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Endocannabinoids and the Endocrine System in Health and Disease

  • Cecilia J. HillardEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 231)

Abstract

Some of the earliest reports of the effects of cannabis consumption on humans were related to endocrine system changes. In this review, the effects of cannabinoids and the role of the CB1 cannabinoid receptor in the regulation of the following endocrine systems are discussed: the hypothalamic–pituitary–gonadal axis, prolactin and oxytocin, thyroid hormone and growth hormone, and the hypothalamic–pituitary–adrenal axis. Preclinical and human study results are presented.

Keywords

Corticosterone Gonadotropin Gonadotropin-releasing hormone Growth hormone HPA axis Oxytocin Prolactin Testosterone Thyroid hormone 

Abbreviations

2-AG

2-Arachidonoylglycerol

ACTH

Adrenocorticotropic hormone

AEA

N-arachidonoylethanolamine

BLA

Basolateral amygdala

CB1R

Type 1 cannabinoid receptor

CB2R

Type 2 cannabinoid receptor

CNS

Central nervous system

CRH

Corticotropin-releasing hormone

DAG

Diacylglycerol

eCB

Endocannabinoid

ECS

Endocannabinoid signaling

FAAH

Fatty acid amide hydrolase

FGR

Fetal growth restriction

FSH

Follicle-stimulating hormone

GABA

Gamma-aminobutyric acid

GH

Growth hormone

GHRH

Growth hormone-releasing hormone

GnRH

Gonadotropin-releasing hormone

GR

Glucocorticoid receptor

HPA

Hypothalamic–pituitary–adrenal

HPG

Hypothalamic–pituitary–gonadal

HPT

Hypothalamic–pituitary–thyroid

i.c.v.

Intracerebroventricular

LH

Luteinizing hormone

MGL

Monoacylglycerol lipase

MR

Mineralocorticoid receptor

OVX

Ovariectomized

OXT

Oxytocin

PLC

Phospholipase C

PVN

Periventricular nucleus

SON

Supraoptic nucleus

THC

Δ9-Tetrahydrocannabinol

TRH

Thyrotropin-releasing hormone

TRß1

ß1 subtype of the thyroid hormone receptor

TSH

Thyroid-stimulating hormone

VTA

Ventral tegmental area

Notes

Acknowledgments

The author was supported during the writing of this review by NIH grant R01 DA26996 and the Research and Education Program, a component of the Advancing a Healthier Wisconsin endowment at the Medical College of Wisconsin.

