Human and animal laboratory studies show that females and males respond differently to drugs and that drug administration during adolescence leads to different behavioral effects than during adulthood. Adult female rats are more sensitive to the behavioral effects of cocaine than adult males, but it is not known if the same effect of sex exists during adolescence. In the present study, sensitivity to the conditioned reward of cocaine was evaluated using a conditioned place preference (CPP) paradigm where adolescent (PND 34) and adult (PND 66) male and female rats were trained and tested for the development of CPP to multiple doses of cocaine. Female rats developed CPP at lower doses than males, regardless of age. In addition, adolescent male and female rats established a CPP at lower doses of cocaine than adult male and female rats, respectively. Thus, both age and sex altered cocaine conditioned reward with the order of sensitivity being adolescent females > adult females > adolescent males > adult males. These data show that adolescents are more sensitive to the conditioned rewarding properties of cocaine than adults and that females respond to lower doses of cocaine compared to males regardless of age.

This study was done to determine whether social and environmental factors alter cocaine reward and proteins implicated in mediating drug reward in rats during early adolescence. On postnatal day (PND) 23, rats were housed under conditions where both social (number of rats per cage) and environmental (availability of toys) factors were manipulated. Socially isolated rats were housed alone impoverished with no toys (II) or enriched with toys (IE). Social rats were housed 2 rats/cage with no toys (SI2) or with toys (SE2), or 3/cage with (SE3) or without (SI3) toys. On PND 43, cocaine conditioned place preference (CPP) sessions began with the post-test done on PND 47. Cocaine CPP was established in response to 5 or 10 mg/kg cocaine in II rats, and CPP was decreased with the addition of cagemates or toys. No CPP was seen to any dose in SI3 or SE3 rats. Enriched housing (SE3) increased dopamine transporter (DAT) protein in the nucleus accumbens compared to II. There also were differential effects of cocaine on tyrosine hydroxylase and DAT depending on housing, with both increased by cocaine in II but not SE3 rats. DARPP-32 was unchanged by housing or cocaine, while phospho-Thr 34 -DARPP-32 was increased by cocaine treatment across conditions. Thus, both social and environmental enrichment decrease cocaine CPP during adolescence and different housing alters proteins that regulate dopaminergic neurotransmission in a manner that may account for the observed differences in cocaine-induced reward.

The mutagenicity of 17 aliphatic epoxides was determined using the specially constructed mutants of Salmonella typhimurium developed by Ames. The activity of these epoxides together with those reported in the literature as mutagens in strains TA100 and TA1535 depended on the degree of substitution around the oxirane ring. Monosubstituted oxiranes were the most potent mutagens in both strains. 1,1-Disubstitution resulted in the complete loss or reduction of mutagenicity, trans-1,2-Disubstituted, and tetrasubstituted oxiranes all lacked mutagenicity, while the cis-1,2-disubstituted oxiranes tested were weakly mutagenic in strain TA100 only. For the monosubstituted compounds the presence of electron-withdrawing substituents increased mutagenicity.

MDMA (ecstasy) is a drug commonly used in adolescence, and many users of MDMA also use other illicit drugs. It is not known whether MDMA during adolescence alters subsequent responses to cocaine differently than in adults. This study examined the effects of MDMA in adolescent and adult rats on cocaine conditioned reward. At the start of these experiments, adolescent rats were at postnatal day (PND) 33 and adult rats at PND 60. Each rat was treated for 7 days with MDMA (2 or 5 mg/kg/day or vehicle) and locomotor activity was measured. Five days later cocaine conditioned place preference (CPP) was begun. Rats were trained for 3 days, in the morning with saline and in the afternoon with 10 mg/kg cocaine in 30 min sessions, and tested on the fourth day. MDMA stimulated activity in both age groups, but with a greater effect in the adult rats. Sensitization to the locomotor-stimulant effects of the lower dose of MDMA occurred in adult rats and in both groups to the higher dose. Cocaine did not produce a CPP in vehicle-treated adolescent rats, but a significant CPP was observed subsequent to treatment with MDMA. In contrast, cocaine-induced CPP was diminished after MDMA in adult rats. These effects were still evident 2 weeks later upon retest. Thus, under the present conditions, MDMA increased cocaine conditioned reward in adolescent and decreased it in adult rats. These findings suggest that exposure to MDMA during this critical developmental period may carry a greater risk than during adulthood and that male adolescents may be particularly vulnerable to the risk of stimulant abuse after use of MDMA.

No abstract

Women constitute half of all smokers and many studies suggest that adult males and females differ in factors that maintain tobacco smoking, yet there is limited information about sex differences in nicotine reward during adolescence. Limited studies suggest that adolescent male rats self-administer more nicotine than adults, suggesting that drug administration during adolescence leads to different behavioral effects than during adulthood. In the present study, male rats developed a significant conditioned place preference (CPP) to lower doses of nicotine than females, regardless of age. In addition, adolescents were more sensitive than adults. In female rats, adolescents exhibited a CPP of greater magnitude than adult females. In males, the magnitude of the CPP did not differ as a function of age, but adolescents exhibited CPP to lower doses than adults. There also were differences in nicotinic acetylcholinergic receptor binding in nucleus accumbens and caudate putamen in response to nicotine across age and sex. These findings suggest that it is necessary to consider sex- and age-specific effects of drugs such as nicotine when developing strategies for improving smoking cessation treatments.

Many factors influence the rewarding effects of drugs such as cocaine. The present study was done to determine whether social and environmental factors alter behavior in adolescent male and female rats. On postnatal day (PND) 23, rats were housed in one of several same-sex conditions. Both social (number of rats per cage) and environmental (availability of toys) factors were manipulated. Socially isolated rats were housed alone (1 rat/cage) in an environment that either was impoverished (with no toys; II)) or enriched (with toys; IE). Standard housing for these studies was social and impoverished, which was 2 rats/cage with no toys (SI2). Other rats were housed 2/cage with toys (SE2), or 3/cage with (SE3) or without (SI3) toys. On PND 37, novelty-induced locomotor activity was measured for 30 minutes. On PND 44-46, locomotor activity in response to an injection of 5 mg/kg cocaine was measured for 60 minutes each day. For male rats, only social conditions altered novelty-induced activity. Males housed in groups of three had the most activity, compared to pair-housed and isolated rats. For females, social and environmental enrichment interacted to alter novelty-induced activity. In contrast to males, isolated females had increased activity, compared to group-housed females. Further, isolated females in impoverished environments had more activity than isolated females in enriched environments and group-housed females in impoverished environments. The effect of environmental enrichment on cocaine-stimulated locomotor activity was altered depending upon the number of rats living in a cage for males. For females, only social conditions altered cocaine-stimulated behavior, with activity increasing with the number of rats in the cage, regardless of environmental enrichment. These data show that social and environmental enrichment differentially alter novelty-induced and cocaine-stimulated locomotor activity in adolescent male and female rats.

A series of 4-alkoxycarbonyl-1,5-diaryl-1,2,3-triazoles were synthesized regioselectively using click chemistry and evaluated at CB1 cannabinoid receptors. The n-propyl ester 11 (Ki = 4.6 nM) and phenyl ester 14 Ki = 11 nM) exhibited the most potent affinity of the series.