Abstract
Rationale
Drugs that stimulate 5-HT1A/1B receptors produce both tolerance and behavioral sensitization in adult rats and mice, yet it is unknown whether the same types of plasticity are evident during earlier ontogenetic periods.
Objective
The purpose of this study was to determine whether repeated treatment with selective 5-HT1A and/or 5-HT1B agonists cause tolerance and/or sensitization in preweanling rats.
Methods
In Experiments 1 and 2, male and female preweanling rats were given a single pretreatment injection of saline, the 5-HT1A agonist (R)-( +)-8-hydroxy-DPAT (8-OH-DPAT), or the 5-HT1B agonist CP-94253 on PD 20. After 48 h, rats received a challenge injection of 8-OH-DPAT or CP-94253, respectively. In Experiment 3, rats were pretreated with saline or DPAT + CP on PD 20 and challenged with the same drug cocktail on PD 22. In Experiment 4, the tolerance- or sensitization-inducing properties of 8-OH-DPAT, CP-94253, or DPAT + CP were tested after a 4-day pretreatment regimen on PD 17–20.
Results
On the first pretreatment day, 8-OH-DPAT, CP-94253, and DPAT + CP increased locomotion and caused hypothermia. Repeated treatment with 8-OH-DPAT (2 or 8 mg/kg) or DPAT + CP caused locomotor sensitization in preweanling rats. In contrast, tolerance to the hypothermic effects of 8-OH-DPAT (8 mg/kg), CP-94253 (5–20 mg/kg), or DPAT + CP was evident after repeated drug treatment.
Conclusions
During the preweanling period, a single injection of a selective 5-HT1A or 5-HT1B agonist is capable of producing drug-induced plasticity. A pretreatment administration of 8-OH-DPAT causes both tolerance (hypothermia) and behavioral sensitization (locomotor activity) in preweanling rats, whereas repeated CP-94253 treatment results in tolerance.
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References
Alkhatib AH, Dvorkin-Gheva A, Szechtman H (2013) Quinpirole and 8-OH-DPAT induce compulsive checking behavior in male rats by acting on different functional parts of an OCD neurocircuit. Behav Pharmacol 24:65–73. https://doi.org/10.1097/FBP.0b013e32835d5b7a
Alter D, Beverley JA, Patel R, Bolaños-Guzmán CA, Steiner H (2017) The 5-HT1B serotonin receptor regulates methylphenidate-induced gene expression in the striatum: differential effects on immediate-early genes. J Psychopharmacol 31:1078–1087. https://doi.org/10.1177/0269881117715598
Badiani A, Camp DM, Robinson TE (1997) Enduring enhancement of amphetamine sensitization by drug-associated environmental stimuli. J Pharmacol Exp Ther 282:787–794
Ball KT, Budreau D, Rebec GV (2006) Context-dependent behavioural and neuronal sensitization in striatum to MDMA (ecstasy) administration in rats. Eur J Neurosci 24:217–228. https://doi.org/10.1111/j.1460-9568.2006.04885.x
Berendsen HH, Broekkamp CL (1990) Behavioural evidence for functional interactions between 5-HT-receptor subtypes in rats and mice. Br J Pharmacol 101:667–673. https://doi.org/10.1111/j.1476-5381.1990.tb14138
Berquist MD, Leth-Petersen S, Kristensen JL, Fantegrossi WE (2020) Locomotor effects of 3,4-methylenedioxymethamphetamine (MDMA) and its deuterated form in mice: psychostimulant effects, stereotypy, and sensitization. Psychopharmacology 237(2020):431–442. https://doi.org/10.1007/s00213-019-05380-3
Bert B, Fink H, Hörtnagl H, Veh RW, Davies B, Theuring F, Kusserow H (2006) Mice over-expressing the 5-HT1A receptor in cortex and dentate gyrus display exaggerated locomotor and hypothermic response to 8-OH-DPAT. Behav Brain Res 167:328–341. https://doi.org/10.1016/j.bbr.2005.09.020
