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NEUROPHARMACOLOGY
9-Tetrahydrocannabinol in Adolescent and Adult RatsDepartments of Pharmacology and Toxicology (J.L.W., M.M.O., M.E.T.) and Psychology (J.L.W., M.J.W.), Virginia Commonwealth University, Richmond, Virginia
Received May 21, 2006; accepted December 14, 2006.
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9-tetrahydrocannabinol (9-THC) differed in adolescent and adult rats. Following initial testing with 9-THC in adolescent [postnatal day (PN)29] and adult (>PN60) rats of both sexes, we injected rats twice daily with 10 mg/kg 9-THC or vehicle for 9.5 days. Subsequently, rats were again injected with their initial dose of 9-THC and tested. In all rats, 9-THC produced dose-dependent locomotor suppression, antinociception, hypothermia and catalepsy. Some age-dependent differences in potency and efficacy were noted. Although 9-THC dose-effect functions were more similar across age after repeated exposure, subchronic dosing produced greater change in the hypothermic and locomotor effects of 9-THC in adolescents, but less change in its antinociceptive effects. These results suggest that the effects of initial exposure to 9-THC may not be entirely predictive of the effects of repeated exposure. Despite similarities in pharmacological effects of 9-THC after repeated use, adolescents and adults may exhibit differences in the pattern of transition from use to abuse.
). Besides the paucity of controlled studies in this area, however, any long-term marijuana effects are potentially confounded with the fact that human users are self-selected. Hence, much of what is known about the acute and long-term effects of marijuana and other cannabinoids on the developing brain derives from preclinical research with immature animals.
Like humans, rodents and other mammals undergo physical and behavioral changes around the time of puberty, albeit the duration of these changes is much shorter for rats than for humans. Importantly, characteristic patterns of adolescent behavior, such as increased risk-taking and increased social interaction with peers that have been observed cross-species occur in the rat from approximately postnatal day (PN) 28 to 42 (PN28–PN42) (Spear, 2000). Concomitant with these behavioral changes are substantial alterations in the central nervous system, including the endocannabinoid system.
In the rat, brain cannabinoid (CB)1 receptors in the brain exhibit a progressive increase in number, but not in affinity, during the preweanling period (i.e., before day 21) and early adolescence (female peak at PN30 and male peak at PN40), with receptor pruning and a decline to adult levels during later adolescence (Rodríguez de Fonseca et al., 1993; McLaughlin et al., 1994; Belue et al., 1995). By PN60, adult levels of CB1 receptors are achieved (Belue et al., 1995). Accompanying these changes in receptor number throughout development are increases in levels of the endogenous cannabinoid anandamide and N-arachidonoyl-phosphatidyleth-anolamine (an anandamide precursor) (Berrendero et al., 1999). Most CB1 receptors present during development are distributed similarly to adult receptors (e.g., high levels in striatum, cerebellum, and cortex) (Romero et al., 1997; Berrendero et al., 1998). Although developmental studies examining receptor distributions in human brain are rare, one such study reported a pattern of development of CB1 receptors in fetal brains that was similar to that seen in rodents: progressive increases followed by pruning of regionally selective receptors by adulthood (Mato et al., 2003).
Given these differences in CB1 receptor densities between adolescent and adult rats as well as the dramatic behavioral differences, one might expect corresponding age differences in the potency and/or efficacy of the in vivo effects of 9-tetrahydrocannabinol (9-THC), the major psychoactive substituent of marijuana. The purpose of this study was to investigate this possibility. In mice, 9-THC and other psychoactive cannabinoids produce a characteristic tetrad of in vivo effects: decrease spontaneous activity and produce antinociception, hypothermia, and catalepsy (Martin et al., 1991; Compton et al., 1993). In the present study, this battery of tests was used to assess the age and sex dependence of cannabinoid effects in rats.
