Unpleasant side effects of drugs of abuse often limit their repeated use; however, such effects may be attenuated in adolescents compared to adults.
We investigated whether the anxiogenic, aversive, or locomotor effects of delta-9-tetrahydrocannabinol (THC) differ between adolescent and adult rats.
We used the elevated plus maze (EPM) and light-dark tests of anxiety, the conditioned taste aversion and conditioned place aversion (CPA) tests of generalized aversion, and measures of stress hormone levels in serum to examine effects of THC in adolescent and adult rats. Locomotor activity was also recorded in the EPM, light-dark task, and CPA association sessions.
In the EPM and light-dark tasks, THC was anxiogenic in both age groups, but the drug was more anxiogenic in adults than in adolescents. In the place and taste aversion tasks, THC was aversive in both ages, and at 1.25 and 5 mg/kg, was more aversive in adults than in adolescents. The locomotor response to THC, as measured in the anxiety tasks and CPA, affected adults more than adolescents. Multiple measures revealed a locomotor-decreasing effect in adults, whereas some measures suggested a small locomotor-increasing effect in adolescent rats.
These results suggest that THC can have greater anxiogenic, aversive, and locomotor-reducing effects in adult rats than in adolescent rats. These findings suggest an explanation for reduced marijuana use in adult humans compared to teenagers.
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Adriani W, Laviola G (2000) A unique hormonal and behavioral hyporesponsivity to both forced novelty and d-amphetamine in periadolescent mice. Neuropharmacology 39:334–346
APA (1994) Diagnostic and statistical manual for mental disorders. American Psychiatric Association
Baldwin HA, Rassnick S, Rivier J, Koob GF, Britton KT (1991) CRF antagonist reverses the “anxiogenic” response to ethanol withdrawal in the rat. Psychopharmacology (Berl) 103:227–232
Basso AM, Spina M, Rivier J, Vale W, Koob GF (1999) Corticotropin-releasing factor antagonist attenuates the “anxiogenic-like” effect in the defensive burying paradigm but not in the elevated plus-maze following chronic cocaine in rats. Psychopharmacology (Berl) 145:21–30
Belue RC, Howlett AC, Westlake TM, Hutchings DE (1995) The ontogeny of cannabinoid receptors in the brain of postnatal and aging rats. Neurotoxicol Teratol 17:25–30
Braida D, Iosue S, Pegorini S, Sala M (2004) Delta9-tetrahydrocannabinol-induced conditioned place preference and intracerebroventricular self-administration in rats. Eur J Pharmacol 506:63–69
Campbell UC, Carroll ME (2001) Effects of ketoconazole on the acquisition of intravenous cocaine self-administration under different feeding conditions in rats. Psychopharmacology (Berl) 154:311–318
Cha YM, White AM, Kuhn CM, Wilson WA, Swartzwelder HS (2006) Differential effects of delta(9)-THC on learning in adolescent and adult rats. Pharmacol Biochem Behav Environ Exp Bot 83:448–455
Cheer JF, Kendall DA, Marsden CA (2000) Cannabinoid receptors and reward in the rat: a conditioned place preference study. Psychopharmacology (Berl) 151:25–30
Chen K, Kandel DB (1995) The natural history of drug use from adolescence to the mid-thirties in a general population sample. Am J Public Health 85:41–47
Chen K, Kandel DB, Davies M (1997) Relationships between frequency and quantity of marijuana use and last year proxy dependence among adolescents and adults in the United States. Drug Alcohol Depend 46:53–67
Crair MC, Malenka RC (1995) A critical period for long-term potentiation at thalamocortical synapses. Nature 375:325–328
Cunningham MG, Bhattacharyya S, Benes FM (2002) Amygdalo-cortical sprouting continues into early adulthood: implications for the development of normal and abnormal function during adolescence. J Comp Neurol 453:116–130
Deroche V, Marinelli M, Le Moal M, Piazza PV (1997) Glucocorticoids and behavioral effects of psychostimulants. II: cocaine intravenous self-administration and reinstatement depend on glucocorticoid levels. J Pharmacol Exp Ther 281:1401–1407
Doremus TL, Brunell SC, Varlinskaya EI, Spear LP (2003) Anxiogenic effects during withdrawal from acute ethanol in adolescent and adult rats. Pharmacol Biochem Behav 75:411–418