References

  1. Asch RH, Smith CG, Siler-Khodr TM, Pauerstein CJ (1979) Acute decreases in serum prolactin concentrations caused by delta 9-tetrahydrocannabinol in nonhuman primates. Fertil Steril 32:571–575PubMedGoogle Scholar
  2. Asch RH, Smith CG, Siler-Khodr TM, Pauerstein CJ (1981) Effects of delta 9-tetrahydrocannabinol during the follicular phase of the rhesus monkey (Macaca mulatta). J Clin Endocrinol Metab 52:50–55PubMedCrossRefGoogle Scholar
  3. Atkinson HC, Leggett JD, Wood SA, Castrique ES, Kershaw YM, Lightman SL (2010) Regulation of the hypothalamic-pituitary-adrenal axis circadian rhythm by endocannabinoids is sexually diergic. Endocrinology 151:3720–3727PubMedCentralPubMedCrossRefGoogle Scholar
  4. Banerjee A, Singh A, Srivastava P, Turner H, Krishna A (2011) Effects of chronic bhang (cannabis) administration on the reproductive system of male mice. Birth Defects Res B Dev Reprod Toxicol 92:195–205PubMedCrossRefGoogle Scholar
  5. Battista N, Rapino C, Di Tommaso M, Bari M, Pasquariello N, Maccarrone M (2008) Regulation of male fertility by the endocannabinoid system. Mol Cell Endocrinol 286:S17–S23PubMedCrossRefGoogle Scholar
  6. Bernal J (2007) Thyroid hormone receptors in brain development and function. Nat Clin Pract Endocrinol Metab 3:249–259PubMedCrossRefGoogle Scholar
  7. Black MD, Stevens RJ, Rogacki N, Featherstone RE, Senyah Y, Giardino O, Borowsky B, Stemmelin J, Cohen C, Pichat P, Arad M, Barak S, De Levie A, Weiner I, Griebel G, Varty GB (2011) AVE1625, a cannabinoid CB1 receptor antagonist, as a co-treatment with antipsychotics for schizophrenia: improvement in cognitive function and reduction of antipsychotic-side effects in rodents. Psychopharmacology (Berl) 215:149–163CrossRefGoogle Scholar
  8. Block RI, Farinpour R, Schlechte JA (1991) Effects of chronic marijuana use on testosterone, luteinizing hormone, follicle stimulating hormone, prolactin and cortisol in men and women. Drug Alcohol Depend 28:121–128PubMedCrossRefGoogle Scholar
  9. Bonnet U (2013) Chronic cannabis abuse, delta-9-tetrahydrocannabinol and thyroid function. Pharmacopsychiatry 46:35–36PubMedGoogle Scholar
  10. Bonnin A, Ramos JA, Rodriguez De Fonseca F, Cebeira M, Fernandez-Ruiz JJ (1993) Acute effects of delta 9-tetrahydrocannabinol on tuberoinfundibular dopamine activity, anterior pituitary sensitivity to dopamine and prolactin release vary as a function of estrous cycle. Neuroendocrinology 58:280–286PubMedCrossRefGoogle Scholar
  11. Bowen R, Mcilwrick J, Baetz M, Zhang X (2005) Lithium and marijuana withdrawal. Can J Psychiatry 50:240–241PubMedGoogle Scholar
  12. Buckley NE, Hansson S, Harta G, Mezey E (1998) Expression of the CB1 and CB2 receptor messenger RNAs during embryonic development in the rat. Neuroscience 82:1131–1149PubMedCrossRefGoogle Scholar
  13. Butovsky E, Juknat A, Elbaz J, Shabat-Simon M, Eilam R, Zangen A, Altstein M, Vogel Z (2006) Chronic exposure to Delta9-tetrahydrocannabinol downregulates oxytocin and oxytocin-associated neurophysin in specific brain areas. Mol Cell Neurosci 31:795–804PubMedCrossRefGoogle Scholar
  14. Cacciola G, Chioccarelli T, Mackie K, Meccariello R, Ledent C, Fasano S, Pierantoni R, Cobellis G (2008) Expression of type-1 cannabinoid receptor during rat postnatal testicular development: possible involvement in adult leydig cell differentiation. Biol Reprod 79(4):758–765PubMedCrossRefGoogle Scholar
  15. Cone EJ, Johnson RE, Moore JD, Roache JD (1986) Acute effects of smoking marijuana on hormones, subjective effects and performance in male human subjects. Pharmacol Biochem Behav 24:1749–1754PubMedCrossRefGoogle Scholar
  16. Cota D, Steiner MA, Marsicano G, Cervino C, Herman JP, Grubler Y, Stalla J, Pasquali R, Lutz B, Stalla GK, Pagotto U (2007) Requirement of cannabinoid receptor type 1 for the basal modulation of hypothalamic-pituitary-adrenal axis function. Endocrinology 148:1574–1581PubMedCrossRefGoogle Scholar
  17. Craft RM, Marusich JA, Wiley JL (2013) Sex differences in cannabinoid pharmacology: a reflection of differences in the endocannabinoid system? Life Sci 92:476–81PubMedCentralPubMedCrossRefGoogle Scholar
  18. Cui SS, Bowen RC, Gu GB, Hannesson DK, Yu PH, Zhang X (2001) Prevention of cannabinoid withdrawal syndrome by lithium: involvement of oxytocinergic neuronal activation. J Neurosci 21:9867–9876PubMedGoogle Scholar
  19. Dalterio S, Bartke A, Burstein S (1977) Cannabinoids inhibit testosterone secretion by mouse testes in vitro. Science 196:1472–1473PubMedCrossRefGoogle Scholar
  20. Dalterio SL, Michael SD, Macmillan BT, Bartke A (1981) Differential effects of cannabinoid exposure and stress on plasma prolactin, growth hormone and corticosterone levels in male mice. Life Sci 28:761–766PubMedCrossRefGoogle Scholar
  21. Dalterio SL, Mayfield DL, Bartke A (1983a) Effects of delta 9-THC on plasma hormone levels in female mice. Subst Alcohol Actions Misuse 4:339–345PubMedGoogle Scholar
  22. Dalterio SL, Mayfield DL, Michael SD, Macmillan BT, Bartke A (1983b) Effects of delta 9-THC and castration on behavior and plasma hormone levels in male mice. Pharmacol Biochem Behav 18:81–86PubMedCrossRefGoogle Scholar