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) and were approved by our Institutional Animal Care and Use Committee. Apparatus. Clear plastic rat cages (22.5 cm in width x 44 cm in length x 20 cm in height) were housed in sound-attenuating cabinets and were used as locomotor chambers. Each cabinet contained up to 12 chambers, with a maximum of two chambers per shelf. Chambers did not contain bedding, and they were wiped with alcohol solution between sessions. Sessions occurred in darkness (i.e., with the cabinet doors closed). A cage rack system with 4 x 8 equally spaced photocell beams on the x- and y-axes (Lafayette Instrument, Lafayette, IN) was placed around each chamber (4.5 cm from bottom of cage), and locomotor activity was measured as total number of beam breaks for the entire session. A tail-flick analgesia meter (Columbus Instruments, Columbus, OH) and a Traceable7 digital thermometer (Control Company, Friendsville, TX) were used to measure antinociception and rectal temperature, respectively. The 8-V (6-amp) high-intensity light of the tail-flick apparatus was set at medium (intensity 13 in range of 1–25), and the light was turned off after a maximum of 10 s, regardless of whether the rat moved its tail. The bar apparatus that was used to measure catalepsy-like behavior consisted of a 280-mm bolt (10 mm in diameter) that was attached to a frame by eyebolts. Height of the bar was adjusted based upon the age of the rat (80 mm at PN29, 98 mm at PN40, and 130 mm for adults). Each bar apparatus was housed in its own box that was open in the front for experimenter access. Testing in the tail-flick, temperature, and elevated bar assays was performed in ambient fluorescent lighting conditions in the laboratory.
Procedure. Male and female adolescent and adult rats were randomly assigned (by cage pairs) to receive either vehicle or one of the doses of 9-THC. Rats in the same home cage were in the same treatment group. Initial tests occurred on PN29 (adolescents) or after PN68 (>PN65 + 
3 habituation days; adults). On the day of testing and at least 1 h before the start of the test battery, rats (in their home cages) were transported to the laboratory, and baseline temperature and tail-flick measures were taken. Temperature was measured by insertion of a rectal thermometer probe 40 mm (adolescents) or 45 mm (adults) into the rectum. To minimize potential stress associated with this procedure, the probe was dipped into mineral oil for lubrication before insertion. Baseline tail-flick latency was assessed by holding the rat gently and placing its tail in the groove of the tail-flick apparatus. The high-intensity light was illuminated and latency (in seconds) to move the tail away from the light source was measured. The light automatically extinguished once the tail was removed (or after 10 s). Immediately after these baseline measurements, rats were injected intraperitoneally with vehicle or with their assigned dose of 9-THC 30 min before the start of testing. At the end of the 30-min presession injection period, each rat was placed in a locomotor chamber for a 10-min session. Forty-five minutes after THC administration, the rat was tested in the tail-flick procedure again followed immediately by measurement of rectal temperature. At 1 h postinjection, the front paws of the rat were placed on the bar apparatus for 5 min. The total amount of time (in seconds) that both of the front paws of a rat remained in contact with the bar during the 5-min session was recorded. If both of the paws dropped from the bar, they were repositioned as before. The session timer was stopped during the brief time needed for repositioning. If the rat voluntarily removed its paws from the bar 10 times during the session, the session was stopped, and amount of time on bar was recorded as zero. Invariably, this situation occurred during the 1st minute of the session and was almost always associated with vehicle (or low-dose) treatment. Each rat was tested in all four procedures.
After these initial tests, rats were returned to the vivarium, where they remained until the next assessment in the tetrad (described below). Beginning the morning after the initial tetrad tests, each rat was weighed and then received subcutaneous injections of vehicle or 10 mg/kg 9-THC twice daily, once in the morning and once in the late afternoon. This dose of 9-THC has been shown in previous studies to induce substantial tolerance in adult mice without producing residual effects during a subsequent test session (Bass and Martin, 2000; Wiley et al., 2005). Other than handling necessary for weighing, injecting, and general cage maintenance, rats remained undisturbed in their home cages in the vivarium during the period of repeated dosing. The twice-daily regimen of injections was continued for 9 days (for the adolescents, PN30–PN38, inclusive). On the 10th day of repeated injections (PN39 for adolescents), rats were injected only in the morning. Twenty-four hours later (PN40 for adolescents), rats were retested in the tetrad following injection with vehicle or with their assigned dose of 9-THC (i.e., same treatment as on initial test). Timing and sequence of tests and injections and handling procedures for the adolescent and adult rats were identical, with the exception that the adult rats were older than PN68 at the beginning of testing. At the conclusion of the study, locomotor activity and time on the bar had been assessed for each rat twice (i.e., once after the initial injection of 9-THC on the 1st test day and a 2nd time after the final injection of 9-THC on the 2nd test day). Tail-flick and rectal temperature were measured four times in each rat over the course of the study (i.e., baseline measurements before injection on each of the two test days and subsequent to injection with 9-THC on each of the two test days). In separate groups of rats, an acute dose of 100 mg/kg 9-THC was tested in combination with 10 mg/kg SR141716A. SR141716A was injected i.p. 10 min before the injection of 100 mg/kg 9-THC, and each group of rats was tested using the same procedure described above for acute tests with 100 mg/kg 9-THC.
