Long‐term, low‐level adolescent nicotine exposure produces dose‐dependent changes in cocaine sensitivity and reward in adult mice

Abstract

Cigarette smoking by adolescents is a strong predictor of future drug use, abuse, and dependence. While this "gateway drug effect" is assumed to be related to psychosocial factors, data from our laboratory suggests that adolescent nicotine use may permanently disrupt reward systems through changes in dopamine receptor function. Behavioral pharmacological methods known to be indirectly (motor activity) and directly (conditioned-place-preference) related to drug reinforcement were used to examine changes in cocaine sensitivity. Testing was performed on adult mice that were exposed to nicotine (0.3, 1.0, and 3.0 mg/kg, SC, M-F, b.i.d.) or saline during adolescence (postnatal days 25-57). Prior to testing, subjects had a 28 day drug-free, time-off period. After acclimation to the testing apparatus, the locomotor effects (30 min, 30 cm traveled) of cocaine (5, 10, and 20 mg/kg, IP) were measured daily; cocaine tests were preceded and followed by saline control tests. Following the acute dose-response curve, mice received saline followed by 5 days of 20.0 mg/kg cocaine. Thereafter, mice underwent condition-place-preference testing. A pre-test was performed to determine compartment preference (i.e., no injection, 20 min test). Cocaine (10 mg/kg, IP) was paired with the subjects non-preferred side and saline with the other. Conditioning sessions were conducted for 8 days with the order of drug/saline injections counter-balanced across subjects. A drug-free, post-test occurred on the day following the final conditioning session. A dose-dependent relationship between adolescent nicotine exposure and cocaine reward was noted in the adult mice across both test conditions. Subjects exposed to nicotine showed an increased response to cocaine's motor activating effects and a decreased response to cocaine's rewarding effects. A follow-up study was undertaken to evaluate dopamine D1, D2, and D3 receptor function in adult mice exposed to the highest dose of nicotine from the first study. While both interesting and revealing, the results of motor activity tests with dopamine agonist only approached significance. Further research will be required to more fully examine the mechanism of action for the observed changes in cocaine reward. In summary, this is the first study to demonstrate a dose-response relationship between adolescent nicotine exposure and changes in cocaine reward and sensitivity during adulthood.

Interactive effects of ethanol and nicotine on learning in C57BL/6J mice depend on both dose and duration of treatment

“…In addition, smokers are at higher risk for alcohol dependence than non-smokers (John et al 2003), and decreased smoking is associated with better outcomes in alcohol abstinence (Friend and Pagiano 2005). Although studies have shown that nicotine interacts with other drugs such as cocaine in modulating reward pathways (Kelley and Rowan 2004) and that cocaine can reverse locomotor deficits in nicotine-withdrawn mice (Vihavainen et al 2006), quitting cocaine use is not associated with increased smoking (Patkar et al 2006). Furthermore, the nicotine patch does not produce tolerance to the positive effects of cocaine or caffeine (Sobel et al 2004).…”

Differential sensitivity to the effects of nicotine and bupropion in adolescent and adult male OF1 mice during social interaction tests

“…These studies have detected that a differential sensitivity to the administration of some drugs exists according to whether the subject is adolescent or adult Cirulli and Laviola, 2000;Markwiese et al, 1998;Spear, 2000]. These differences have been related to the neuroanatomical and neurochemical alterations that occur during adolescence [Kelley and Rowan, 2004;Spear, 2000].…”

Nicotine pretreatment reduced cocaine-induced CPP and its reinstatement in a sex- and dose-related manner in adult C57BL/6J mice

“…This period of life is a very sensitive age in which the negative affective state associated with nicotine withdrawal is reduced while the rewarding action of nicotine is enhanced compared to adults (Carcoba et al, 2014;Dickson et al, 2014;Dickson et al, 2011;Hutchison and Riley, 2008;Lee et al, 2015;McQuown et al, 2009;Natividad et al, 2012;Natividad et al, 2010;Natividad et al, 2013;O'Dell et al, 2004;O'Dell et al, 2006;O'Dell et al, 2007;Shram et al, 2008;Torres et al, 2008;Wilmouth and Spear, 2004), making adolescents a vulnerable target to nicotine use and abuse as well as for use of other addictive drugs during adulthood. Consistent with this notion, previous studies have shown that nicotine exposure during adolescence can prime the use and abuse of cocaine, alcohol, and other addictive substances (Bechtholt and Mark, 2002;DiFranza and Guerrera, 1990;Horger et al, 1992;Hutchison and Riley, 2008;Kandel and Kandel, 2015;Kandel and Kandel, 2014;Kelley and Rowan, 2004;Kouri et al, 2001;Levine et al, 2011;Li et al, 2014;McQuown et al, 2007;McQuown et al, 2009;Meliska et al, 1995;Natividad et al, 2010;Rinker et al, 2011;Rosenberg, 2014;Schindler et al, 2012;Schneider et al, 2012). There is also evidence showing that about 90% of regular smokers start using tobacco at an early age, and that early onset smoking carries a major risk for the development of addiction to other drugs of abuse (Rimm et al, 1995).…”

“…Additionally, pretreatment with nicotine (0.32 mg/kg) produced a leftward shift in the cocaine's dose-response curve in Rhesus monkeys (Mello and Newman, 2011). Together, these findings suggest that nicotine may serve as a gateway drug to facilitate the rewarding and reinforcing actions of cocaine [but see, (Kelley and Middaugh, 1999;Kelley and Rowan, 2004)]. …”

“…There is also evidence showing that about 90% of regular smokers start using tobacco at an early age, and that early onset smoking carries a major risk for the development of addiction to other drugs of abuse (Rimm et al, 1995). Indeed, previous studies have shown that nicotine exposure during adolescence period alter the aversive (Hutchison and Riley, 2008) and rewarding (Kelley and Rowan, 2004;Schochet et al, 2004) effects of cocaine. Although an earlier study reported that prior nicotine treatment only enhanced the rewarding action of cocaine in adolescents but not adult rats (McQuown et al, 2009;Mojica et al, 2014), limited information is available on the impact of nicotine exposure during adulthood on cocaine reward, extinction and reinstatement in mice.…”