Bespalov A, Müller R, Relo AL, Hudzik T (2016) Drug tolerance: a known unknown in translational neuroscience. Trends Pharmacol Sci 37(2016):364–378. https://doi.org/10.1016/j.tips.2016.01.008
Bhargava HN, Gulati A (1990) Down-regulation of brain and spinal cord mu-opiate receptors in morphine tolerant-dependent rats. Eur J Pharmacol 190:305–311. https://doi.org/10.1016/0014-2999(90)94194-3
Bjorvatn B, Neckelmann D, Bjørkum AA, Ursin R (1996) Hypothermia and the 5-HT syndrome induced by CGS 12066B independently of 5-HT1B receptor activation. Behav Pharmacol 7:462–469
Blanchard RJ, Shepherd JK, Armstrong J, Tsuda SF, Blanchard DC (1993) An ethopharmacological analysis of the behavioral effects of 8-OH-DPAT. Psychopharmacology 112:55–63. https://doi.org/10.1007/BF02247363
Borycz J, Zapata A, Quiroz C, Volkow ND, Ferré S (2008) 5-HT1B receptor-mediated serotoninergic modulation of methylphenidate-induced locomotor activation in rats. Neuropsychopharmacology 33:619–626. https://doi.org/10.1038/sj.npp.1301445
Brookshire BR, Jones SR (2009) Direct and indirect 5-HT receptor agonists produce gender-specific effects on locomotor and vertical activities in C57 BL/6J mice. Pharmacol Biochem Behav 94:194–203. https://doi.org/10.1016/j.pbb.2009.08.008
Burton CK, Ho IK, Hoskins B (1990) Evidence for involvement of cyclic GMP phosphodiesterase in morphine tolerance. J Pharmacol Exp Ther 252:104–111
Cameron DL, Crosbie J, Crocker AD (1988) A fixed interval momentary sampling method for assessing on-going behaviours induced by dopamine receptor agonists. Prog Neuro-Psychopharmacol Biol Psychi 12:595–606. https://doi.org/10.1016/0278-5846(88)90005-x
Carey RJ, Gui J (1998) Cocaine conditioning and cocaine sensitization: what is the relationship? Behav Brain Res 92:67–76. https://doi.org/10.1016/s0166-4328(97)00126-5
Cepeda-Benito A, Reynoso J, McDaniel EH (1998) Associative tolerance to nicotine analgesia in the rat: tail-flick and hot-plate tests. Exp Clin Psychopharmacol 6:248–254. https://doi.org/10.1037//1064-1297.6.3.248
Cheetham SC, Heal DJ (1993) Evidence that RU 24969-induced locomotor activity in C57/B1/6 mice is specifically mediated by the 5-HT1B receptor. Br J Pharmacol 110:1621–1629. https://doi.org/10.1111/j.1476-5381.1993.tb14010.x
De La Garza RII, Cunningham KA (2000) The effects of the 5-hydroxytryptamine1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin on spontaneous activity, cocaine-induced hyperactivity and behavioral sensitization: a microanalysis of locomotor activity. J Pharmacol Exp Ther 292:610–617
Der-Ghazarian TS, Call T, Scott SN, Dai K, Brunwasser SJ, Noudali SN, Pentkowski NS, Neisewander JL (2017) Effects of a 5-HT1B receptor agonist on locomotion and reinstatement of cocaine-conditioned place preference after abstinence from repeated injections in mice. Front Syst Neurosci 11:73. https://doi.org/10.3389/fnsys.2017.00073
De Souza RJ, Goodwin GM, Green AR, Heal DJ (1986) Effect of chronic treatment with 5-HT1 agonist (8-OH-DPAT and RU 24969) and antagonist (isapirone) drugs on the behavioural responses of mice to 5-HT1 and 5-HT2 agonists. Br J Pharmacol 89:377–384. https://doi.org/10.1111/j.1476-5381.1986.tb10270.x
Dews PB (1978) Behavioral tolerance. NIDA Res Monogr 18:18–26
Evenden JL, Ängeby-Möller K (1990) Effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on locomotor activity and rearing of mice and rats. Psychopharmacology 102:485–491. https://doi.org/10.1007/BF02247129