Drugs. 9-THC (National Institute on Drug Abuse, Bethesda, MD) and SR141716A (National Institute on Drug Abuse) were mixed in a vehicle of absolute ethanol, Emulphor-620 (Sanofi-aventis, Bridgewater, NJ), and saline in a ratio of 1:1:18. All injections were administered at a volume of 1 ml/kg, with the exception that 9-THC doses of 100, 176, and 300 mg/kg were volume-adjusted from a 50 mg/ml solution.
Data Analysis. Maximal tail-flick latency of 10 s was used. Antinociception was calculated as percent maximal possible effect = [(test - control latency)/(10 - control)] x 100. Rectal temperature values were expressed as the difference between control temperature (before injection) and temperatures following drug administration (°C). Spontaneous activity was measured as total number of photocell beam interruptions during the 10-min session. During placement on the bar apparatus, the total amount of time (in seconds) that the rat had both front feet in contact with the bar was measured, and this value was used as an indication of catalepsy-like behavior. This value was divided by 300 s and multiplied by 100 to obtain a percentage of time on bar rating.
Mean ± S.E.M. values for the four dependent measures were calculated across dose and time for each sex and age separately. For each dependent measure, separate mixed factorial ANOVAs (age x sex x repeated time) were performed on baseline values (V/V/V control: rats that received vehicle for all injections). Subsequently, separate mixed factorial ANOVAs (dose x repeated time) were performed on data from each sex and age group. Due to concerns about lethality, 300 mg/kg 9-THC was only tested on the 2nd test day for each age group [rats in these groups received 176 mg/kg on the 1st test day (data not shown)]; hence, data for 300 mg/kg 9-THC were omitted from analyses for each measure. Given that there were differences in the acute effects of 9-THC across age, the degree of tolerance was assessed through calculation of difference scores (prepost score) for each age/sex group. These difference scores were subjected to separate two-way ANOVAs (age x dose). When any ANOVA was significant, Tukey-Kramer post hoc tests (
= 0.05) were used to compare individual means. When appropriate, ED50 values (±95% confidence limits) were calculated separately for each group using least-squares linear regression on the linear part of the dose-effect curves (Tallarida and Murray, 1987) for each measure plotted against log10 transformation of the dose. For the purposes of potency calculations, antinociception and catalepsy were expressed as percent maximal possible effect and percentage of time on bar, respectively. Locomotor suppression was transformed to percentage of inhibition of vehicle baseline. Change in rectal temperature was expressed as percentage of the mean maximal empirical effect that occurred at the highest initial dose tested [(°C for test dose)/(mean °C at 176 mg/kg dose)] x 100 and was calculated separately for each treatment group. The maximal value for each measure was 100%. Results of the antagonism tests for each group were analyzed separately for each measure with a t test comparing mean value at 100 mg/kg 9-THC to mean value obtained with this dose of 9-THC in combination with 10 mg/kg SR141716A.
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9-THC during the intervening period.
The patterns of acute effects of 9-THC before repeated dosing were similar for all groups of rats. At both ages and across sexes, significant dose-dependent increases in percentage of time on the bar (Fig. 1), antinociception (Fig. 2), hypothermia (Fig. 3), and suppression of locomotor activity (Fig. 4) were noted. Results of the bar test are shown in Fig. 1. Acute dosing with 9-THC dose-dependently increased time on the bar for both sexes and ages (Fig. 1). Furthermore, the effects of 100 mg/kg 9-THC on this measure were significantly attenuated by prior administration of 10 mg/kg SR141716A in each age and sex. Potency differences were noted in female rats (but not in male rats), with female adolescents being less sensitive to this cataleptic effect than female adults (Table 1). Following repeated dosing with 9-THC, pronounced tolerance for this measure occurred in all four groups as indicated by significant differences from predosing values (Fig. 1, top and middle). Significant age-related differences (main effect of age) in the degree of change were observed for female, but not male, rats (Fig. 1, bottom). The magnitude of the change in time on bar scores for female adolescents was significantly less than for adult females. After dosing, the overall percentage of time on bar for all groups of rats was no greater than 35% (and, at most doses, was substantially less), suggesting that animals were no longer sensitive to this effect of 9-THC.