Doremus TL, Varlinskaya EI, Spear LP (2004) Age-related differences in elevated plus maze behavior between adolescent and adult rats. Ann NY Acad Sci 1021:427–430
Ehrenreich H, Rinn T, Kunert HJ, Moeller MR, Poser W, Schilling L, Gigerenzer G, Hoehe MR (1999) Specific attentional dysfunction in adults following early start of cannabis use. Psychopharmacology (Berl) 142:295–301
Ettenberg A, Geist TD (1991) Animal model for investigating the anxiogenic effects of self-administered cocaine. Psychopharmacology 103:455–461
Freeman KB, Riley AL (2005) Cocaine-induced conditioned taste avoidance over extended conditioned stimulus-unconditioned stimulus intervals. Behav Pharmacol 16:591–595
Freeman KB, Konaklieva MI, Riley AL (2005) Assessment of the contributions of Na+ channel inhibition and general peripheral action in cocaine-induced conditioned taste aversion. Pharmacol Biochem Behav 80:281–288
Goeders NE, Guerin GF (1996) Role of corticosterone in intravenous cocaine self-administration in rats. Neuroendocrinology 64:337–348
Gomez F (2002) Conditioned saccharin aversion induced by self-administered cocaine negatively correlates with the rate of cocaine self-administration in rats. Brain Res 946:214–220
Guitton MJ, Dudai Y (2004) Anxiety-like state associates with taste to produce conditioned taste aversion. Biol Psychiatry 56:901–904
Haertzen CA, Kocher TR, Miyasato K (1983) Reinforcements from the first drug experience can predict later drug habits and/or addiction: results with coffee, cigarettes, alcohol, barbiturates, minor and major tranquilizers, stimulants, marijuana, hallucinogens, heroin, opiates and cocaine. Drug Alcohol Depend 11:147–165
Heinrichs SC, Joppa M (2001) Dissociation of arousal-like from anxiogenic-like actions of brain corticotropin-releasing factor receptor ligands in rats. Behav Brain Res 122:43–50
Heinrichs SC, Koob GF (2004) Corticotropin-releasing factor in brain: a role in activation, arousal, and affect regulation. J Pharmacol Exp Ther 311:427–440
Heinrichs SC, Klaassen A, Koob GF, Schulteis G, Ahmed S, De Souza EB (1998) Corticotropin-releasing factor receptor blockade enhances conditioned aversive properties of cocaine in rats. Psychopharmacology (Berl) 136:247–255
Infurna RN, Spear LP (1979) Developmental changes in amphetamine-induced taste aversions. Pharmacol Biochem Behav 11:31–35
Izumi Y, Zorumski CF (1995) Developmental changes in long-term potentiation in CA1 of rat hippocampal slices. Synapse 20:19–23
Kirkwood A, Lee HK, Bear MF (1995) Co-regulation of long-term potentiation and experience-dependent synaptic plasticity in visual cortex by age and experience. Nature 375:328–331
Laviola G, Adriani W, Morley-Fletcher S, Terranova ML (2002) Peculiar response of adolescent mice to acute and chronic stress and to amphetamine: evidence of sex differences. Behav Brain Res 130:117–125
Liao D, Malinow R (1996) Deficiency in induction but not expression of LTP in hippocampal slices from young rats. Learn Mem 3:138–149
Little PJ, Kuhn CM, Wilson WA, Swartzwelder HS (1996) Differential effects of ethanol in adolescent and adult rats. Alcohol Clin Exp Res 20:1346–1351
Lu L, Liu D, Ceng X (2001) Corticotropin-releasing factor receptor type 1 mediates stress-induced relapse to cocaine-conditioned place preference in rats. Eur J Pharmacol 415:203–208
McGilveray IJ (2005) Pharmacokinetics of cannabinoids. Pain Res Manag 10:15A–22A
Menzaghi F, Rassnick S, Heinrichs S, Baldwin H, Pich EM, Weiss F, Koob GF (1994) The role of corticotropin-releasing factor in the anxiogenic effects of ethanol withdrawal. Ann NY Acad Sci 739:176–184
Morozov YM, Freund TF (2003) Post-natal development of type 1 cannabinoid receptor immunoreactivity in the rat hippocampus. Eur J Neurosci 18:1213–1222
Parker LA (1995) Rewarding drugs produce taste avoidance, but not taste aversion. Neurosci Biobehav Rev 19:143–157
Partridge JG, Tang KC, Lovinger DM (2000) Regional and postnatal heterogeneity of activity-dependent long-term changes in synaptic efficacy in the dorsal striatum. J Neurophysiol 84:1422–1429
