Behavioral and Neurochemical Vulnerability During Adolescence in Mice: Studies with Nicotine

Abstract

People are very likely to start psychoactive drug use during adolescence, an earlier onset being associated with a higher risk of developing addiction later in life. In experiment I, Pre-(postnatal day (pnd) 23-35), Mid-(pnd 36-48), or Post-(pnd 49-61) adolescent mice underwent a restricted-drinking period (2 h/day for 12 days), one bottle containing water and the other containing nicotine (10 mg/l) or water. After this period, Mid-adolescents showed prominent exploration and reduced anxiety in the plus-maze. This ontogenetic profile was dampened by nicotine consumption. After 2 months, these mice were tested in a novel environment (30 min/day for 3 days). Locomotor-habituation profiles were specifically disrupted by nicotine consumption during Mid-adolescence, suggesting this age as a critical period. In experiment II, Mid-adolescent (pnd 35-44) and adult (pnd 470) mice were pretreated with nicotine (0, 0.03, 0.10, 0.30 mg/kg/day for 10 days). Acute nicotine administration had opposite effects on anxiety in adolescents and adults. At 2 months after pretreatment, we measured levels of AMPA GluR2/3 subunits, thought to be involved in the control of addictive behaviors. Nicotine exposure during Mid-adolescence dose-dependently downregulated these subunits in the striatum and hippocampus, but comparable exposure during adulthood had either opposite or no effects. NMDA NR2A/B subunits were affected by nicotine, but without agerelated differences. The present data identified a nicotine-vulnerable age window, characterized by long-term disruption of locomotor habituation and downregulation of AMPA receptors. These findings support neurobiological vulnerability to drugs in adolescent humans.

Combined Exposure to Nicotine and Ethanol in Adolescent Mice Differentially Affects Anxiety Levels during Exposure, Short-Term, and Long-Term Withdrawal

“…Although we found a trend toward anxiolytic effects of nicotine during adolescent exposure, this failed to reach statistical significance. Previous findings Combined exposure to nicotine and ethanol Y Abreu-Villaça et al in adolescent mice indicate that a lower dose of oral nicotine elicits an anxiogenic response (Adriani et al, 2004). However, our results seem to corroborate recent findings describing that adolescent nicotine does not alter the anxiety state in rats (Marco et al, 2006).…”

“…Our current results also indicate that ethanol reduces anxiety during adolescence, reinforcing the hypothesis that anxiety could be a critical factor in the etiology of alcohol drinking (Colombo et al, 1995) and extending the period of susceptibility to include adolescence, when alcohol use typically begins. Nicotine exposure has been described as both anxiogenic and anxiolytic (Adriani et al, 2004;Brioni et al, 1993;Cheeta et al, 2001;Elliott et al, 2004;Marco et al, 2006;Ouagazzal et al, 1999;Slawecki et al, 2003). Although we found a trend toward anxiolytic effects of nicotine during adolescent exposure, this failed to reach statistical significance.…”

“…C57BL/6 mice were chosen because prior reports demonstrate that adult and periadolescent mice from this strain consume nicotine in the concentration used in the present study. In fact, oral nicotine has also been shown to be effective in eliciting behavioral (Adriani et al, 2002(Adriani et al, , 2004Gaddnas et al, 2001) and neurochemical alterations, including nicotinic receptors upregulation (Nuutinen et al, 2005;Sparks and Pauly, 1999), altered monoamine levels, and metabolism (Gaddnas et al, 2000;Tammimaki et al, 2006;Vihavainen et al, 2006) as well as altered expression of genes implicated in synaptic plasticity induced by drugs of abuse (Marttila et al, 2006) and in Alzheimer's disease (Gutala et al, 2006) in this and other mouse strains. This strain of mice is known to present particular features, such as higher voluntary ethanol consumption (Crawley et al, 1997), which should be taken into consideration in studies that involve the administration of this substance, even though the bases underlying these strain-specific characteristics remain poorly understood (Crabbe et al, 1999).…”

“…In accordance with the aforementioned differences between adolescent and adult human smokers, these conflicting patterns of response seem to depend on the age (adolescence vs adulthood) (Elliott et al, 2004;Smith et al, 2006). In addition, the regimen of administration, nicotine dose, sex, species/strain, and the method of assessing anxiety may also play a role (Adriani et al, 2004;Balerio et al, 2006;Cheeta et al, 2001;Elliott et al, 2004;Marco et al, 2006;Slawecki et al, 2003;Smith et al, 2006).…”

Protracted ‘Pro-Addictive’ Phenotype Produced in Mice by Pre-Adolescent Phenylpropanolamine

“…For each experiment, pups from three different litters were weaned on postnatal day (PND) 21 and housed in same-sex pairs in brown, clear standard polyethylene cages (15 cm wide  23 cm long  16 cm high) with woodchip bedding, under a regular 12-h light cycle (lights on 0700 hours). Between PND 21 and 30, a time corresponding to preadolescence in rodents (Adriani et al, 2004;Cirulli and Laviola, 2000;Spear and Brake, 1983), pups were administered, once daily, intraperitoneal (i.p.) injection of either saline vehicle (vol ¼ 0.01 ml/g) or 5, 10, and 40 mg/kg PPA.…”