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Figure 2 shows the antinociceptive effects of 9-THC in male and female rats of both ages. Acutely, 9-THC produced dose-dependent antinociception in all groups of rats with similar efficacy. The antinociceptive effect of 100 mg/kg 9-THC was also significantly attenuated by 10 mg/kg SR141716A in all groups. The antinociceptive potency of 9-THC was less in female adolescent rats than in female adults (Table 1). In contrast, antinociceptive potencies did not significantly differ in male rats. Following repeated dosing, age-dependent differences in 9-THC-induced antinociception occurred in both sexes. Although substantial tolerance to the antinociceptive effects of 9-THC was observed in adult rats (Fig. 2, middle) across the entire dose range tested, significant differences in antinociception only occurred at lower 9-THC doses in adolescent rats (Fig. 2, top). Maximal antinociceptive effect produced by 176 mg/kg 9-THC in both sexes of adolescent rats was similar preand postdosing. The ED50 values for antinociception after repeated dosing with 9-THC were 101 mg/kg (CL 66–154) for male adolescent rats and 124 mg/kg (CL 90–170) for female adolescent rats. Confidence limits were not overlapping for data from adolescents of either sex, suggesting that pre- and postdosing potencies were different. Postdosing potencies could not be calculated for antinociception in adult rats because the maximum observed effect following repeated dosing did not reach 50%. Antinociception difference scores were also significantly greater for female adolescents than for female adults (main effect of age; Fig. 1, bottom), but those for male adolescents and adults did not reach significance, although there was a main effect for dose, indicating that difference scores increased at doses where scores were initially higher (i.e., decreased sensitivity to higher doses that originally produced full antinociception).
Acute 9-THC produced its characteristic dose-dependent hypothermia in all four groups of rats (Fig. 3). Whereas the maximal magnitude of temperature decrease was similar for male and female adolescents (Fig. 3, top) and male adults (Fig. 3, left middle), female adult rats (Fig. 3, right middle) showed a more robust acute hypothermic response. In contrast, potency differences were noted for male rats, with adolescents being more sensitive to 9-THC-induced hypothermia than adults (Table 1). The hypothermic effect of 100 mg/kg 9-THC was significantly attenuated by 10 mg/kg SR141716A in male adolescents and in both groups of female rats, but not in male adults. This latter finding is probably related to the relatively small decrease in temperature produced by this dose of 9-THC in male adults compared with that seen in females (i.e., a floor effect). Repeated dosing with 9-THC resulted in pronounced tolerance to its hypothermic effects in male adolescents (Fig. 3, top left); however, temperature changes in male adult rats were similar during the 1st and 2nd tests (Fig. 3, left middle). Consequently, difference scores for male adults were significantly less than those for male adolescents (main effect of age), particularly at doses of 30 mg/kg 9-THC and above (Fig. 1, bottom left). Female adolescents also tended to show greater tolerance to the hypothermic effects of 9-THC than did female adults (Fig. 3, top and middle right), although age-related differences for this measure were not significant as they were for males (Fig. 3, bottom right).
Acute suppression of locomotor activity was of similar magnitude across age and sex (Fig. 4); however, potency differences across age for males (but not for females) were observed (Table 1). Acute 9-THC was more potent at suppressing locomotor activity in male adolescents than in male adults (Fig. 4, top and middle left). Locomotor suppression produced by 100 mg/kg 9-THC was significantly attenuated by 10 mg/kg SR141716A in both groups of females and in male adolescents. In male adults, substantial variability in the group that received the 9-THC and SR141716A combination resulted in lack of significance for this group. Following a 10-day period of twice daily injections of 10 mg/kg 9-THC, time-dependent changes occurred across age and sex. Comparison of difference scores showed that male adolescents exhibited greater change in locomotor activity than did adult males (main effect of age), whereas females of both ages exhibited similar time-dependent changes in 9-THC-induced suppression of locomotor activity (Fig. 4, bottom). On the 2nd test day, significant locomotor suppression was still observed after injection of 176 mg/kg 9-THC in both male and female adult rats (Fig. 4, middle).
