The effect of sazetidine-A and other nicotinic ligands on nicotine controlled goal-tracking in female and male rats.

Nicotine is the primary addictive component of tobacco products and its complex stimulus effects are readily discriminated by human and non-human animals. Previous research with rodents directly investigating the nature of the nicotine stimulus has been limited to males. The current study began to address this significant gap in the literature by training female and male rats to discriminate 0.4 mg/kg nicotine from saline in the discriminated goal-tracking task. In this task, access to sucrose was intermittently available on nicotine session. On interspersed saline session, sucrose was not available. Both sexes acquired the discrimination as evidenced by increased head entries into sucrose receptacle (goal-tracking) evoked by nicotine; the nicotine generalization curves were also similar between females and males. The pharmacological profile of the nicotine stimulus was assessed using substitution and targeted combination tests with the following ligands: sazetidine-A, PHA-543613, PNU-120596, bupropion, nornicotine, and cytisine. For females and males, nornicotine fully substituted for the nicotine stimulus, whereas sazetidine-A, bupropion, and cytisine all evoked partial substitution. Female and male rats responded in a similar manner to interaction tests where a combination of 1 mg/kg of sazetidine-A plus nicotine or nornicotine shifted the nicotine dose-effect curve to the left. The combination of sazetidine-A plus bupropion or cytisine failed to do so. These findings begin to fill a significant gap the in scientific literature by studying the nature of the nicotine stimulus and response to therapeutically interesting combinations using a model that includes both sexes.

Developmental alterations in locomotor and anxiety-like behavior as a function of D1 and D2 mRNA expression.

The majority of smokers start smoking in adolescence, beginning a potentially lifelong struggle with nicotine use and abuse. In rodent models of the effects of nicotine, the drug has been shown to elicit both locomotor and anxiety-like behavioral effects. Research suggests that these behavioral effects may be due in part to dopamine (DA) receptors D1 and D2 in the mesolimbic system, specifically the nucleus accumbens (NAc). We examined early adolescent (P28), late adolescent (P45), and adult (P80) male Long-Evans rats in the elevated plus maze (EPM) under normal conditions and the open field (OF) post-nicotine in order to test locomotor and anxiety-like behavior. These behavioral findings were then correlated with expression of DA D1 and D2 mRNA levels as determined via in situ hybridization. Nicotine-induced locomotor behavior was found to be significantly different between age groups. After a single injection of nicotine, early adolescents exhibited increases in locomotor behavior, whereas both late adolescents and adults responded with decreases in locomotor behavior. In addition, it was found that among, early adolescents, open arm and center time in the EPM were negatively correlated with D2 mRNA expression. In contrast, among adults, distance traveled in the center and center time in the OF were negatively correlated with D2 mRNA expression. This study suggests that DA D2 receptors play a role in anxiety-like behavior and that the relationship between observed anxiety-like behaviors and D2 receptor expression changes through the lifespan.

Persisting changes in basolateral amygdala mRNAs after chronic ethanol consumption.

Adolescent alcohol use is common and evidence suggests that early use may lead to an increased risk of later dependence. Persisting neuroadaptions in the amygdala as a result of chronic alcohol use have been associated with negative emotional states that may lead to increased alcohol intake. This study assessed the long-term impact of ethanol consumption on levels of several basolateral amygdala mRNAs in rats that consumed ethanol in adolescence or adulthood. Male Long-Evans rats were allowed restricted access to ethanol or water during adolescence (P28, n=11, controls=11) or adulthood (P80, n=8, controls=10) for 18 days. After a sixty day abstinent period, the brain was removed and sections containing the basolateral amygdala were taken. In situ hybridization was performed for GABA(A) alpha(1), glutamic acid decarboxylase (GAD(67)), corticotropin releasing factor (CRF), and N-methyl-D-aspartate (NMDA) NR2A mRNAs. A significant decrease was observed in GABA(A) alpha(1), GAD(67), and CRF, but not NR2A, mRNAs in adult rats that consumed ethanol in comparison to controls. No significant changes were seen in adolescent consumers of ethanol for any of the probes tested. A separate analysis for each probe in the piriform cortex ascertained that the changes after ethanol consumption were specific to the basolateral amygdala. These results indicate that chronic ethanol consumption induces age-dependent alterations in basolateral amygdala neurochemistry.