Patton GC, Coffey C, Carlin JB, Degenhardt L, Lynskey M, Hall W (2002) Cannabis use and mental health in young people: cohort study. BMJ 325:1195–1198
Pellow S, File SE (1986) Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: a novel test of anxiety in the rat. Pharmacol Biochem Behav 24:525–529
Pellow S, Chopin P, File SE, Briley M (1985) Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167
Phillips TJ, Broadbent J, Burkhart-Kasch S, Henderson C, Wenger CD, McMullin C, McKinnon CS, Cunningham CL (2005) Genetic correlational analyses of ethanol reward and aversion phenotypes in short-term selected mouse lines bred for ethanol drinking or ethanol-induced conditioned taste aversion. Behav Neurosci 119:892–910
Piazza PV, Maccari S, Deminiere JM, Le Moal M, Mormede P, Simon H (1991) Corticosterone levels determine individual vulnerability to amphetamine self-administration. Proc Natl Acad Sci USA 88:2088–2092
Pope HG Jr, Gruber AJ, Hudson JI, Cohane G, Huestis MA, Yurgelun-Todd D (2003) Early-onset cannabis use and cognitive deficits: what is the nature of the association? Drug Alcohol Depend 69:303–310
Rodriguez de Fonseca F, Ramos JA, Bonnin A, Fernandez-Ruiz JJ (1993) Presence of cannabinoid binding sites in the brain from early postnatal ages. Neuroreport 4:135–138
Romero J, Garcia-Palomero E, Berrendero F, Garcia-Gil L, Hernandez ML, Ramos JA, Fernandez-Ruiz JJ (1997) Atypical location of cannabinoid receptors in white matter areas during rat brain development. Synapse 26:317–323
Sanudo-Pena MC, Tsou K, Delay ER, Hohman AG, Force M, Walker JM (1997) Endogenous cannabinoids as an aversive or counter-rewarding system in the rat. Neurosci Lett 223:125–128
Sarnyai Z, Biro E, Gardi J, Vecsernyes M, Julesz J, Telegdy G (1995) Brain corticotropin-releasing factor mediates ‘anxiety-like’ behavior induced by cocaine withdrawal in rats. Brain Res 675:89–97
Schramm-Sapyta NL, Pratt AR, Winder DG (2004) Effects of periadolescent versus adult cocaine exposure on cocaine conditioned place preference and motor sensitization in mice. Psychopharmacology (Berl) 84:344–352
Schramm-Sapyta NL, Morris RW, Kuhn CM (2006) Adolescent rats are protected from the conditioned aversive properties of cocaine and lithium chloride. Pharmacol Biochem Behav 173:41–48
Schramm NL, Egli RE, Winder DG (2002) LTP in the mouse nucleus accumbens is developmentally regulated. Synapse 45:213–219
Shram MJ, Funk D, Li Z, Le AD (2006) Periadolescent and adult rats respond differently in tests measuring the rewarding and aversive effects of nicotine. Psychopharmacology (Berl) 186:201–208
Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24:417–463
Spear LP, Brake SC (1983) Periadolescence: age-dependent behavior and psychopharmacological responsivity in rats. Dev Psychobiol 16:83–109
Thomas H (1996) A community survey of adverse effects of cannabis use. Drug Alcohol Depend 42:201–207
Varlinskaya EI, Spear LP (2004a) Acute ethanol withdrawal (hangover) and social behavior in adolescent and adult male and female Sprague–Dawley rats. Alcohol Clin Exp Res 28:40–50
Varlinskaya EI, Spear LP (2004b) Changes in sensitivity to ethanol-induced social facilitation and social inhibition from early to late adolescence. Ann NY Acad Sci 1021:459–461
Wenger T, Gerendai I, Fezza F, Gonzalez S, Bisogno T, Fernandez-Ruiz J, Di Marzo V (2002) The hypothalamic levels of the endocannabinoid, anandamide, peak immediately before the onset of puberty in female rats. Life Sci 70:1407–1414
Wilmouth CE, Spear LP (2004) Adolescent and adult rats’ aversion to flavors previously paired with nicotine. Ann NY Acad Sci 1021:462–464
York JL, Welte J, Hirsch J (2005) Regulation of alcohol intake with advancing age. Alcohol 36:41–46
The authors wish to thank Reynold Francis for expert technical assistance. This work was funded by DA019346 to Dr. Swartzwelder and by VA Senior Research Career Scientist awards to Drs. Swartzwelder and Wilson.
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Schramm-Sapyta, N.L., Cha, Y.M., Chaudhry, S. et al. Differential anxiogenic, aversive, and locomotor effects of THC in adolescent and adult rats. Psychopharmacology 191, 867–877 (2007). https://doi.org/10.1007/s00213-006-0676-9
- HPA axis
- Elevated plus maze