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9-THC produces reliable dose-dependent suppression of spontaneous activity, antinociception, hypothermia, and catalepsy in adult male mice with similar i.v. potency across measures (for review, see Compton et al., 1993). The present results extend these observations by demonstrating that acute i.p. administration of 9-THC produces a similar profile of effects in adolescent and adult rats of both sexes, although potencies across measures were more variable in this species. In both sexes and at both ages, locomotor suppression occurred at potencies 3- to 6-fold lower than those for catalepsy-like effects. Although seemingly a contradiction, a couple of modulatory factors should be mentioned. First, catalepsy here was operationally defined as an increase in the amount of time the forepaws of a rat remained in contact with an elevated bar, a definition that implies a restriction of voluntary movement without necessarily implying immobility. Second, catalepsy-like behavior was measured through direct experimenter observation with concomitant exposure to fluorescent lighting and ambient noise of the laboratory, whereas locomotion was measured in a darkened chamber of the same size and shape as the home cage of the rat. Under similar differences in measurement conditions, research has shown that transition from laboratory lighting to sudden darkness was associated with increased locomotion and decreased immobility in an open field test in male and female rats (Nasello et al., 2003). Third, previous research has also shown that drugs may severely reduce spontaneous activity without inducing catalepsy (Wiley and Martin, 2003), suggesting independent mediation of the two effects. Hence, both measures were included, despite the possibility of their behavioral interaction.
Although the overall pattern of 9-THC-induced acute tetrad effects was not age- or sex-dependent, the magnitude of some of the effects differed as a function of both factors. For males and females, initial efficacies were similar across ages and sexes, with the exception that maximal hypothermia in adult females was 
25% greater than that seen in male adults (also see Borgen et al., 1973). In contrast, a comparable difference in male and prepubertal females was not observed, suggesting an age-dependent increase in the sensitivity of females, but not males, to this effect. Interestingly, research has shown that CB1 receptor densities in the hypothalamus (associated with thermoregulation) varied with the estrous cycle in female rats (Rodríguez de Fonseca et al., 1994). Given that in vivo efficacy may be affected by receptor density (Kenakin, 1993), sex differences in the hypothermic efficacy of 9-THC may be related to estrous status in the adult female rats.
Despite similarities of baseline values and the pattern of acute 9-THC effects across groups, age- and sex-related potency differences were evident. In comparison with their respective adult counterparts, adolescent males showed enhanced sensitivity to locomotor and hypothermic effects of 9-THC and female adolescents were less sensitive to 9-THC-induced antinociception and catalepsy-like behavior. One obvious mechanistic factor to consider is differential pharmacokinetics. If this factor played a major role, consistent age differences in potencies and a similar magnitude of differences across all measures would have been expected. Because neither occurred, the data suggest (at minimum), an age-dependent regional specificity of pharmacokinetic variables.
To verify CB1 receptor mediation of the observed effects, 100 mg/kg 9-THC was tested in combination with 10 mg/kg SR141716A, a selective CB1 receptor antagonist. SR141716A significantly attenuated the effects of 9-THC in all groups, with two exceptions: hypomobility and hypothermia in male adults. Failure of SR141716A to attenuate these two effects in male adults may be related to the small magnitude of the effect (temperature) and to excessive variability in the combination group (activity). Although the results of the antagonist test are not entirely conclusive, they are suggestive that CB1 receptors play a strong role in the acute effects of 9-THC.
Given the diversity of tetrad tests, it would not be unreasonable to suppose mediation of each response by different brain areas. In support of this hypothesis, investigators have shown that local cerebral glucose use following 9-THC administration varied across dose, time, and brain area (Freedland et al., 2002; Whitlow et al., 2002). In addition, these changes paralleled the time course of 9-THC-induced effects (Whitlow et al., 2002). Similar differences in G protein activation across brain regions have also been reported (Sim et al., 1995; Brevogel et al., 1997; Selley et al., 2001). These results suggest that regionally selective 9-THC-induced functional alterations in the brain coupled with developmental differences in CB1 receptor number and distribution may be responsible for the effect-selective nature of the age-related differences in effects of 9-THC.
Within each age group in this study, sex differences were not noted. The latter finding contrasts with those of studies in which adult female rodents were more sensitive to the acute antinociceptive, cataleptic, and locomotor effects of cannabinoids than were adult males (Tseng and Craft, 2001; Wiley, 2003). These differences occurred across all stages of the estrous cycle of the females, suggesting that hormonal levels were not the primary mediators of these differences (Tseng and Craft, 2001; Tseng et al., 2004). Furthermore, prepubertal female rats also showed greater sensitivity to the antinociceptive effects of the synthetic cannabinoid CP 55,940 compared with their male counterparts (Romero et al., 2002); however, similar to the results of the present study, adolescents of both sexes showed comparable locomotor effects (Romero et al., 2002). (Age differences were not directly evaluated in either of these previous studies.) The present study differed from previous studies in important ways that undoubtedly affected the results obtained, including rat strain and several procedural variables.
