Alcohol binge drinking is common among adolescents and may challenge the signalling systems that process affective stimuli, including calcitonin gene-related peptide (CGRP) signalling. Here, we employed a rat model of adolescent binge drinking to evaluate reward-, social- and aversion-related behaviour, glucocorticoid output and CGRP levels in affect-related brain regions. As a potential rescue, the effect of the phytocannabinoid cannabidiol was explored. Adolescent male rats underwent the intermittent 20% alcohol two-bottle choice paradigm; at the binge day (BD) and the 24 h withdrawal day (WD), we assessed CGRP expression in medial prefrontal cortex (mPFC), nucleus accumbens (NAc), amygdala, hypothalamus and brainstem; in addition, we evaluated sucrose preference, social motivation and drive, nociceptive response, and serum corticosterone levels. Cannabidiol (40 mg/kg, i.p.) was administered before each drinking session, and its effect was measured on the above-mentioned readouts. At BD and WD, rats displayed decreased CGRP expression in mPFC, NAc and amygdala; increased CGRP levels in the brainstem; increased response to rewarding- and nociceptive stimuli and decreased social drive; reduced serum corticosterone levels. Cannabidiol reduced alcohol consumption and preference; normalised the abnormal corticolimbic CGRP expression, and the reward and aversion-related hyper-responsivity, as well as glucocorticoid levels in alcohol binge-like drinking rats. Overall, CGRP can represent both a mediator and a target of alcohol binge-like drinking and provides a further piece in the intricate puzzle of alcohol-induced behavioural and neuroendocrine sequelae. CBD shows promising effects in limiting adolescent alcohol binge drinking and rebalancing the bio-behavioural abnormalities.

Department of Biomedicine Neuroscience and Advanced Diagnostics University of Palermo Palermo Italy

Department of Health Promotion Mother and Child Care Internal Medicine and Medical Specialties of Excellence G D'Alessandro University of Palermo Palermo Italy

Fondazione Policlinico Universitario A Gemelli IRCSS Rome Italy

Forensic Laboratory of Biologically Active Compounds Department of Chemistry of Natural Compounds University of Chemistry and Technology Prague Czechia

Pharmacology Section Department of Health Care Surveillance and Bioethics Università Cattolica del Sacro Cuore Rome Italy

Psychedelics Research Centre National Institute of Mental Health Prague Czechia

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Agoglia, A. E., Holstein, S. E., Eastman, V. R., & Hodge, C. W. (2016). Cannabinoid CB1 receptor inhibition blunts adolescent-typical increased binge alcohol and sucrose consumption in male C57BL/6J mice. Pharmacology, Biochemistry, and Behavior, 143, 11-17.

Barik, J., Marti, F., Morel, C., Fernandez, S. P., Lanteri, C., Godeheu, G., Tassin, J. P., Mombereau, C., Faure, P., & Tronche, F. (2013). Chronic stress triggers social aversion via glucocorticoid receptor in dopaminoceptive neurons. Science, 339(6117), 332-335.

Belmer, A., Depoortere, R., Beecher, K., Newman-Tancredi, A., & Bartlett, S. E. (2022). Neural serotonergic circuits for controlling long-term voluntary alcohol consumption in mice. Molecular Psychiatry, 27(11), 4599-4610.

Bowe, J. E., Li, X. F., Kinsey-Jones, J. S., Brain, S. D., Lightman, S. L., & O'Byrne, K. T. (2008). The role of corticotrophin-releasing hormone receptors in the calcitonin gene-related peptide-induced suppression of pulsatile luteinising hormone secretion in the female rat. Stress, 11(4), 312-319.

Bowen, A. J., Huang, Y. W., Chen, J. Y., Pauli, J. L., Campos, C. A., & Palmiter, R. D. (2023). Topographic representation of current and future threats in the mouse nociceptive amygdala. Nature Communications, 14(1), 196.

Brancato, A., & Cannizzaro, C. (2018). Mothering under the influence: How perinatal drugs of abuse alter the mother-infant interaction. Reviews in the Neurosciences, 29(3), 283-294.