  23. De Laurentiis A, Fernandez-Solari J, Mohn C, Burdet B, Zorrilla Zubilete MA, Rettori V (2010) The hypothalamic endocannabinoid system participates in the secretion of oxytocin and tumor necrosis factor-alpha induced by lipopolysaccharide. J Neuroimmunol 221:32–41PubMedCrossRefGoogle Scholar
  24. Deli L, Wittmann G, Kallo I, Lechan RM, Watanabe M, Liposits Z, Fekete C (2009) Type 1 cannabinoid receptor-containing axons innervate hypophysiotropic thyrotropin-releasing hormone-synthesizing neurons. Endocrinology 150:98–103PubMedCentralPubMedCrossRefGoogle Scholar
  25. Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, Katz R, Di Marzo V, Jutras-Aswad D, Notcutt WG, Martinez-Orgado J, Robson PJ, Rohrback BG, Thiele E, Whalley B, Friedman D (2014) Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 55:791–802PubMedCrossRefGoogle Scholar
  26. Di S, Malcher-Lopes R, Halmos KC, Tasker JG (2003) Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism. J Neurosci 23:4850–4857PubMedGoogle Scholar
  27. Di S, Boudaba C, Popescu IR, Weng FJ, Harris C, Marcheselli VL, Bazan NG, Tasker JG (2005a) Activity-dependent release and actions of endocannabinoids in the rat hypothalamic supraoptic nucleus. J Physiol 569:751–760PubMedCentralPubMedCrossRefGoogle Scholar
  28. Di S, Malcher-Lopes R, Marcheselli VL, Bazan NG, Tasker JG (2005b) Rapid glucocorticoid-mediated endocannabinoid release and opposing regulation of glutamate and GABA inputs to hypothalamic magnocellular neurons. Endocrinology 146:4292–4301PubMedCrossRefGoogle Scholar
  29. Di S, Maxson MM, Franco A, Tasker JG (2009) Glucocorticoids regulate glutamate and GABA synapse-specific retrograde transmission via divergent nongenomic signaling pathways. J Neurosci 29:393–401PubMedCentralPubMedCrossRefGoogle Scholar
  30. Di S, Popescu IR, Tasker JG (2013) Glial control of endocannabinoid heterosynaptic modulation in hypothalamic magnocellular neuroendocrine cells. J Neurosci 33:18331–18342PubMedCentralPubMedCrossRefGoogle Scholar
  31. Dixit VP, Gupta CL, Agrawal M (1977) Testicular degeneration and necrosis induced by chronic administration of cannabis extract in dogs. Endokrinologie 69:299–305PubMedGoogle Scholar
  32. D’Souza DC, Perry E, Macdougall L, Ammerman Y, Cooper T, Wu YT, Braley G, Gueorguieva R, Krystal JH (2004) The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology 29:1558–1572PubMedCrossRefGoogle Scholar
  33. D’Souza DC, Ranganathan M, Braley G, Gueorguieva R, Zimolo Z, Cooper T, Perry E, Krystal J (2008) Blunted psychotomimetic and amnestic effects of delta-9-tetrahydrocannabinol in frequent users of cannabis. Neuropsychopharmacology 33:2505–2516PubMedCentralPubMedCrossRefGoogle Scholar
  34. Evanson NK, Tasker JG, Hill MN, Hillard CJ, Herman JP (2010) Fast feedback inhibition of the HPA axis by glucocorticoids is mediated by endocannabinoid signaling. Endocrinology 151:4811–4819PubMedCentralPubMedCrossRefGoogle Scholar
  35. Falkenstein BA, Holley DC (1992) Effect of acute intravenous administration of delta-9-tetrahydrocannabinol on the episodic secretion of immunoassayable growth hormone in the rat. Life Sci 50:1109–1116PubMedCrossRefGoogle Scholar
  36. Farkas I, Kallo I, Deli L, Vida B, Hrabovszky E, Fekete C, Moenter SM, Watanabe M, Liposits Z (2010) Retrograde endocannabinoid signaling reduces GABAergic synaptic transmission to gonadotropin-releasing hormone neurons. Endocrinology 151:5818–5829PubMedCentralPubMedCrossRefGoogle Scholar
  37. Fernandez-Ruiz JJ, Munoz RM, Romero J, Villanua MA, Makriyannis A, Ramos JA (1997) Time course of the effects of different cannabimimetics on prolactin and gonadotrophin secretion: evidence for the presence of CB1 receptors in hypothalamic structures and their involvement in the effects of cannabimimetics. Biochem Pharmacol 53:1919–1927PubMedCrossRefGoogle Scholar
  38. Fernandez-Solari J, Scorticati C, Mohn C, De Laurentiis A, Billi S, Franchi A, Mccann SM, Rettori V (2004) Alcohol inhibits luteinizing hormone-releasing hormone release by activating the endocannabinoid system. Proc Natl Acad Sci U S A 101(9):3264–3268PubMedCentralPubMedCrossRefGoogle Scholar
  39. Flamant F, Gauthier K, Samarut J (2007) Thyroid hormones signaling is getting more complex: STORMs are coming. Mol Endocrinol 21:321–333PubMedCrossRefGoogle Scholar
  40. Freund TF, Katona I, Piomelli D (2003) Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 83:1017–1066PubMedCrossRefGoogle Scholar
  41. Fronczak CM, Kim ED, Barqawi AB (2012) The insults of illicit drug use on male fertility. J Androl 33:515–528PubMedCrossRefGoogle Scholar
  42. Gammon CM, Freeman GM Jr, Xie W, Petersen SL, Wetsel WC (2005) Regulation of gonadotropin-releasing hormone secretion by cannabinoids. Endocrinology 146:4491–4499PubMedCentralPubMedCrossRefGoogle Scholar
  43. Ganon-Elazar E, Akirav I (2009) Cannabinoid receptor activation in the basolateral amygdala blocks the effects of stress on the conditioning and extinction of inhibitory avoidance. J Neurosci 29:11078–11088PubMedCrossRefGoogle Scholar
  44. Gine E, Echeverry-Alzate V, Lopez-Moreno JA, Lopez-Jimenez A, Torres-Romero D, Perez-Castillo A, Santos A (2013) Developmentally-induced hypothyroidism alters the expression of Egr-1 and Arc genes and the sensitivity to cannabinoid agonists in the hippocampus. Possible implications for memory and learning. Mol Cell Endocrinol 365:119–128PubMedCrossRefGoogle Scholar
