Nicotine-induced conditioned place preference in adolescent and adult rats

Abstract

About 1 million American adolescents start smoking every year. Adolescents may be unusually sensitive to certain consequences of nicotine, demonstrating, for instance, significantly higher rates of dependence than adults at the same level of nicotine use. To explore whether adolescents may be more sensitive to rewarding properties of nicotine than adults, the present study used an animal model to assess the rewarding effects of a low nicotine dose (0.6 mg/kg) in a conditioned place preference (CPP) paradigm. Locomotor activity during conditioning and testing was also evaluated. Nicotine was observed to induce place preference conditioning in adolescent Sprague–Dawley rats, whereas the training dose of 0.6 mg/kg failed to produce convincing place preference in their adult counterparts. Age differences were also apparent in terms of nicotine influences on motor activity, with adults being more sensitive to nicotine-suppressant effects and only adolescents showing an emergence of nicotine-stimulatory effects upon repeated exposures. An increased predisposition to stimulatory nicotine effects during adolescence may contribute to age-specific rewarding properties of the drug as revealed using the CPP paradigm in this experiment. Increased sensitivity to stimulatory and rewarding effects during adolescence could potentially contribute to the high rate of nicotine use and dependence among human adolescents.

Introduction

The rate of smoking among American adolescents has grown since 1992 [1]. About 1 million adolescents start smoking every year [2], and 28–36% of teenagers are current smokers [3]. This increased rate of nicotine use has been also accompanied by a decrease in the age of smoking initiation [1]. Given that adolescent smoking is a strong predictor of extensive smoking and nicotine dependence in adulthood [4], [5], [6], [7], early initiation of smoking is of particular concern.

There are some pieces of evidence that human adolescents may be extremely sensitive to certain effects of nicotine. In spite of relatively short smoking histories, a high percent of adolescent smokers can be considered dependent on nicotine [8]. Furthermore, adolescents demonstrate significantly higher rates of dependence than adults at the same (relatively low) level of nicotine use [9]. To a large extent, the attractiveness of nicotine at this age may be based on its rewarding or reinforcing properties.

A number of studies have shown that nicotine stimulates dopamine (DA)-secreting cells projecting from the ventral tegmental area to limbic structures such as the nucleus accumbens and prefrontal cortex (PFC; see Ref. [10] for references and review). Stimulation of DA projections to the nucleus accumbens has been implicated in both the locomotor-stimulant effects of nicotine and its rewarding properties [11], [12], [13]. These mesolimbic and mesocortical brain regions and their DA projections undergo substantial remodeling during the adolescence period (for review and references, see Ref. [14]). Among the brain regions undergoing extensive changes during adolescence in humans [15], nonhuman primates [16], and rats [17] is the PFC. For instance, DA input to PFC reaches its peak during adolescence in nonhuman primates [18], [19]. In the same way, increased DA fiber density in PFC [20] and pronounced increases in DA concentrations in the frontal pole [21] are evident during adolescence in rats. Developmental overproduction followed by pruning of DA receptors in mesolimbic and striatal brain regions has been reported in both human and rodent adolescents [22], [23], [24].

Similarities found between human adolescents and adolescents of other mammalian species in terms of these neural changes, as well as developmental history and age-related behavioral and hormonal characteristics, provide a background for further elaboration of animal models (for references and review, see Ref. [14]). Many age-specific neurobehavioral alterations seen in human adolescents are also observed in adolescent rats from postnatal day (P) 30 to P42 (see Ref. [14]), making them a useful experimental model for the study of adolescent responsiveness and sensitivity to the rewarding effects of nicotine.

Conditioned place preference (CPP), a widely used behavioral paradigm to measure drug reward in laboratory animals, has been successfully employed in adolescent animals (e.g. [25], [26]). This paradigm permits the testing of animals in a drug-free state, allows assessment of locomotor activity, and does not require extended periods of training [27]. Attempts to assess the rewarding properties of nicotine employing the CPP paradigm have yielded contradictory results, since both nicotine-induced place preferences [28], [29], [30] and aversions [31], as well as no significant place conditioning with nicotine [32], have been reported in adult rats. Experimental design seems to play a major role in eliciting different results: nicotine has been found to produce CPP predominantly when using a so-called ‘biased design,’ i.e. where the drug is paired with an initially nonpreferred compartment (for references and review, see Ref. [33]). Effects of nicotine in the conditioned CPP paradigm also seem to be dose-dependent and biphasic. Low to moderate doses (0.6–0.8 mg/kg) have been reported to produce CPP [28], [29], [30], [34], [35], whereas higher doses (1.2 mg/kg and above) result in conditioned place aversions [30].

The main objective of the present study was to assess the rewarding properties of a low nicotine dose in adolescent and adult male and female rats using a biased CPP design. Given that the rewarding efficacy of a drug is often correlated with its ability to elicit locomotor stimulation [36], locomotor activity during conditioning and testing was also assessed.