Brancato, A., Castelli, V., Cannizzaro, C., & Tringali, G. (2023). Adolescent binge-like alcohol exposure dysregulates NPY and CGRP in rats: Behavioural and immunochemical evidence. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 123, 110699.

Brancato, A., Castelli, V., Cavallaro, A., Lavanco, G., Plescia, F., & Cannizzaro, C. (2018). Pre-conceptional and peri-gestational maternal binge alcohol drinking produces inheritance of mood disturbances and alcohol vulnerability in the adolescent offspring. Frontiers in Psychiatry, 9, 150.

Brancato, A., Castelli, V., Lavanco, G., D'Amico, C., Feo, S., Pizzolanti, G., Kuchar, M., & Cannizzaro, C. (2022). Social stress under binge-like alcohol withdrawal in adolescence: Evidence of cannabidiol effect on maladaptive plasticity in rats. Psychological Medicine, 1-13. https://doi.org/10.1017/S0033291722002744

Brancato, A., Castelli, V., Lavanco, G., Tringali, G., Micale, V., Kuchar, M., D'Amico, C., Pizzolanti, G., Feo, S., & Cannizzaro, C. (2021). Binge-like alcohol exposure in adolescence: behavioural, neuroendocrine and molecular evidence of abnormal neuroplasticity… and return. Biomedicine, 9(9), 1161.

Brancato, A., Lavanco, G., Cavallaro, A., Plescia, F., & Cannizzaro, C. (2016). The use of the emotional-object recognition as an assay to assess learning and memory associated to an aversive stimulus in rodents. Journal of Neuroscience Methods, 274, 106-115.

Brown, M. R., & Gray, T. S. (1988). Peptide injections into the amygdala of conscious rats: Effects on blood pressure, heart rate and plasma catecholamines. Regulatory Peptides, 21(1-2), 95-106.

Campos, C. A., Bowen, A. J., Roman, C. W., & Palmiter, R. D. (2018). Encoding of danger by parabrachial CGRP neurons. Nature, 555(7698), 617-622.

Cappell, H., & Herman, C. P. (1972). Alcohol and tension reduction. A review. Quarterly Journal of Studies on Alcohol, 33(1), 33-64.

Capuano, A., Currò, D., Navarra, P., & Tringali, G. (2011). Cortistatin modulates calcitonin gene-related peptide release from neuronal tissues of rat. Comparison with Somatostatin. Peptides, 32(1), 138-143.

Carboni, L., El Khoury, A., Beiderbeck, D. I., Neumann, I. D., & Mathé, A. A. (2022). Neuropeptide Y, calcitonin gene-related peptide, and neurokinin A in brain regions of HAB rats correlate with anxiety-like behaviours. European Neuropsychopharmacology: The Journal of the European College of Neuropsychopharmacology, 57, 1-14.

Carnicella, S., Ron, D., & Barak, S. (2014). Intermittent ethanol access schedule in rats as a preclinical model of alcohol abuse. Alcohol (Fayetteville, N.Y.), 48(3), 243-252.

Carrigan, M. H., & Randall, C. L. (2003). Self-medication in social phobia: A review of the alcohol literature. Addictive Behaviors, 28(2), 269-284.

Castelli, V., Plescia, F., Maniaci, G., Lavanco, G., Pizzolanti, G., Brancato, A., & Cannizzaro, C. (2022). Alcohol binge drinking in adolescence and psychological profile: Can the preclinical model crack the chicken-or-egg question? Frontiers in Psychiatry, 13, 996965.

Chesney, E., Oliver, D., Green, A., Sovi, S., Wilson, J., Englund, A., Freeman, T. P., & McGuire, P. (2020). Adverse effects of cannabidiol: A systematic review and meta-analysis of randomized clinical trials. Neuropsychopharmacology, 45(11), 1799-1806.

Crews, F. T., Vetreno, R. P., Broadwater, M. A., & Robinson, D. L. (2016). Adolescent alcohol exposure persistently impacts adult neurobiology and behavior. Pharmacological Reviews, 68(4), 1074-1109.