Fish EW, Faccidomo S, Miczek KA (1999) Aggression heightened by alcohol or social instigation in mice: reduction by the 5-HT1B receptor agonist CP-94,253. Psychopharmacology 146:391–399. https://doi.org/10.1007/pl00005484
Fish EW, Sekinda M, Ferrari PF, Dirks A, Miczek KA (2000) Distress vocalizations in maternally separated mouse pups: modulation via 5-HT1A, 5-HT1B and GABAA receptors. Psychopharmacology 149:277–285. https://doi.org/10.1007/s002130000370
Garcia R, Le T, Scott SN, Charmchi D, Sprout JML, Pentkowski NS, Neisewander JL (2020) Preclinical support for the therapeutic potential of zolmitriptan as a treatment for cocaine use disorders. Transl Psychiatry 10:266. https://doi.org/10.1038/s41398-020-00956-6
Geisser S, Greenhouse SW (1958) An extension of Box’s results on the use of the F distribution in multivariate analysis. Ann Math Statist 29:885–891. https://doi.org/10.1214/aoms/1177706545
Goodwin GM, De Souza RJ, Green AR (1986) The effects of a 5-HT1 receptor ligand isapirone (TVX Q 7821) on 5-HT synthesis and the behavioural effects of 5-HT agonists in mice and rats. Psychopharmacology 89(1986):382–387. https://doi.org/10.1007/bf00174379
Hedlund PB, Kelly L, Mazur C, Lovenberg T, Sutcliffe JG, Bonaventure P (2004) 8-OH-DPAT acts on both 5-HT1A and 5-HT7 receptors to induce hypothermia in rodents. Eur J Pharmacol 487:125–132. https://doi.org/10.1016/j.ejphar.2004.01.031
Hensler J, Durgam H (2001) Regulation of 5-HT1A receptor-stimulated [35S]-GTPγS binding as measured by quantitative autoradiography following chronic agonist administration. Br J Pharmacol 132:605–611. https://doi.org/10.1038/sj.bjp.0703855
Hernández-Delgadillo GP, Ventura Martínez R, Díaz Reval MI, Domínguez Ramírez AM, López-Muñoz FJ (2002) Metamizol potentiates morphine antinociception but not constipation after chronic treatment. Eur J Pharmacol 441:177–183. https://doi.org/10.1016/s0014-2999(02)01344-4
Hillegaart V, Wadenberg ML, Ahlenius S (1989) Effects of 8-OH-DPAT on motor activity in the rat. Pharmacol Biochem Behav 32:797–800. https://doi.org/10.1016/0091-3057(89)90036-1
Holson RR, Pearce B (1992) Principles and pitfalls in the analysis of prenatal treatment effects in multiparous species. Neurotoxicol Teratol 14:221–228. https://doi.org/10.1016/0892-0362(92)90020-B
Jackson HC, Kitchen I (1989) Behavioural profiles of putative 5-hydroxytryptamine receptor agonists and antagonists in developing rats. Neuropharmacology 28:635–642. https://doi.org/10.1016/0028-3908(89)90143-3
Johansson C, Ahlenius S (1989) Evidence for the involvement of 5-HT1A receptors in the mediation of exploratory locomotor activity in the rat. J Psychopharmacol 3:32–35. https://doi.org/10.1177/026988118900300106
Johansson CE, Meyerson BJ (1991) The effects of long-term treatment with 8-OH-DPAT on the lordosis response and hypothermia in female rats. Eur J Pharmacol 196:143–147. https://doi.org/10.1016/0014-2999(91)90420-u
Johansson-Wallsten CE, Meyerson BJ (1994) The ontogeny of tolerance to the 5-HT1A agonist 8-OH-DPAT: a study in the rat. Neuropharmacology 33:325–330. https://doi.org/10.1016/0028-3908(94)90061-2
Johnson EF, Szechtman H (2016) A dose-response study of separate and combined effects of the serotonin agonist 8-OH-DPAT and the dopamine agonist quinpirole on locomotor sensitization, cross-sensitization, and conditioned activity. Behav Pharmacol 27:439–450. https://doi.org/10.1097/FBP.0000000000000219
