Adolescence is a critical period of vulnerability for the onset of substance abuse. Those who begin drug use in early adolescence show a pattern of heavier lifetime consumption and greater difficulty quitting than those who start as older adolescents or young adults. Epidemiological studies have characterized a progression of drug use from alcohol and tobacco to marijuana and other illicit drugs. Such findings have led to the hypothesis that alcohol and tobacco may serve as 'gateway' drugs that sensitize reward pathways to the action of illicit drugs. We propose to undertake integrative behavioral and neurochemical/neuroanatomical studies in rats to evaluate this hypothesis.
In Specific Aim 1, we will use intravenous self-administration to determine whether there are age and sex differences in the rewarding effects of cocaine and amphetamine. Acquisition tests will be conducted for each drug during early adolescence (postnatal day (P) 28), late adolescence (P38) and adulthood (P90). In separate groups of animals, the effects of acute and chronic administration of drug on locomotor activity will be examined at each age. The brains of these animals will then be processed by in situ hybridization for analysis of drug-induced neuronal activation, as measured by expression of mRNA for the immediate early gene c-fos.
In Specific Aim 2, we will conduct studies to evaluate whether nicotine increases the sensitivity of adolescent and/or adult brain to the actions of amphetamine and cocaine. Self-administration studies will be undertaken to determine whether acute, non-contingent nicotine treatment can increase the reinforcing value of cocaine or amphetamine in adolescents or adults. The effect of chronic, intermittent daily injection of nicotine on subsequent acquisition of cocaine and amphetamine self-administration will also be examined. In parallel studies, the effect of chronic nicotine on psychostimulant-induced locomotor activity and neuronal activation will also be studied in adolescents and adults. Although adolescence is the principal timeframe for initiation of drug use, few studies have evaluated mechanisms of drug action at this developmental timepoint. The combined behavioral and neuroanatomical studies of psychostimulant action that we propose should provide critical understanding of the actions of abused drugs on adolescent brain, and clarify whether these are different or similar to those in adult.
| Dwyer, Jennifer B; Leslie, Frances M (2016) Adolescent Maturation of Dopamine D1 and D2 Receptor Function and Interactions in Rodents. PLoS One 11:e0146966 |
| Mojica, Celina Y; Dao, Jasmin M; Yuan, Menglu et al. (2014) Nicotine modulation of adolescent dopamine receptor signaling and hypothalamic peptide response. Neuropharmacology 77:285-93 |
| Mojica, Celina Y; Belluzzi, James D; Leslie, Frances M (2014) Age-dependent alterations in reward-seeking behavior after brief nicotine exposure. Psychopharmacology (Berl) 231:1763-73 |
| Dao, Jasmin M; McQuown, Susan C; Loughlin, Sandra E et al. (2011) Nicotine alters limbic function in adolescent rat by a 5-HT1A receptor mechanism. Neuropsychopharmacology 36:1319-31 |
| Villégier, Anne-Sophie; Belluzzi, James D; Leslie, Frances M (2011) Serotonergic mechanism underlying tranylcypromine enhancement of nicotine self-administration. Synapse 65:479-89 |
| Lotfipour, Shahrdad; Arnold, Monica M; Hogenkamp, Derk J et al. (2011) The monoamine oxidase (MAO) inhibitor tranylcypromine enhances nicotine self-administration in rats through a mechanism independent of MAO inhibition. Neuropharmacology 61:95-104 |
| Cao, Junran; Belluzzi, James D; Loughlin, Sandra E et al. (2010) Locomotor and stress responses to nicotine differ in adolescent and adult rats. Pharmacol Biochem Behav 96:82-90 |
| Villegier, Anne-Sophie; Gallager, Brittney; Heston, Jon et al. (2010) Age influences the effects of nicotine and monoamine oxidase inhibition on mood-related behaviors in rats. Psychopharmacology (Berl) 208:593-601 |
| Dwyer, Jennifer B; McQuown, Susan C; Leslie, Frances M (2009) The dynamic effects of nicotine on the developing brain. Pharmacol Ther 122:125-39 |
| McQuown, Susan C; Dao, Jasmin M; Belluzzi, James D et al. (2009) Age-dependent effects of low-dose nicotine treatment on cocaine-induced behavioral plasticity in rats. Psychopharmacology (Berl) 207:143-52 |
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