Dina, O. A., Messing, R. O., & Levine, J. D. (2006). Ethanol withdrawal induces hyperalgesia mediated by PKCepsilon. The European Journal of Neuroscience, 24(1), 197-204.

Ehinger, Y., Phamluong, K., Darevesky, D., Welman, M., Moffat, J. J., Sakhai, S. A., Whiteley, E. L., Berger, A. L., Laguesse, S., Farokhnia, M., Leggio, L., Lordkipanidzé, M., & Ron, D. (2021). Differential correlation of serum BDNF and microRNA content in rats with rapid or late onset of heavy alcohol use. Addiction Biology, 26(2), e12890.

Ehlers, C. L., Somes, C., Li, T. K., Lumeng, L., Hwang, B. H., Jimenez, P., & Mathé, A. A. (1999). Calcitonin gene-related peptide (CGRP) levels and alcohol. The International Journal of Neuropsychopharmacology, 2(3), 173-179.

Eiden, L. E., Hernández, V. S., Jiang, S. Z., & Zhang, L. (2022). Neuropeptides and small-molecule amine transmitters: Cooperative signaling in the nervous system. Cellular and Molecular Life Sciences, 79(9), 492.

Etemad, L., Karimi, G., Alavi, M. S., & Roohbakhsh, A. (2022). Pharmacological effects of cannabidiol by transient receptor potential channels. Life Sciences, 300, 120582.

Galaj, E., & Xi, Z. X. (2020). Possible receptor mechanisms underlying cannabidiol effects on addictive-like behaviors in experimental animals. International Journal of Molecular Sciences, 22(1), 134.

Gatch, M. B., & Lal, H. (1999). Effects of ethanol and ethanol withdrawal on nociception in rats. Alcoholism, Clinical and Experimental Research, 23(2), 328-333.

Gonzalez-Cuevas, G., Martin-Fardon, R., Kerr, T. M., Stouffer, D. G., Parsons, L. H., Hammell, D. C., Banks, S. L., Stinchcomb, A. L., & Weiss, F. (2018). Unique treatment potential of cannabidiol for the prevention of relapse to drug use: Preclinical proof of principle. Neuropsychopharmacology, 43(10), 2036-2045.

Greco, M. C., Navarra, P., & Tringali, G. (2016). The analgesic agent tapentadol inhibits calcitonin gene-related peptide release from isolated rat brainstem via a serotonergic mechanism. Life Sciences, 145, 161-165.

Gregor, D. M., Zuo, W., Fu, R., Bekker, A., & Ye, J. H. (2019). Elevation of transient receptor potential vanilloid 1 function in the lateral habenula mediates aversive behaviors in alcohol-withdrawn rats. Anesthesiology, 130(4), 592-608.

Harrigan, E. A., Magnuson, D. J., Thunstedt, G. M., & Gray, T. S. (1994). Corticotropin releasing factor neurons are innervated by calcitonin gene-related peptide terminals in the rat central amygdaloid nucleus. Brain Research Bulletin, 33(5), 529-534.

Hikida, T., Yawata, S., Yamaguchi, T., Danjo, T., Sasaoka, T., Wang, Y., & Nakanishi, S. (2013). Pathway-specific modulation of nucleus accumbens in reward and aversive behavior via selective transmitter receptors. Proceedings of the National Academy of Sciences of the United States of America, 110(1), 342-347.

Hiller-Sturmhöfel, S., & Spear, L. P. (2018). Binge drinking's effects on the developing brain-animal models. Alcohol Research: Current Reviews, 39(1), 77-86.

Hložek, T., Uttl, L., Kadeřábek, L., Balíková, M., Lhotková, E., Horsley, R. R., Nováková, P., Šíchová, K., Štefková, K., Tylš, F., Kuchař, M., & Páleníček, T. (2017). Pharmacokinetic and behavioural profile of THC, CBD, and THC+CBD combination after pulmonary, oral, and subcutaneous administration in rats and confirmation of conversion in vivo of CBD to THC. European Neuropsychopharmacology, 27(12), 1223-1237.