Kalivas PW, Duffy P, White SR (1998) MDMA elicits behavioral and neurochemical sensitization in rats. Neuropsychopharmacology 18:469–479. https://doi.org/10.1016/S0893-133X(97)00195-4
Kaur P, Ahlenius S (2000) Non-serotonergic potentiation by (-)-pindolol of DOI-induced forward locomotion in rats: possible involvement of beta-adrenoceptors? J Neural Transm 107:903–917. https://doi.org/10.1007/s007020070041
Kelder D, Ross SB (2001) Differential sensitivity to 8-hydroxy-2-(di-n-propylamino)tetralin-induced corticosterone secretion and hypothermia between Sprague-Dawley rats from different breeding colonies. Pharmacol Toxicol 89:295–300. https://doi.org/10.1034/j.1600-0773.2001.d01-163.x
Kelder D, Ross SB (2002) Counteraction of the rapid tolerance to 8-hydroxy-2-(di-n-propylamino)tetralin-induced hypothermia in rats by activation of the GABAA receptor-chloride channel complex. Pharmacol Toxicol 90:14–19. https://doi.org/10.1034/j.1600-0773.2002.900104.x
King GR, Xiong Z, Ellinwood EH (1999) Blockade of accumbens 5-HT3 receptor down-regulation by ondansetron administered during continuous cocaine administration. Eur J Pharmacol 364:79–87. https://doi.org/10.1016/s0014-2999(98)00795-x
Koe BK, Nielsen JA, Macor JE, Heym J (1992) Biochemical and behavioral studies of the 5-HT1B receptor agonist, CP94,253. Drug Dev Res 26:241–250. https://doi.org/10.1002/ddr.430260305
Larsson LG, Rényi L, Ross SB, Svensson B, Ängeby-Möller K (1990) Different effects on the responses of functional pre- and postsynaptic 5-HT1A receptors by repeated treatment of rats with the 5-HT1A receptor agonist 8-OH-DPAT. Neuropharmacology 29:85–91. https://doi.org/10.1016/0028-3908(90)90047-u
Lin D, Parsons LH (2002) Anxiogenic-like effect of serotonin1B receptor stimulation in the rat elevated plus-maze. Pharmacol Biochem Behav 71:581–587. https://doi.org/10.1016/s0091-3057(01)00712-2
Ling GSF, Paul D, Simantov R, Pasternak GW (1989) Differential development of acute tolerance to analgesia, respiratory depression, gastrointestinal transit and hormone release in a morphine infusion model. Life Sci 45:1627–1636. https://doi.org/10.1016/0024-3205(89)90272-5
Lucchetti J, Marzo CM, Passoni A, Moro F, di Clemente A, Bagnati R, Cervo L, Gobbi M (2018) Brain disposition, metabolism and behavioral effects of the synthetic opioid AH-7921 in rats. Neuropharmacology 133:51–62. https://doi.org/10.1016/j.neuropharm.2018.01.023
McCreary AC, Bankson MG, Cunningham KA (1999) Pharmacological studies of the acute and chronic effects of (+)-3,4-methylenedioxymethamphetamine on locomotor activity: role of 5-hydroxytryptamine1A and 5-hydroxytryptamine1B/1D receptors. J Pharmacol Exp Ther 290:965–973
McDougall SA, Charntikov S, Cortez AM, Amodeo DA, Martinez CE, Crawford CA (2009) Persistence of one-trial cocaine-induced behavioral sensitization in young rats: regional differences in Fos immunoreactivity. Psychopharmacology 203:617–628. https://doi.org/10.1007/s00213-008-1407-1
McDougall SA, Montejano NR, Park GI, Robinson JAM (2021a) Importance of dopaminergic neurotransmission for the RU 24969-induced locomotor activity of male and female rats during the preweanling period. Naunyn Schmiedebergs Arch Pharmacol 394:903–913. https://doi.org/10.1007/s00210-020-02011-z