As indicated by rightward shift or flattening of dose-response functions, repeated 9-THC resulted in tolerance to all effects in all groups, although the degree of tolerance varied somewhat across measures. These results are consistent with those of studies that have demonstrated pronounced tolerance to the effects of 9-THC in mammalian species (for a recent review, see Lichtman and Martin, 2005). Furthermore, specific effects showed differential magnitude of tolerance or cross-tolerance to cannabinoids of the same or different classes (Fan et al., 1994; Bass and Martin, 2000; Sim-Selley and Martin, 2002; De Vry et al., 2004; Wiley et al., 2005; this study). These results suggest site-selective regulation of CB1 receptors subsequent to repeated dosing, a hypothesis that has been confirmed by in vitro studies of CB1 receptors and glucose use (Romero et al., 1998; Breivogel et al., 1999; Whitlow et al., 2003).
Age differences in the effects of repeated 9-THC were also evident. Male adolescents were less sensitive to the hypolocomotor and hypothermic effects of 9-THC after repeated administration than were male adults, despite the fact that the younger males were more sensitive to acute effects of 9-THC on these measures. Although substantial tolerance to 9-THC-induced antinociceptive effects was observed for all groups, adolescents of both sexes nonetheless remained more sensitive to 9-THC-induced antinociception than did adults. The degree of tolerance to the cataleptic effects of 9-THC was similar for adolescents and adults of each sex. Previous studies have suggested that differences in the magnitude and/or rate of tolerance development across assays may indicate mediation by different mechanisms or brain areas (Bass and Martin, 2000; Wiley et al., 2005). Age-dependent differences in the magnitude of tolerance seen here resemble the measure-dependent effects noted in adult rodents (Bass and Martin, 2000; Wiley et al., 2005; this study), suggesting that developmental differences in regional CB1 receptor density and/or functioning may play a role in our results in much the same way as different mechanisms may effect measure-dependent differences in tolerance (Romero et al., 1998; Breivogel et al., 1999; Whitlow et al., 2003). Given that baseline values for each measure are similar across age and sex (and do not change as a result of repeated vehicle), these age differences are likely to be the result of interaction of 9-THC with neuronal systems rather than an effect of age differences in the brain per se.
These results have several implications for research and practice with adolescents. Initiation of marijuana use and transition to abuse are viewed as steps in the progression of substance abuse disorder. Our results suggest that age-dependent differences in initial effects of 9-THC are more variable than its effects after repeated use. With repeated use, the pattern and magnitude of tolerance in adolescents of both sexes is similar across measures. Furthermore, this pattern differs from the adult pattern in a way that does not necessarily parallel the more variable age-dependent differences observed initially, suggesting that trajectories of progression from initiation to marijuana abuse and dependence may not be the same for adolescents and adults. Hence, although observable responses following repeated use may be similar in adults and adolescents, the behavior of adolescents may exhibit greater alteration compared with effects after initial use. Previously reported variations in the brain cannabinoid system between these two age groups suggest that these age differences may be, to some extent, physiologically based. Given that substance abuse (by definition) implies repeated use, delineation of age-dependent differences of drug-induced changes following repeated administration is a crucial first step toward investigation of mechanisms that may underlie developmental differences in transition from use to abuse.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: PN, postnatal; CB, cannabinoid; 9-THC, 9-tetrahydrocannabinol; SR141716A, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl; ANOVA, analysis of variance; CL, confidence limits; CP 55,940, (-)-cis-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexanol.
Address correspondence to: Dr. Jenny Wiley, Department of Pharmacology and Toxicology, Virginia Commonwealth University, P.O. Box 980613, Richmond, VA 23298-0613. E-mail: jwiley{at}vcu.edu
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) and on the 1st test day for adults (
). Filled symbols represent mean ± S.E.M. values following 10 days of repeated dosing with 
) and on the 2nd test day for adults (
)]. For all figures, bottom panels show difference scores (i.e., pre - post) for males (bottom left) and females (bottom right) of each age (