  45. Glanowska KM, Moenter SM (2011) Endocannabinoids and prostaglandins both contribute to GnRH neuron-GABAergic afferent local feedback circuits. J Neurophysiol 106:3073–3081PubMedCentralPubMedCrossRefGoogle Scholar
  46. Gorzalka BB, Dang SS (2012) Minireview: Endocannabinoids and gonadal hormones: bidirectional interactions in physiology and behavior. Endocrinology 153:1016–1024PubMedCrossRefGoogle Scholar
  47. Gorzalka BB, Hill MN, Chang SC (2010) Male-female differences in the effects of cannabinoids on sexual behavior and gonadal hormone function. Horm Behav 58(1):91–99PubMedCrossRefGoogle Scholar
  48. Gray M, Veccharelli H, Kim A, Hassan K, Hermanson D, Mclaughlin RJ, Lee T, Deussing J, Patel S, Hill MN (2013) Corticotropin-releasing hormone signaling drives anandamide hydrolysis to promote anxiety. In: International Cannabinoid Research Society Annual Meeting, Vancouver, BC, p. 40Google Scholar
  49. Hall W, Solowij N (1998) Adverse effects of cannabis. Lancet 352:1611–1616PubMedCrossRefGoogle Scholar
  50. Hanlon E, Tasali E, Leproult R, Stuhr K, Doncheck E, De Wit H, Hillard C, Van Cauter E (2014) Circadian rhythm of circulating levels of the endocannabinoid 2-arachidonoylglycerol. J Clin Endocrinol Metab 100(1):220–226. doi: 10.1210/jc20143455 CrossRefGoogle Scholar
  51. Hao S, Avraham Y, Mechoulam R, Berry EM (2000) Low dose anandamide affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice. Eur J Pharmacol 392:147–156PubMedCrossRefGoogle Scholar
  52. Heindel JJ, Keith WB (1989) Specific inhibition of FSH-stimulated cAMP accumulation by delta 9-tetrahydrocannabinol in cultures of rat Sertoli cells. Toxicol Appl Pharmacol 101:124–134PubMedCrossRefGoogle Scholar
  53. Herbison AE, Moenter SM (2011) Depolarising and hyperpolarising actions of GABA(A) receptor activation on gonadotrophin-releasing hormone neurones: towards an emerging consensus. J Neuroendocrinol 23:557–569PubMedCentralPubMedCrossRefGoogle Scholar
  54. Herkenham M, Lynn AB, Johnson MR, Melvin LS, De Costa BR, Rice KC (1991) Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 11:563–583PubMedGoogle Scholar
  55. Herman JP, Figueiredo H, Mueller NK, Ulrich-Lai Y, Ostrander MM, Choi DC, Cullinan WE (2003) Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness. Front Neuroendocrinol 24:151–180PubMedCrossRefGoogle Scholar
  56. Hermanson DJ, Gamble-George JC, Marnett LJ, Patel S (2014) Substrate-selective COX-2 inhibition as a novel strategy for therapeutic endocannabinoid augmentation. Trends Pharmacol Sci 35:358–367PubMedCentralPubMedCrossRefGoogle Scholar
  57. Hill MN, Mclaughlin RJ, Morrish AC, Viau V, Floresco SB, Hillard CJ, Gorzalka BB (2009) Suppression of amygdalar endocannabinoid signaling by stress contributes to activation of the hypothalamic-pituitary-adrenal axis. Neuropsychopharmacology 34:2733–2745PubMedCentralPubMedCrossRefGoogle Scholar
  58. Hill MN, Mclaughlin RJ, Pan B, Fitzgerald ML, Roberts CJ, Lee TT, Karatsoreos IN, Mackie K, Viau V, Pickel VM, Mcewen BS, Liu QS, Gorzalka BB, Hillard CJ (2011) Recruitment of prefrontal cortical endocannabinoid signaling by glucocorticoids contributes to termination of the stress response. J Neurosci 31:10506–10515PubMedCentralPubMedCrossRefGoogle Scholar
  59. Hillard CJ, Farber NE, Hagen TC, Bloom AS (1984) The effects of delta 9-tetrahydrocannabinol on serum thyrotropin levels in the rat. Pharmacol Biochem Behav 20:547–550PubMedCrossRefGoogle Scholar
  60. Hirasawa M, Schwab Y, Natah S, Hillard CJ, Mackie K, Sharkey KA, Pittman QJ (2004) Dendritically released transmitters cooperate via autocrine and retrograde actions to inhibit afferent excitation in rat brain. J Physiol 559:611–624PubMedCentralPubMedCrossRefGoogle Scholar
  61. Huang GZ, Woolley CS (2012) Estradiol acutely suppresses inhibition in the hippocampus through a sex-specific endocannabinoid and mGluR-dependent mechanism. Neuron 74:801–808PubMedCentralPubMedCrossRefGoogle Scholar
  62. Hughes CL Jr, Everett JW, Tyrey L (1981) Delta 9-tetrahydrocannabinol suppression of prolactin secretion in the rat: lack of direct pituitary effect. Endocrinology 109:876–880PubMedCrossRefGoogle Scholar
  63. Huizink AC, Mulder EJ (2006) Maternal smoking, drinking or cannabis use during pregnancy and neurobehavioral and cognitive functioning in human offspring. Neurosci Biobehav Rev 30:24–41PubMedCrossRefGoogle Scholar
  64. Jakubovic A, Mcgeer EG, Mcgeer PL (1979) Effects of cannabinoids on testosterone and protein synthesis in rat testis Leydig cells in vitro. Mol Cell Endocrinol 15:41–50PubMedCrossRefGoogle Scholar
  65. Johnston J, Lintzeris N, Allsop DJ, Suraev A, Booth J, Carson DS, Helliwell D, Winstock A, Mcgregor IS (2014) Lithium carbonate in the management of cannabis withdrawal: a randomized placebo-controlled trial in an inpatient setting. Psychopharmacology (Berl) 231:4623–4636CrossRefGoogle Scholar
  66. Karamikheirabad M, Behzadi G, Faghihi M, Raoofian R, Ejtemaei Mehr S, Zuure WA, Sadeghipour HR (2013) A role for endocannabinoids in acute stress-induced suppression of the hypothalamic-pituitary-gonadal axis in male rats. Clin Exp Reprod Med 40:155–162PubMedCentralPubMedCrossRefGoogle Scholar