Hwang, B. H., Kunkler, P. E., Lumeng, L., & Li, T. K. (1995). Calcitonin gene-related peptide (CGRP) content and CGRP receptor binding sites in discrete forebrain regions of alcohol-preferring vs. -nonpreferring rats, and high alcohol-drinking vs. low alcohol-drinking rats. Brain Research, 690(2), 249-253.

Kang, S. J., Liu, S., Ye, M., Kim, D. I., Pao, G. M., Copits, B. A., Roberts, B. Z., Lee, K. F., Bruchas, M. R., & Han, S. (2022). A central alarm system that gates multi-sensory innate threat cues to the amygdala. Cell Reports, 40(7), 111222.

Kovács, A., Biró, E., Szeleczky, I., & Telegdy, G. (1995). Role of endogenous CRF in the mediation of neuroendocrine and behavioral responses to calcitonin gene-related peptide in rats. Neuroendocrinology, 62(4), 418-424.

Kovács, A., & Telegdy, G. (1995). Effects of CGRP on active avoidance behavior in rats. Physiology & Behavior, 58(3), 429-435.

Kwee, C. M., van Gerven, J. M., Bongaerts, F. L., Cath, D. C., Jacobs, G., Baas, J. M., & Groenink, L. (2022). Cannabidiol in clinical and preclinical anxiety research. A systematic review into concentration-effect relations using the IB-de-risk tool. Journal of Psychopharmacology, 36(12), 1299-1314.

Laux, L. C., Bebin, E. M., Checketts, D., Chez, M., Flamini, R., Marsh, E. D., Miller, I., Nichol, K., Park, Y., Segal, E., Seltzer, L., Szaflarski, J. P., Thiele, E. A., & Weinstock, A. (2019). Long-term safety and efficacy of cannabidiol in children and adults with treatment resistant Lennox-Gastaut syndrome or Dravet syndrome: Expanded access program results. Epilepsy Research, 154, 13-20. https://doi.org/10.1016/j.eplepsyres.2019.03.015

Li, J., Chen, P., Han, X., Zuo, W., Mei, Q., Bian, E. Y., Umeugo, J., & Ye, J. (2019). Differences between male and female rats in alcohol drinking, negative affects and neuronal activity after acute and prolonged abstinence. International Journal of Physiology, Pathophysiology and Pharmacology, 11(4), 163-176.

Loy, J. K., Seitz, N. N., Bye, E. K., Raitasalo, K., Soellner, R., Törrönen, J., & Kraus, L. (2021). Trends in alcohol consumption among adolescents in Europe: Do changes occur in concert? Drug and Alcohol Dependence, 228, 109020.

Maccioni, P., Bratzu, J., Carai, M. A. M., Colombo, G., & Gessa, G. L. (2022). Reducing effect of cannabidiol on Alcohol Self-Administration in Sardinian Alcohol-Preferring Rats. Cannabis and Cannabinoid Research, 7(2), 161-169.

Maniaci, G., Picone, F., Dimarco, T., Lipari, A., Brancato, A., & Cannizzaro, C. (2015). Psychodiagnostic assessment of pathological gamblers: A focus on personality disorders, clinical syndromes and alexithymia. International Journal of Mental Health and Addiction, 13(6), 728-739. https://doi.org/10.1007/s11469-015-9550-5

Merighi, A., Salio, C., Ferrini, F., & Lossi, L. (2011). Neuromodulatory function of neuropeptides in the normal CNS. Journal of Chemical Neuroanatomy, 42(4), 276-287.

Metz, V. G., da Rosa, J. L. O., Rossato, D. R., Milanesi, L. H., Burger, M. E., & Pase, C. S. (2021). Cannabidiol prevents amphetamine relapse and modulates D1- and D2-receptor levels in mesocorticolimbic brain areas of rats. European Neuropsychopharmacology, 50, 23-33. https://doi.org/10.1016/j.euroneuro.2021.04.008

Myers, B., McKlveen, J. M., & Herman, J. P. (2014). Glucocorticoid actions on synapses, circuits, and behavior: Implications for the energetics of stress. Frontiers in Neuroendocrinology, 35(2), 180-196.