McDougall SA, Park GI, Ramirez GI, Gomez V, Adame BC, Crawford CA (2019) Sex-dependent changes in ketamine-induced locomotor activity and ketamine pharmacokinetics in preweanling, adolescent, and adult rats. Eur Neuropsychopharmacol 29:740–755. https://doi.org/10.1016/j.euroneuro.2019.03.013
McDougall SA, Razo JL, Rios JW, Taylor JA (2021b) Effects of repeated RU 24969 treatment on the locomotor activity, motoric capacity, and axillary temperatures of male and female preweanling rats. Behav Brain Res 398:112982. https://doi.org/10.1016/j.bbr.2020.112982
McDougall SA, Robinson JAM, Ramirez EL, Diaz HA (2020) Serotonin 5-HT1A and 5-HT1B receptors co-mediate the RU 24969-induced locomotor activity of male and female preweanling rats. Pharmacol Biochem Behav 189:172857. https://doi.org/10.1016/j.pbb.2020.172857
Meller E, Chalfin M, Bohmaker K (1992) Serotonin 5-HT1A receptor-mediated hypothermia in mice: absence of spare receptors and rapid induction of tolerance. Pharmacol Biochem Behav 43:405–411. https://doi.org/10.1016/0091-3057(92)90169-g
Middlemiss DN, Fozard JR (1983) 8-Hydroxy-2-(di-n-propylamino)-tetralin discriminates between subtypes of the 5-HT1 recognition site. Eur J Pharmacol 90:151–153. https://doi.org/10.1016/0014-2999(83)90230-3
National Research Council (2010) Guide for the care and use of laboratory animals, 8th edn. National Academies Press, Washington
Oberlander C, Demassey Y, Verdu A, Van de Velde D, Bardelay C (1987) Tolerance to the serotonin 5-HT1 agonist RU24969 and effects on dopaminergic behavior. Eur J Pharmacol 139:205–214. https://doi.org/10.1016/0014-2999(87)90253-6
O’Connell MT, Curzon G (1996) A comparison of the effects of 8-OH-DPAT pretreatment of different behavioural responses to 8-OH-DPAT. Eur J Pharmacol 312:137–143. https://doi.org/10.1016/0014-2999(96)00496-7
Oerther S, Ahlenius S (2001) Involvement of 5-HT1A and 5-HT1B receptors for citalopram-induced hypothermia in the rat. Psychopharmacology 154:429–434. https://doi.org/10.1007/s002130000659
O’Neill MF, Parameswaran T (1997) RU24969-induced behavioural syndrome requires activation of both 5HT1A and 5HT1B receptors. Psychopharmacology 132:255–260. https://doi.org/10.1007/s002130050343
O’Neill MF, Sanger GJ (1999) GR46611 potentiates 5-HT1A receptor-mediated locomotor activity in the guinea pig. Eur J Pharmacol 370:85–92. https://doi.org/10.1016/s0014-2999(99)00090-4
Perez M, Pauwels PJ, Fourrier C, Chopin P, Valentin JP, John GW, Marien M, Halazy S (1998) Dimerization of sumatriptan as an efficient way to design a potent, centrally and orally active 5-HT1B agonist. Bioorg Med Chem Lett 8:675–680. https://doi.org/10.1016/s0960-894x(98)00090-0
Pierce RC, Kalivas PW (1997) A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants. Brain Res Rev 25:192–216. https://doi.org/10.1016/s0165-0173(97)00021-0
Rempel N, Callaway CW, Geyer MA (1993) Serotonin1B receptor activation mimics behavioral effects of presynaptic serotonin release. Neuropsychopharmacology 8:201–212. https://doi.org/10.1038/npp.1993.22
Schechter LE, Bolaños FJ, Gozlan H, Lanfumey L, Haj-Dahmane S, Laporte AM, Fattaccini CM, Hamon M (1990) Alterations of central serotoninergic and dopaminergic neurotransmission in rats chronically treated with ipsapirone: biochemical and electrophysiological studies. J Pharmacol Exp Ther 255:1335–1347
Schlicker E, Werner U, Hamon M, Gozlan H, Nickel B, Szelenyi I, Göthert M (1992) Anpirtoline, a novel, highly potent 5-HT1B receptor agonist with antinociceptive/antidepressant-like actions in rodents. Br J Pharmacol 105:732–738. https://doi.org/10.1111/j.1476-5381.1992.tb09047.x