  67. Kearn CS, Greenberg MJ, Dicamelli R, Kurzawa K, Hillard CJ (1999) Relationships between ligand affinities for the cerebellar cannabinoid receptor CB1 and the induction of GDP/GTP exchange. J Neurochem 72:2379–2387PubMedCrossRefGoogle Scholar
  68. Khare M, Taylor AH, Konje JC, Bell SC (2006) Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod 12:321–333PubMedCrossRefGoogle Scholar
  69. King GR, Ernst T, Deng W, Stenger A, Gonzales RM, Nakama H, Chang L (2011) Altered brain activation during visuomotor integration in chronic active cannabis users: relationship to cortisol levels. J Neurosci 31:17923–17931PubMedCentralPubMedCrossRefGoogle Scholar
  70. Kleinloog D, Liem-Moolenaar M, Jacobs G, Klaassen E, De Kam M, Hijman R, Van Gerven J (2012) Does olanzapine inhibit the psychomimetic effects of Delta(9)-tetrahydrocannabinol? J Psychopharmacol 26:1307–1316PubMedCrossRefGoogle Scholar
  71. Klumpers LE, Cole DM, Khalili-Mahani N, Soeter RP, Te Beek ET, Rombouts SA, Van Gerven JM (2012) Manipulating brain connectivity with delta(9)-tetrahydrocannabinol: a pharmacological resting state FMRI study. Neuroimage 63:1701–1711PubMedCrossRefGoogle Scholar
  72. Kokka N, Garcia JF (1974) Effects of delta 9-THC on growth hormone and ACTH secretion in rats. Life Sci 15:329–338PubMedCrossRefGoogle Scholar
  73. Kola B, Wittman G, Bodnar I, Amin F, Lim CT, Olah M, Christ-Crain M, Lolli F, Van Thuijl H, Leontiou CA, Fuzesi T, Dalino P, Isidori AM, Harvey-White J, Kunos G, Nagy GM, Grossman AB, Fekete C, Korbonits M (2013) The CB1 receptor mediates the peripheral effects of ghrelin on AMPK activity but not on growth hormone release. FASEB J 27:5112–5121PubMedCentralPubMedCrossRefGoogle Scholar
  74. Kostellow AB, Ziegler D, Kunar J, Fujimoto GI, Morrill GA (1980) Effect of cannabinoids on estrous cycle, ovulation and reproductive capacity of female A/J mice. Pharmacology 21:68–75PubMedCrossRefGoogle Scholar
  75. Kouznetsova M, Kelley B, Shen M, Thayer SA (2002) Desensitization of cannabinoid-mediated presynaptic inhibition of neurotransmission between rat hippocampal neurons in culture. Mol Pharmacol 61:477–485PubMedCrossRefGoogle Scholar
  76. Kramer J, Ben-David M (1978) Prolactin suppression by (-) delta-9-tetrahydrocannabinol (THC): involvement of serotonergic and dopaminergic pathways. Endocrinology 103:452–457PubMedCrossRefGoogle Scholar
  77. Kumar MS, Chen CL (1983) Effect of an acute dose of delta 9-THC on hypothalamic luteinizing hormone releasing hormone and met-enkephalin content and serum levels of testosterone and corticosterone in rats. Subst Alcohol Actions Misuse 4:37–43PubMedGoogle Scholar
  78. Kumar RN, Chambers WA, Pertwee RG (2001) Pharmacological actions and therapeutic uses of cannabis and cannabinoids. Anaesthesia 56:1059–1068PubMedCrossRefGoogle Scholar
  79. Liedhegner ES, Sasman A, Hillard CJ (2014) Brain region-specific changes in N-acylethanolamine contents with time of day. J Neurochem 128:491–506PubMedCentralPubMedCrossRefGoogle Scholar
  80. Liem-Moolenaar M, Te Beek ET, De Kam ML, Franson KL, Kahn RS, Hijman R, Touw D, Van Gerven JM (2010) Central nervous system effects of haloperidol on THC in healthy male volunteers. J Psychopharmacol 24:1697–1708PubMedCrossRefGoogle Scholar
  81. Luce V, Fernandez Solari J, Rettori V, De Laurentiis A (2014) The inhibitory effect of anandamide on oxytocin and vasopressin secretion from neurohypophysis is mediated by nitric oxide. Regul Pept 188:31–39PubMedCrossRefGoogle Scholar
  82. Maccarrone M, Cecconi S, Rossi G, Battista N, Pauselli R, Finazzi-Agro A (2003) Anandamide activity and degradation are regulated by early postnatal aging and follicle-stimulating hormone in mouse Sertoli cells. Endocrinology 144:20–28PubMedCrossRefGoogle Scholar
  83. Majumdar A, Mangal NS (2013) Hyperprolactinemia. J Hum Reprod Sci 6:168–175PubMedCentralPubMedCrossRefGoogle Scholar
  84. Mani SK, Mitchell A, O’malley BW (2001) Progesterone receptor and dopamine receptors are required in Delta 9-tetrahydrocannabinol modulation of sexual receptivity in female rats. Proc Natl Acad Sci U S A 98:1249–1254PubMedCentralPubMedGoogle Scholar
  85. Manzanares J, Corchero J, Fuentes JA (1999) Opioid and cannabinoid receptor-mediated regulation of the increase in adrenocorticotropin hormone and corticosterone plasma concentrations induced by central administration of delta(9)-tetrahydrocannabinol in rats. Brain Res 839:173–179PubMedCrossRefGoogle Scholar
  86. Marks BH (1973) Delta1-tetrahydrocannabinol and luteinizing hormone secretion. Prog Brain Res 39:331–338PubMedCrossRefGoogle Scholar
  87. Marrs WR, Blankman JL, Horne EA, Thomazeau A, Lin YH, Coy J, Bodor AL, Muccioli GG, Hu SS, Woodruff G, Fung S, Lafourcade M, Alexander JP, Long JZ, Li W, Xu C, Moller T, Mackie K, Manzoni OJ, Cravatt BF, Stella N (2010) The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors. Nat Neurosci 13:951–957PubMedCentralPubMedCrossRefGoogle Scholar
  88. Martin-Calderon JL, Munoz RM, Villanua MA, Del Arco I, Moreno JL, De Fonseca FR, Navarro M (1998) Characterization of the acute endocrine actions of (-)-11-hydroxy-delta8-tetrahydrocannabinol-dimethylheptyl (HU-210), a potent synthetic cannabinoid in rats. Eur J Pharmacol 344:77–86PubMedCrossRefGoogle Scholar