National Institute on Alcohol Abuse and Alcoholism. (2004). NIAAA council approves definition of binge drinking, NIAAA newsletter, No. 3. National Institute on Alcohol Abuse and Alcoholism.

Neugebauer, V., Mazzitelli, M., Cragg, B., Ji, G., Navratilova, E., & Porreca, F. (2020). Amygdala, neuropeptides, and chronic pain-related affective behaviors. Neuropharmacology, 170, 108052.

Nicoletti, P., Trevisani, M., Manconi, M., Gatti, R., De Siena, G., Zagli, G., Benemei, S., Capone, J. A., Geppetti, P., & Pini, L. A. (2008). Ethanol causes neurogenic vasodilation by TRPV1 activation and CGRP release in the trigeminovascular system of the Guinea pig. Cephalalgia: An International Journal of Headache, 28(1), 9-17.

Nona, C. N., Hendershot, C. S., & Le Foll, B. (2019). Effects of cannabidiol on alcohol-related outcomes: A review of preclinical and human research. Experimental and Clinical Psychopharmacology, 27(4), 359-369.

Pajser, A., Limoges, A., Long, C., & Pickens, C. L. (2019). Individual differences in voluntary alcohol consumption are associated with conditioned fear in the fear incubation model. Behavioural Brain Research, 362, 299-310. https://doi.org/10.1016/j.bbr.2019.01.027

Pape, H., Rossow, I., & Brunborg, G. S. (2018). Adolescents drink less: How, who and why? A review of the recent research literature. Drug and Alcohol Review, 37(1), S98-S114.

Pascual, M., Boix, J., Felipo, V., & Guerri, C. (2009). Repeated alcohol administration during adolescence causes changes in the mesolimbic dopaminergic and glutamatergic systems and promotes alcohol intake in the adult rat. Journal of Neurochemistry, 108(4), 920-931.

Paxinos, G., & Watson, C. (1998). The rat Brain in stereotaxic coordinates. Academic Press.

Poore, L. H., & Helmstetter, F. J. (1996). The effects of central injections of calcitonin gene-related peptide on fear-related behaviour. Neurobiology of Learning and Memory, 66(2), 241-245.

Qin, N., Neeper, M. P., Liu, Y., Hutchinson, T. L., Lubin, M. L., & Flores, C. M. (2008). TRPV2 is activated by cannabidiol and mediates CGRP release in cultured rat dorsal root ganglion neurons. The Journal of Neuroscience, 28(24), 6231-6238.

Romeo, R. D., Karatsoreos, I. N., & McEwen, B. S. (2006). Pubertal maturation and time of day differentially affect behavioral and neuroendocrine responses following an acute stressor. Hormones and Behavior, 50(3), 463-468.

Rossetti, I., Zambusi, L., Maccioni, P., Sau, R., Provini, L., Castelli, M. P., Gonciarz, K., Colombo, G., & Morara, S. (2019). Predisposition to alcohol drinking and alcohol consumption alter expression of calcitonin gene-related peptide, neuropeptide Y, and microglia in bed nucleus of stria terminalis in a subnucleus-specific manner. Frontiers in Cellular Neuroscience, 13, 158.

Schramm-Sapyta, N. L., Francis, R., MacDonald, A., Keistler, C., O'Neill, L., & Kuhn, C. M. (2014). Effect of sex on ethanol consumption and conditioned taste aversion in adolescent and adult rats. Psychopharmacology, 231(8), 1831-1839.

Sink, K. S., Chung, A., Ressler, K. J., Davis, M., & Walker, D. L. (2013). Anxiogenic effects of CGRP within the BNST may be mediated by CRF acting at BNST CRFR1 receptors. Behavioural Brain Research, 243, 286-293.