Schuster CR (1978) Theoretical basis of behavioral tolerance: implications of the phenomenon for problems of drug abuse. NIDA Res Monogr 18:4–17
Sershen H, Hashim A, Lajtha A (1996) Effect of ibogaine on cocaine-induced efflux of [3H] dopamine and [3H] serotonin from mouse striatum. Pharmacol Biochem Behav 53:863–869. https://doi.org/10.1016/0091-3057(95)02098-5
Shanahan NA, Holick Pierz KA, Masten VL, Waeber C, Ansorge M, Gingrich JA, Geyer MA, Hen R, Dulawa SC (2009) Chronic reductions in serotonin transporter function prevent 5-HT1B-induced behavioral effects in mice. Biol Psychiatry 65:401–408. https://doi.org/10.1016/j.biopsych.2008.09.026
Shayit M, Yadid G, Overstreet DH, Weller A (2003) 5-HT1A receptor subsensitivity in infancy and supersensitivity in adulthood in an animal model of depression. Brain Res 980:100–108. https://doi.org/10.1016/s0006-8993(03)02944-5
Siegel S, Baptista MA, Kim JA, McDonald RV, Weise-Kelly L (2000) Pavlovian psychopharmacology: the associative basis of tolerance. Exp Clin Psychopharmacol 8:276–293. https://doi.org/10.1037//1064-1297.8.3.276
Sipos ML, Bauman RA, Widholm JJ, Kant GJ (2000) Behavioral effects of 8-OH-DPAT in chronically stressed male and female rats. Pharmacol Biochem Behav 66:403–411. https://doi.org/10.1016/s0091-3057(00)00178-7
Smith KS, Morrell JL (2008) Behavioral responses during the initial exposures to a low dose of cocaine in late preweanling and adult rats. Neurotoxicol Teratol 30:202–212. https://doi.org/10.1016/j.ntt.2008.01.003
Tirelli E, Laviola G, Adriani W (2003) Ontogenesis of behavioral sensitization and conditioned place preference induced by psychostimulants in laboratory rodents. Neurosci Biobehav Rev 27:163–178. https://doi.org/10.1016/s0149-7634(03)00018-6
Uphouse L, Salamanca S, Caldarola-Pastuszka M (1991) Gender and estrous cycle differences in the response to the 5-HT1A agonist 8-OH-DPAT. Pharmacol Biochem Behav 40:901–906. https://doi.org/10.1016/0091-3057(91)90104-a
van der Laan JW, Jansen van’t Land C, de Groot G (1993) Tolerance and withdrawal after chronic lorazepam treatment in rats. Eur Neuropsychopharmacol 3:521–531. https://doi.org/10.1016/0924-977x(93)90278-t
Vanderschuren LJ, Kalivas PW (2000) Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharmacology 151:99–120. https://doi.org/10.1007/s002130000493
Wieland S, Fischette CT, Lucki I (1993) Effect of chronic treatments with tandospirone and imipramine on serotonin-mediated behavioral responses and monoamine receptors. Neuropharmacology 32:561–573. https://doi.org/10.1016/0028-3908(93)90052-5
Wolf ME (1998) The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog Neurobiol 54:679–720. https://doi.org/10.1016/s0301-0082(97)00090-7
Zorrilla EP (1997) Multiparous species present problems (and possibilities) to developmentalists. Dev Psychobiol 30:141–150. https://doi.org/10.1002/(SICI)1098-2302(199703)30:2%3c141::AID-DEV5%3e3.0.CO;2-Q
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McDougall, S.A., Taylor, J.A., Roe, M.J. et al. Effects of repeated treatment with the 5-HT1A and 5-HT1B agonists (R)-( +)-8-hydroxy-DPAT and CP-94253 on the locomotor activity and axillary temperatures of preweanling rats: evidence of tolerance and behavioral sensitization. Psychopharmacology 239, 413–427 (2022). https://doi.org/10.1007/s00213-021-06012-5
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DOI: https://doi.org/10.1007/s00213-021-06012-5