  89. Mcdonald NA, Kuzmiski JB, Naderi N, Schwab Y, Pittman QJ (2008) Endogenous modulators of synaptic transmission: cannabinoid regulation in the supraoptic nucleus. Prog Brain Res 170:129–136PubMedCentralPubMedCrossRefGoogle Scholar
  90. Mcgregor IS, Callaghan PD, Hunt GE (2008) From ultrasocial to antisocial: a role for oxytocin in the acute reinforcing effects and long-term adverse consequences of drug use? Br J Pharmacol 154:358–368PubMedCentralPubMedCrossRefGoogle Scholar
  91. Mclaughlin RJ, Hill MN, Gorzalka BB (2009) Monoaminergic neurotransmission contributes to cannabinoid-induced activation of the hypothalamic-pituitary-adrenal axis. Eur J Pharmacol 624:71–76PubMedCrossRefGoogle Scholar
  92. Moon JY, Kwon W, Suh S, Cheong JC, In MK, Chung BC, Kim JY, Choi MH (2014) Reference ranges for urinary levels of testosterone and epitestosterone, which may reveal gonadal function, in a Korean male population. J Steroid Biochem Mol Biol 140:100–105PubMedCrossRefGoogle Scholar
  93. Moschovakis A, Liakopoulos D, Armaganidis A, Kapsambelis V, Papanikolaou G, Petroulakis G (1978) Cannabis interferes with nest-building behavior in mice. Psychopharmacology (Berl) 58:181–183CrossRefGoogle Scholar
  94. Murillo-Rodriguez E, Vazquez E, Millan-Aldaco D, Palomero-Rivero M, Drucker-Colin R (2007) Effects of the fatty acid amide hydrolase inhibitor URB597 on the sleep-wake cycle, c-Fos expression and dopamine levels of the rat. Eur J Pharmacol 562:82–91PubMedCrossRefGoogle Scholar
  95. Murillo-Rodriguez E, Palomero-Rivero M, Millan-Aldaco D, Arias-Carrion O, Drucker-Colin R (2011) Administration of URB597, oleoylethanolamide or palmitoylethanolamide increases waking and dopamine in rats. PLoS One 6, e20766PubMedCentralPubMedCrossRefGoogle Scholar
  96. Murphy LL, Steger RW, Smith MS, Bartke A (1990) Effects of delta-9-tetrahydrocannabinol, cannabinol and cannabidiol, alone and in combinations, on luteinizing hormone and prolactin release and on hypothalamic neurotransmitters in the male rat. Neuroendocrinology 52:316–321PubMedCrossRefGoogle Scholar
  97. Murphy LL, Newton SC, Dhali J, Chavez D (1991a) Evidence for a direct anterior pituitary site of delta-9-tetrahydrocannabinol action. Pharmacol Biochem Behav 40:603–607PubMedCrossRefGoogle Scholar
  98. Murphy LL, Rodriguez De Fonseca F, Steger RW (1991b) delta 9-Tetrahydrocannabinol antagonism of the anterior pituitary response to estradiol in immature female rats. Steroids 56:97–102PubMedCrossRefGoogle Scholar
  99. Natelson BH, Holaday J, Meyerhoff J, Stokes PE (1975) Temporal changes in growth hormone, cortisol, and glucose: relation to light onset and behavior. Am J Physiol 229:409–415PubMedGoogle Scholar
  100. Nazar B, Kairys DJ, Fowler R, Harclerode J (1977) Effects of delta9-tetrahydrocannabinol on serum thyroxine concentrations in the rat. J Pharm Pharmacol 29:778–779PubMedCrossRefGoogle Scholar
  101. Neumann I, Ludwig M, Engelmann M, Pittman QJ, Landgraf R (1993) Simultaneous microdialysis in blood and brain: oxytocin and vasopressin release in response to central and peripheral osmotic stimulation and suckling in the rat. Neuroendocrinology 58:637–645PubMedCrossRefGoogle Scholar
  102. Newsom RJ, Osterlund C, Masini CV, Day HE, Spencer RL, Campeau S (2012) Cannabinoid receptor type 1 antagonism significantly modulates basal and loud noise induced neural and hypothalamic-pituitary-adrenal axis responses in male Sprague-Dawley rats. Neuroscience 204:64–73PubMedCentralPubMedCrossRefGoogle Scholar
  103. Niederhoffer N, Hansen HH, Fernandez-Ruiz JJ, Szabo B (2001) Effects of cannabinoids on adrenaline release from adrenal medullary cells. Br J Pharmacol 134:1319–1327PubMedCentralPubMedCrossRefGoogle Scholar
  104. Ninan I (2011) Oxytocin suppresses basal glutamatergic transmission but facilitates activity-dependent synaptic potentiation in the medial prefrontal cortex. J Neurochem 119(2):324–331PubMedCrossRefGoogle Scholar
  105. Nir I, Ayalon D, Tsafriri A, Cordova T, Lindner HR (1973) Letter: suppression of the cyclic surge of luteinizing hormone secretion and of ovulation in the rat by delta 1-tetrahydrocannabinol. Nature 243:470–471PubMedCrossRefGoogle Scholar
  106. Ohara N, Tsujino T, Maruo T (2004) The role of thyroid hormone in trophoblast function, early pregnancy maintenance, and fetal neurodevelopment. J Obstet Gynaecol Can 26:982–990PubMedGoogle Scholar
  107. Oliet SH, Baimoukhametova DV, Piet R, Bains JS (2007) Retrograde regulation of GABA transmission by the tonic release of oxytocin and endocannabinoids governs postsynaptic firing. J Neurosci 27:1325–1333PubMedCrossRefGoogle Scholar
  108. O’shea M, Singh ME, Mcgregor IS, Mallet PE (2004) Chronic cannabinoid exposure produces lasting memory impairment and increased anxiety in adolescent but not adult rats. J Psychopharmacol 18:502–508PubMedCrossRefGoogle Scholar
  109. O’shea M, Mcgregor IS, Mallet PE (2006) Repeated cannabinoid exposure during perinatal, adolescent or early adult ages produces similar long-lasting deficits in object recognition and reduced social interaction in rats. J Psychopharmacol 20:611–621PubMedCrossRefGoogle Scholar