Solié, C., Contestabile, A., Espinosa, P., Musardo, S., Bariselli, S., Huber, C., Carleton, A., & Bellone, C. (2022). Superior colliculus to VTA pathway controls orienting response and influences social interaction in mice. Nature Communications, 13(1), 817.

Spear, L. P. (2011). Adolescent neurobehavioral characteristics, alcohol sensitivities, and intake: Setting the stage for alcohol use disorders? Child Development Perspectives, 5(4), 231-238.

Spear, L. P. (2015). Adolescent alcohol exposure: Are there separable vulnerable periods within adolescence? Physiology & Behavior, 148, 122-130.

Stuber, G. D., Hopf, F. W., Hahn, J., Cho, S. L., Guillory, A., & Bonci, A. (2008). Voluntary ethanol intake enhances excitatory synaptic strength in the ventral tegmental area. Alcoholism, Clinical and Experimental Research, 32(10), 1714-1720.

Tang, J., Yang, C., Shi, M., & Chen, W. (2022). Activation of dopamine D2 receptors in the shell of nucleus accumbens triggers conditioned avoidance responses in rats. Behavioural Brain Research, 422, 113759.

Taylor, L., Gidal, B., Blakey, G., Tayo, B., & Morrison, G. (2018). A phase I, randomized, double-blind, placebo-controlled, single ascending dose, multiple dose, and food effect trial of the safety, tolerability and pharmacokinetics of highly purified cannabidiol in healthy subjects. CNS Drugs, 32(11), 1053-1067.

Tetteh-Quarshie, S., & Risher, M. L. (2023). Adolescent brain maturation and the neuropathological effects of binge drinking: A critical review. Frontiers in Neuroscience, 16, 1040049.

Tringali, G., & Navarra, P. (2019). Anti-CGRP and anti-CGRP receptor monoclonal antibodies as antimigraine agents. Potential differences in safety profile postulated on a pathophysiological basis. Peptides, 116, 16-21.

van Rossum, D., Hanisch, U. K., & Quirion, R. (1997). Neuroanatomical localization, pharmacological characterization and functions of CGRP, related peptides and their receptors. Neuroscience and Biobehavioral Reviews, 21(5), 649-678.

Viudez-Martínez, A., García-Gutiérrez, M. S., & Manzanares, J. (2020). Gender differences in the effects of cannabidiol on ethanol binge drinking in mice. Addiction Biology, 25(3), e12765.

Viudez-Martínez, A., García-Gutiérrez, M. S., Medrano-Relinque, J., Navarrón, C. M., Navarrete, F., & Manzanares, J. (2019). Cannabidiol does not display drug abuse potential in mice behavior. Acta Pharmacologica Sinica, 40(3), 358-364.

Viudez-Martínez, A., García-Gutiérrez, M. S., Navarrón, C. M., Morales-Calero, M. I., Navarrete, F., Torres-Suárez, A. I., & Manzanares, J. (2018). Cannabidiol reduces ethanol consumption, motivation and relapse in mice. Addiction Biology, 23(1), 154-164.

Warfvinge, K., & Edvinsson, L. (2019). Distribution of CGRP and CGRP receptor components in the rat brain. Cephalalgia: An International Journal of Headache, 39(3), 342-353.

Wills, T. A., Knapp, D. J., Overstreet, D. H., & Breese, G. R. (2009). Sensitization, duration, and pharmacological blockade of anxiety-like behavior following repeated ethanol withdrawal in adolescent and adult rats. Alcoholism, Clinical and Experimental Research, 33(3), 455-463.

Wukitsch, T. J., & Cain, M. E. (2021). The effects of voluntary adolescent alcohol consumption on alcohol taste reactivity in Long Evans rats. Psychopharmacology, 238(6), 1713-1728.

Zhou, Y., Schwartz, B. I., Giza, J., Gross, S. S., Lee, F. S., & Kreek, M. J. (2017). Blockade of alcohol escalation and “relapse” drinking by pharmacological FAAH inhibition in male and female C57BL/6J mice. Psychopharmacology, 234(19), 2955-2970.