adolescence is a developmental period of particular importance given the host of neurobiological changes that occur during this stage of development. Drug use and abuse is said to be a function of the balance of its rewarding and aversive effects, and any age-dependent differences in morphine's aversive effects could impact drug intake. The present experiments examined the ability of morphine sulfate (0, 3.2, 10, and 18 mg/kg) to induce taste aversions in adolescent and adult rats under high (20-min fluid access each day; Experiment 1A/B) and low (50% of ad libitum access; Experiment 2A/B) deprivation conditions. In both studies, adolescent and adult rats were given a novel saccharin solution to drink and were subsequently injected with morphine. Independent of the deprivation condition, adults acquired stronger aversions than adolescents and did so at a faster rate. On a subsequent two-bottle aversion test, all morphine-injected subjects drank a significantly lower percentage of saccharin than vehicle-injected controls with adults exhibiting stronger aversions than adolescents. These age-dependent differences in morphine-induced CTAs extend the findings with other drugs of abuse for which adolescents exhibit weaker aversions. The possible basis for and implications of these differences were discussed.

Differential modulation of cocaine's discriminative cue by repeated and variable stress exposure: relation to monoamine transporter levels.

Discriminative stimulus functions of drugs of abuse play an important role in the acquisition, maintenance and reinstatement of drug-taking behavior. The present study tested whether two different schedules of stressor presentation, i.e., repeated and variable, for 10 days, can modify the discriminative stimulus effects of cocaine in male rats trained to discriminate cocaine (10 mg/kg, i.p.) from saline. Dopamine (DAT), serotonin (SERT) and norepinephrine (NET) transporter levels in mesocorticolimbic areas were also measured using western blotting after stress exposure to determine if the relative ratio of these proteins may explain differences in behavior. Rats exposed to both repeated and variable stress displayed shifts in the cocaine dose-response curve but with different patterns of responding. In handled controls, ED(50) values for cocaine-like responding were stable after 10 days of handling compared to baseline. Repeated stress produced a transient left-ward shift in cocaine-like responding, indicating increased sensitivity to the cocaine cue. ED(50) values after variable stress did not differ from baseline, although maximal cocaine-like responding was lower at the two highest doses of cocaine tested at which variably stressed rats exhibited more saline-like responding. Alterations in DAT and NET were found in the Repeated Stress group and DAT and SERT in the Variable Stress group in select brain regions which may be responsible for differences in behavior.

The differential expression of male sexual behavior in the Lewis, Fischer and Sprague-Dawley rat strains.

Several indices of sexual behavior were characterized for male rats of the Lewis (LEW), Sprague-Dawley (SD) and Fischer (F344) strains. Males were permitted access to a receptive female of their own strain for five 50-min sessions every fifth day. LEW males emitted longer latencies (first mount, intromission, ejaculation and post-ejaculatory interval) and lower frequencies (mounts, intromissions, ejaculations, intromission ratio) relative to F344 males, with the SD strain in general, lying intermediate. Following this assessment, males of each strain were randomly assigned to females of their own or another strain to ascertain whether differences were due to differential female receptivity. Although there were no significant differences during this phase indicative of differential receptivity, the sample size may preclude a definitive interpretation of such results. The data were discussed in the context of other behavioral differences between the strains and the possible neurobiological mechanisms underlying these differences.

The antiepileptic primidone impairs male rat sexual behavior.

Many antiepileptic drugs (AEDs) produce sexual impairments. Of commonly prescribed AEDs, primidone produces the greatest impairments. Here we examined the effects of primidone on male rat sexual behavior. Sexually-experienced male rats received administration of either vehicle or primidone. After baseline measures were obtained, the effects of daily primidone treatment on home cage sexual performance were assessed three times over the course of 14 days. Motor activity and sucrose preference were also assessed during this time period. Results indicate that primidone impaired copulation but not sexual motivation. Specifically, animals receiving primidone displayed fewer ejaculations, required more time to achieve an intromission, and displayed fewer intromissions per attempted mount as evidenced by a lower intromission ratio. However, animals treated with primidone also chose a goal box containing a sexually-receptive female in an x-maze as often as animals receiving vehicle. The lower intromission ratio suggests an inability to achieve intromissions perhaps as a result of impaired erectile function. Primidone did not affect motor activity or sucrose consumption, an additional measure of natural reward. Together, these data indicate that primidone impairs male sexual activity and suggest that these impairments result primarily from changes in erectile function and not changes to mechanisms mediating motivation.