Despite the high prevalence of adolescent smoking, few studies have examined nicotine sensitivity during this developmental period. In the present study we examined adolescent and adult rats' preference/aversion for a flavor previously paired with nicotine. Paired (nicotine + Kool-Aid) and unpaired (Kool-Aid) solutions were presented in the home cage on alternating nights, with water given during the light phase for six days. A choice test was conducted 24 hr after the last night of conditioning, with both flavors presented simultaneously during the dark cycle. On test day, although the flavor previously paired with nicotine was not preferred at either age, adolescent rats consumed significantly more of the paired flavor than adults. These results suggest that adolescent rats are less sensitive to the aversive properties of nicotine. This finding taken together with adolescents' increased sensitivity to the rewarding properties of nicotine, may result in an increased vulnerability to nicotine dependence.

Adolescents have been hypothesized to exhibit an age-related partial anhedonia that may lead them to seek out natural and drug rewards to compensate for this attenuated hedonic sensitivity. In the present series of experiments, taste reactivity (TR) and 2 bottle choice tests were used to assess hedonic reactions to sucrose. In Exp 1, total positive taste responses to 10% sucrose solution were significantly higher in adolescent than adult rats during the infusion period. In Exp 2, adolescent animals exhibited a concentration-effect shift that was consistent with a greater hedonic sensitivity compared to adults. Conversely, adolescents exhibited fewer negative responses to quinine. Using a shortened infusion period, adolescents in Exp 3 exhibited a trend for greater positive TR than adults in response to 10 and 34% sucrose. Consistent with the TR results of Exp 1–3, adolescents consumed significantly more sucrose solution (ml/kg) than adults, although no significant age difference in sucrose preference rates emerged. The results of the current series of experiments do not support the hypothesis that adolescents exhibit an age-related, partial anhedonia, with adolescent animals, under a number of test circumstances showing greater positive taste reactivity and reduced negative responding.

The purpose of the present experiment is to assess potential differences in nicotine withdrawal in both adolescent and adult rats. Nicotine dependence was induced via osmotic minipump in adolescent rats (releasing 22.2 mg/kg/day on Postnatal Day 28) and adults (release rate of 18.4 mg/kg/day on Postnatal Day 60); differential initial release rates were used across age to compensate for the more rapid weight gain of adolescence. On Day 7 of nicotine exposure, withdrawal was induced via the administration of a nicotinic antagonist, mecamylamine (1.0 mg/kg i.p.), and withdrawal-induced anxiogenesis assessed on the elevated plus maze. On Days 1 and 4 after pump removal, animals were examined for startle responses and prepulse inhibition in an acoustic startle chamber. Adult animals exhibited a nicotine withdrawal-induced increase in anxiety, while adolescents did not. One day following the removal of minipumps, only nicotine dependent adolescent animals exhibited a disruption in prepulse inhibition. Nicotine withdrawal failed to produce an alteration in acoustic startle response in either group. Together these data suggest that ontogenic differences in nicotine withdrawal are dependent on the withdrawal measure examined, with adolescents being less sensitive than adults to anxiety-like symptoms, while being more sensitive to withdrawal-induced cognitive disruption.Despite the overall decrease in adolescent tobacco use that has occurred in the past 10 years, the prevalence of use among teens is still quite high, with 50% of 12 th graders reporting trying smoking and 23% reporting smoking within the last 30 days in 2005 (Johnston, et al

Environmental factors influence a variety of health-related outcomes. In general, being raised in an environment possessing social, sensory, and motor enrichment reduces the rewarding effects of various drugs, thus protecting against abuse vulnerability. However, in the case of methamphetamine (METH), which acts at the vesicular monoamine transporter 2 (VMAT2) to enhance dopamine release from the cytosol, previous evidence suggests that METH reward may not be altered by environmental enrichment. This study examined the influence of an enriched environment on measures of METH reward, METH seeking, and VMAT2 function. Rats were raised from weaning to adulthood in either an enriched environment (presence of social cohorts and novel objects) or an isolated environment (no cohorts or novel objects). Rats in these two conditions were subsequently tested for their acquisition of conditioned place preference (CPP), METH self-administration, maintenance of self-administration at various unit doses of METH (0.001–0.5 mg/kg/infusion), and cue-induced reinstatement. VMAT2 function in striatum from these two groups also was assessed. No significant environment effects were found in CPP or METH self-administration, which paralleled a lack of effect in VMAT2 function between groups. However, cue-induced reinstatement was reduced by environmental enrichment. Together, these results suggest that environmental enrichment does not alter VMAT2 function involved in METH reward. However, the enrichment-induced decrease in cue-induced reinstatement indicates that enrichment may have a beneficial effect against relapse following a period of extinction via a neural mechanism other than striatal VMAT2 function.

Despite the high prevalence of use of methamphetamine (METH), there is no FDA-approved pharmacological treatment available currently for METH addiction. The vesicular monoamine transporter (VMAT2) has been proposed as a novel target to treat METH abuse. GZ-793A, a lobelane analog and selective VMAT2 inhibitor, has been shown previously to decrease METH self-administration specifically when administered via the subcutaneous route in rats. Since oral administration is the preferred clinical route, the present experiments determined if oral administration of GZ-793A would decrease specifically METH self-administration. Experiments 1 and 2 assessed the dose-effect functions of oral administration of GZ-793A (30-240 mg/kg) on intravenous METH self-administration and food-maintained responding, respectively. Experiments 3 and 4 assessed the time-course (20-180 min pretreatment) of oral administration of GZ-793A on METH self-administration and food-maintained responding, respectively. Oral administration of GZ-793A dose-dependently decreased METH self-administration, with the highest dose (240 mg/kg) producing a 85% decrease compared to control baseline. The decrease in METH self-administration produced by GZ-793A (120 mg/kg) lasted at least 180 min. In contrast, GZ-793A failed to alter food-maintained responding at any of the doses or pretreatment intervals tested. The oral effectiveness and the specificity of GZ-793A to decrease methamphetamine self-administration supports the feasibility of developing VMAT2 inhibitors as treatments for METH abuse.