  110. Pagotto U, Marsicano G, Fezza F, Theodoropoulou M, Grubler Y, Stalla J, Arzberger T, Milone A, Losa M, Di Marzo V, Lutz B, Stalla GK (2001) Normal human pituitary gland and pituitary adenomas express cannabinoid receptor type 1 and synthesize endogenous cannabinoids: first evidence for a direct role of cannabinoids on hormone modulation at the human pituitary level. J Clin Endocrinol Metab 86:2687–2696PubMedGoogle Scholar
  111. Patel S, Roelke CT, Rademacher DJ, Cullinan WE, Hillard CJ (2004) Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal axis. Endocrinology 145:5431–5438PubMedCrossRefGoogle Scholar
  112. Penela P, Alvarez-Dolado M, Munoz A, Mayor F Jr (2000) Expression patterns of the regulatory proteins G protein-coupled receptor kinase 2 and beta-arrestin 1 during rat postnatal brain development: effect of hypothyroidism. Eur J Biochem 267:4390–4396PubMedCrossRefGoogle Scholar
  113. Penela P, Barradas M, Alvarez-Dolado M, Munoz A, Mayor F Jr (2001) Effect of hypothyroidism on G protein-coupled receptor kinase 2 expression levels in rat liver, lung, and heart. Endocrinology 142:987–991PubMedGoogle Scholar
  114. Pichini S, De Luca R, Pellegrini M, Marchei E, Rotolo MC, Spoletini R, D’aloja P, Pacifici R, Mortali C, Scaravelli G (2012) Hair and urine testing to assess drugs of abuse consumption in couples undergoing assisted reproductive technology (ART). Forensic Sci Int 218:57–61PubMedCrossRefGoogle Scholar
  115. Porcella A, Marchese G, Casu MA, Rocchitta A, Lai ML, Gessa GL, Pani L (2002) Evidence for functional CB1 cannabinoid receptor expressed in the rat thyroid. Eur J Endocrinol 147:255–261PubMedCrossRefGoogle Scholar
  116. Quinn HR, Matsumoto I, Callaghan PD, Long LE, Arnold JC, Gunasekaran N, Thompson MR, Dawson B, Mallet PE, Kashem MA, Matsuda-Matsumoto H, Iwazaki T, Mcgregor IS (2008) Adolescent rats find repeated Delta(9)-THC less aversive than adult rats but display greater residual cognitive deficits and changes in hippocampal protein expression following exposure. Neuropsychopharmacology 33:1113–1126PubMedCrossRefGoogle Scholar
  117. Ranganathan M, Braley G, Pittman B, Cooper T, Perry E, Krystal J, D’Souza DC (2009) The effects of cannabinoids on serum cortisol and prolactin in humans. Psychopharmacology (Berl) 203:737–744CrossRefGoogle Scholar
  118. Rettori V, Wenger T, Snyder G, Dalterio S, Mccann SM (1988) Hypothalamic action of delta-9-tetrahydrocannabinol to inhibit the release of prolactin and growth hormone in the rat. Neuroendocrinology 47:498–503PubMedCrossRefGoogle Scholar
  119. Rettori V, Aguila MC, Gimeno MF, Franchi AM, Mccann SM (1990) In vitro effect of delta 9-tetrahydrocannabinol to stimulate somatostatin release and block that of luteinizing hormone-releasing hormone by suppression of the release of prostaglandin E2. Proc Natl Acad Sci USA 87:10063–10066PubMedCentralPubMedCrossRefGoogle Scholar
  120. Rodriguez De Fonseca F, Fernandez-Ruiz JJ, Murphy LL, Cebeira M, Steger RW, Bartke A, Ramos JA (1992) Acute effects of delta-9-tetrahydrocannabinol on dopaminergic activity in several rat brain areas. Pharmacol Biochem Behav 42:269–275PubMedCrossRefGoogle Scholar
  121. Rodriguez De Fonseca F, Cebeira M, Martin M, Fernandez-Ruiz JJ (1994) Cannabinoid receptors in rat brain areas: sexual differences, fluctuations during estrous cycle and changes after gonadectomy and sex steroid replacement. Life Sci 54:159–170PubMedCrossRefGoogle Scholar
  122. Rosenkrantz H, Esber HJ (1980) Cannabinoid-induced hormone changes in monkeys and rats. J Toxicol Environ Health 6:297–313PubMedCrossRefGoogle Scholar
  123. Sabatier N, Leng G (2006) Presynaptic actions of endocannabinoids mediate {alpha}-MSH-induced inhibition of oxytocin cells. Am J Physiol Regul Integr Comp Physiol 290:R577–R584PubMedCrossRefGoogle Scholar
  124. Saber-Tehrani A, Naderi N, Hosseini Najarkolaei A, Haghparast A, Motamedi F (2010) Cannabinoids and their interactions with diazepam on modulation of serum corticosterone concentration in male mice. Neurochem Res 35:60–66PubMedCrossRefGoogle Scholar
  125. Schechter M, Pinhasov A, Weller A, Fride E (2012) Blocking the postpartum mouse dam’s CB1 receptors impairs maternal behavior as well as offspring development and their adult social-emotional behavior. Behav Brain Res 226:481–492PubMedCrossRefGoogle Scholar
  126. Schechter M, Weller A, Pittel Z, Gross M, Zimmer A, Pinhasov A (2013) Endocannabinoid receptor deficiency affects maternal care and alters the dam’s hippocampal oxytocin receptor and brain-derived neurotrophic factor expression. J Neuroendocrinol 25:898–909PubMedCrossRefGoogle Scholar
  127. Scorticati C, Mohn C, De Laurentiis A, Vissio P, Fernandez Solari J, Seilicovich A, Mccann SM, Rettori V (2003) The effect of anandamide on prolactin secretion is modulated by estrogen. Proc Natl Acad Sci USA 100:2134–2139PubMedCentralPubMedCrossRefGoogle Scholar
  128. Scorticati C, Fernandez-Solari J, De Laurentiis A, Mohn C, Prestifilippo JP, Lasaga M, Seilicovich A, Billi S, Franchi A, Mccann SM, Rettori V (2004) The inhibitory effect of anandamide on luteinizing hormone-releasing hormone secretion is reversed by estrogen. Proc Natl Acad Sci USA 101:11891–11896PubMedCentralPubMedCrossRefGoogle Scholar
