The 5-HT7 receptor as a potential target for treating drug and alcohol abuse

Abstract

Alcohol and drug abuse take a large toll on society and affected individuals. However, very few effective treatments are currently available to treat alcohol and drug addiction. Basic and clinical research has begun to provide some insights into the underlying neurobiological systems involved in the addiction process. Several neurotransmitter pathways have been implicated and distinct reward neurocircuitry have been proposed—including the mesocorticolimbic dopamine (MCL-DA) system and the extended amygdala. The serotonin (5-HT) neurotransmitter system is of particular interest and multiple 5-HT receptors are thought to play significant roles in alcohol and drug self-administration and the development of drug dependence. Among the 5-HT receptors, the 5-HT7 receptor is currently undergoing characterization as a potential target for the treatment of several psychiatric disorders. Although this receptor has received only limited research regarding addictive behaviors, aspects of its neuroanatomical, biochemical, physiological, pharmacological, and behavioral profiles suggest that it could play a key role in the addiction process. For instance, genomic studies in humans have suggested a link between variants in the gene encoding the 5-HT7 receptor and alcoholism. Recent behavioral testing using high-affinity antagonists in mice and preliminary tests with alcohol-preferring rats suggest that this receptor could mediate alcohol consumption and/or reinforcement and play a role in seeking/craving behavior. Interest in the development of new and more selective pharmacological agents for this receptor will aid in examining the 5-HT7 receptor as a novel target for treating addiction.

A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction

“…Clinical and basic research indicate that alcohol abuse and dependence are mediated in part by a number of neurobiological systems (c.f., Koob, Arends, & Le Moal, 2014; Koob, Buck, et al, 2014; Noronha, Cui, Harris, & Crabbe, 2014; Pierce & Kenny, 2013; Robbins, Everitt, & Nutt, 2010; Self & Staley, 2010; Sommer & Spanagel, 2013; Spanagel, 2009): acetylcholine (ACh: Chatterjee & Bartlett, 2010; Davis & de Fiebre, 2006; Rahman, Engleman, & Bell, 2015, 2016; Soderpalm, Ericson, Olausson, Blomqvist, & Engel, 2000), adenosine (Filip, Zaniewska, Frankowska, Wydra, & Fuxe, 2012; Nam, Bruner, & Choi, 2013), dopamine (DA: Bhaskar & Kumar, 2014; Engel & Jerlhag, 2014; Heinz, 2002; Nutt, Lingfor-Hughes, Erritzoe, & Stokes, 2015; Soderpalm & Ericson, 2013), endocannabinoid (Moreira, Jupp, Belin, & Dalley, 2015), gamma-aminobutyric-acid (GABA: Agabio & Colombo, 2014; Kumar et al, 2009; Liang & Olsen, 2014; Maccioni & Colombo, 2009), glutamate (Barron et al, 2012; Bell et al, 2016; Davis & Wu, 2001; Gass & Olive, 2008; Rao, Bell, Engleman, & Sari, 2015), purinergic (Franklin et al, 2014), serotonin (5-HT: Engleman, Rodd, Bell, & Murphy, 2008; Hauser et al, 2014; Lovinger, 1999), melanocortin (Olney, Navarro, & Thiele, 2014), opiate (Charbogne, Kieffer, Befort, 2014; Drews & Zimmer, 1997), orexin (Baimel et al, 2015), oxytocin (Buisman-Pijlman et al, 2014), neuropeptide-Y (NPY: Heilig & Thorsell, 2002), corticotropin releasing factor (CRF: Burke & Miczek, 2014; Koob, 2010), substance P (George et al, 2008), nociceptin/orphanin FQ (NOP, N/OFQ: Economidou et al, 2008; Witkin et al, 2014); ghrelin (Jerlhag, Egecioglu, Dickson, & Engel, 2011; Jerlhag et al, 2009; Jerlhag, Landgren, et al, 2011); neurotrophic factors such as BDNF (Logrip, Janak, & Ron, 2009), and hypothalamic-pituitary-adrenal (HPA) activity including corticosteroids, etc. (Gianoulakis, Guillaume, De Waele, & Angelogianni, 1995; Keith, Roberts, Wisen, & Crabbe, 1995; Kiefer, Jahn, Otte, Nakovics, & Wiedemann, 2006…”

“…Self-administer or consume drugs of abuse by (a) orally consuming nicotine-adulterated solutions (Hauser et al, 2012); (b) operantly self-administering nicotine both orally (Hauser et al, 2014) and intravenously (Le et al, 2006); and (c) intracranially self-administering cocaine (Katner et al, 2011), nicotine (Deehan et al, 2015; Hauser et al, 2014), and nicotine + ethanol (Truitt et al, 2015). …”

“…In addition, pretreatment with nicotine increases operant ethanol-self administration and relapse behavior in P rats (Hauser et al, 2012). Furthermore, P rats have higher sensitivity to the reinforcing effects of nicotine in the pVTA compared with outbred Wistar rats (Hauser et al, 2014). These reinforcing effects of nicotine can be blocked by mecamylamine, an nAChR antagonist, when injected simultaneously into the pVTA of P rats (Hauser et al, 2014), indicating that mesolimbic cholinergic activity modulates the reinforcing effects of ethanol and nicotine.…”

Serotonergic Systems in the Pathophysiology of Ethanol Dependence: Relevance to Clinical Alcoholism

“…The 5-HT 7 receptor has until recently been largely neglected in addiction studies, but a interesting and important role for these receptors is beginning to emerge 115 . The 5-HT 7 receptor gene has been linked to traits that predict drug-taking behavior such as impulsivity and novelty seeking.…”

Drug design of 5-substituted-2-aminotetralins targeting the serotonin 5-HT7 receptor

“…In regard to therapeutic potential, activation has been shown to have antinociceptive effects when acting on central receptors, while also showing pro-cognitive effects in certain behavioral models. 17 Preliminary data also suggests that 5-HT 7 , through its activity in reward pathways, may influence impulsivity and addictive behaviors 30 , although it is not clear whether activation or inactivation would play a beneficial role in the possible treatment of substance use disorders.…”