  129. Sieber B, Frischknecht HR, Waser PG (1980) Behavioral effects of hashish in mice. I. Social interactions and nest-building behavior of males. Psychopharmacology (Berl) 70:149–154CrossRefGoogle Scholar
  130. Silvestri C, Ligresti A, Di Marzo V (2011) Peripheral effects of the endocannabinoid system in energy homeostasis: adipose tissue, liver and skeletal muscle. Rev Endocr Metab Disord 12:153–162PubMedCrossRefGoogle Scholar
  131. Smith CG, Besch NF, Smith RG, Besch PK (1979) Effect of tetrahydrocannabinol on the hypothalamic-pituitary axis in the ovariectomized rhesus monkey. Fertil Steril 31:335–339PubMedGoogle Scholar
  132. Somaini L, Manfredini M, Amore M, Zaimovic A, Raggi MA, Leonardi C, Gerra ML, Donnini C, Gerra G (2012) Psychobiological responses to unpleasant emotions in cannabis users. Eur Arch Psychiatry Clin Neurosci 262:47–57PubMedCrossRefGoogle Scholar
  133. Steger RW, Murphy LL, Bartke A, Smith MS (1990) Effects of psychoactive and nonpsychoactive cannabinoids on the hypothalamic-pituitary axis of the adult male rat. Pharmacol Biochem Behav 37:299–302PubMedCrossRefGoogle Scholar
  134. Steiner MA, Wotjak CT (2008) Role of the endocannabinoid system in regulation of the hypothalamic-pituitary-adrenocortical axis. Prog Brain Res 170:397–432PubMedCrossRefGoogle Scholar
  135. Takahashi Y, Kipnis DM, Daughaday WH (1968) Growth hormone secretion during sleep. J Clin Invest 47:2079–2090PubMedCentralPubMedCrossRefGoogle Scholar
  136. Tyrey L (1978) delta-9-Tetrahydrocannabinol suppression of episodic luteinizing hormone secretion in the ovariectomized rat. Endocrinology 102:1808–1814PubMedCrossRefGoogle Scholar
  137. Vaccari C, Lolait SJ, Ostrowski NL (1998) Comparative distribution of vasopressin V1b and oxytocin receptor messenger ribonucleic acids in brain. Endocrinology 139:5015–5033PubMedGoogle Scholar
  138. Van Leeuwen AP, Verhulst FC, Reijneveld SA, Vollebergh WA, Ormel J, Huizink AC (2011) Can the gateway hypothesis, the common liability model and/or, the route of administration model predict initiation of cannabis use during adolescence? A survival analysis—the TRAILS study. J Adolesc Health 48:73–78PubMedCrossRefGoogle Scholar
  139. Veiga M, Bloise F, Costa ESR, Souza L, Almeida N, Oliveira K, Pazos-Moura C (2008) Acute effects of endocannabinoid anandamide and CB-1 receptor antagonist, AM251 in the regulation of thyrotropin secretion. J Endocrinol 199:235–242PubMedCrossRefGoogle Scholar
  140. Vilela FC, Giusti-Paiva A (2014) Cannabinoid receptor agonist disrupts behavioral and neuroendocrine responses during lactation. Behav Brain Res 263:190–197PubMedCrossRefGoogle Scholar
  141. Vilela FC, Ruginsk SG, De Melo CM, Giusti-Paiva A (2013) The CB1 cannabinoid receptor mediates glucocorticoid-induced effects on behavioural and neuronal responses during lactation. Pflugers Arch 465:1197–1207PubMedCrossRefGoogle Scholar
  142. Wade MR, Degroot A, Nomikos GG (2006) Cannabinoid CB1 receptor antagonism modulates plasma corticosterone in rodents. Eur J Pharmacol 551:162–167PubMedCrossRefGoogle Scholar
  143. Wang L, Armstrong WE (2012) Tonic regulation of GABAergic synaptic activity on vasopressin neurones by cannabinoids. J Neuroendocrinol 24:664–673PubMedCentralPubMedCrossRefGoogle Scholar
  144. Wang M, Hill MN, Zhang L, Gorzalka BB, Hillard CJ, Alger BE (2012) Acute restraint stress enhances hippocampal endocannabinoid function via glucocorticoid receptor activation. J Psychopharmacol 26:56–70PubMedCentralPubMedCrossRefGoogle Scholar
  145. Wenger T, Rettori V, Snyder GD, Dalterio S, Mccann SM (1987) Effects of delta-9-tetrahydrocannabinol on the hypothalamic-pituitary control of luteinizing hormone and follicle-stimulating hormone secretion in adult male rats. Neuroendocrinology 46:488–493PubMedCrossRefGoogle Scholar
  146. Wenger T, Ledent C, Csernus V, Gerendai I (2001) The central cannabinoid receptor inactivation suppresses endocrine reproductive functions. Biochem Biophys Res Commun 284:363–368PubMedCrossRefGoogle Scholar
  147. Wittmann G, Deli L, Kallo I, Hrabovszky E, Watanabe M, Liposits Z, Fekete C (2007) Distribution of type 1 cannabinoid receptor (CB1)-immunoreactive axons in the mouse hypothalamus. J Comp Neurol 503:270–279PubMedCrossRefGoogle Scholar
  148. Yasuo S, Fischer C, Bojunga J, Iigo M, Korf HW (2014) 2-Arachidonoyl glycerol sensitizes the pars distalis and enhances forskolin-stimulated prolactin secretion in Syrian hamsters. Chronobiol Int 31:337–342PubMedCrossRefGoogle Scholar
  149. Ziegler CG, Mohn C, Lamounier-Zepter V, Rettori V, Bornstein SR, Krug AW, Ehrhart-Bornstein M (2010) Expression and function of endocannabinoid receptors in the human adrenal cortex. Horm Metab Res 42:88–92PubMedCrossRefGoogle Scholar
  150. Zuckerman B, Frank DA, Hingson R, Amaro H, Levenson SM, Kayne H, Parker S, Vinci R, Aboagye K, Fried LE et al (1989) Effects of maternal marijuana and cocaine use on fetal growth. N Engl J Med 320:762–768PubMedCrossRefGoogle Scholar

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© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Neuroscience Research Center and Department of Pharmacology and ToxicologyMedical College of WisconsinMilwaukeeUSA

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