Prospects for serotonin 5-HT2R pharmacotherapy in psychostimulant abuse

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Abstract

The serotonin (5-HT) neurotransmitter system provides fundamental modulatory regulation of the limbic-corticostriatal circuitry known to be vital in the development of addiction as well as the aspects of addiction that hinder recovery and contribute to relapse. Thus, components of the 5-HT system may provide novel targets for the development of pharmacological treatments for psychostimulant dependence, which is associated with significant aberrations in dopamine (DA) neurotransmission. Two key modulators of DA signalling within the limbic-corticostriatal circuit are the 5-HT2A receptor (5-HT2AR) and the 5-HT2CR. These receptors are known to control the neurochemical and behavioural effects of psychostimulants, and in particular the in vivo effects of cocaine. Pre-clinical studies indicate that 5-HT2AR antagonists and/or 5-HT2CR agonists may effectively reduce craving and/or relapse, and likewise, enhance abstinence, while 5-HT2CR agonists may also effectively reduce cocaine intake in active cocaine users. At present, the progression of studies to probe the effectiveness of 5-HT2AR and 5-HT2CR ligands in the clinical setting is hindered by a lack of available, selective 5-HT2AR antagonists or 5-HT2CR agonists for use in human cocaine abusers. However, a number of selective 5-HT2R ligands currently under development, or in early clinical trials for psychiatric and/or neurological disorders, may soon be available for translational studies to explore their effectiveness in modulating drug use and dependence.

Introduction

Substance abuse and dependence continue to plague society, with an estimated economic cost of over $245 billion annually (Office of National Drug Control Policy, 2001). Addiction is a chronic disorder punctuated by multiple remissions and relapses. Pharmacotherapeutic approaches to maintain recovery in addicts are available and can be effective in reducing ‘craving’ (desire for drug) and drug seeking, primarily in nicotine, alcohol and heroin users (for review, see O’Brien, 2005). However, approximately 60% of alcohol-, opioid- or cocaine-dependent patients who received treatment medications relapsed into drug use within 1 year (McLellan et al., 1996, McLellan et al., 2000). Furthermore, only 8.5% of those who needed treatment of drug abuse and addiction received treatment in 2005, with cost and inaccessibility cited as barriers (Substance Abuse and Mental Health Services Administration, 2005). Thus, validation of new medications is an important step in developing a larger toolbox of effective treatment modalities for addiction.

The dopamine (DA) neurotransmitter system has been the primary focus of studies on the mechanisms underlying addiction as well as a key target for the development of pharmacotherapeutic agents for the treatment of substance use disorders (for review, see Vocci et al., 2005). This focus has been justifiably driven by the key role for DA in the rewarding aspects of abused drugs. The DA mesoaccumbens pathway, originating in DA somata of the ventral tegmental area (VTA) and terminating in the nucleus accumbens (NAc; see Fig. 1), mediates the reinforcing effects of natural rewards (i.e. food and sex; for review, see Kelley and Berridge, 2002) and also serves as a common substrate for the acute rewarding effects of all drugs of abuse regardless of their individual mechanisms of action (for reviews, see Koob and Le, 2001; Nestler, 2001, Nestler, 2005). In addition, dopaminergic influence, in conjunction with glutamatergic neurotransmission, within nodes of the limbic-corticostriatal circuitry [prefrontal cortex (PFC), amygdala, hippocampus; see Fig. 1] is integral in coordinating reward-related associative learning and motivated behaviours that contribute to aspects of addiction such as craving, withdrawal and relapse (for reviews, see Kalivas and Volkow, 2005; Hyman et al., 2006; Kauer and Malenka, 2007). Despite the undisputed evidence for the importance of DA in mediating addictive processes associated with drug use, dopaminergic ligands have not proven optimal as successful therapeutic medications in addiction. This is likely because pharmacological manipulations of DA systems interfere with normal physiological and behavioural function subserved by this system, and the use of DA ligands is associated with a myriad of negative side effects (Donna et al., 2002; Soares et al., 2003).

The serotonin (5-hydroxytryptamine, 5-HT) neurotransmitter system has been shown to provide tonic and phasic control of DA and glutamate neurotransmission within the limbic-corticostriatal reward pathway (for review, see Alex and Pehek, 2007), and, as such, has become a favourable target for novel strategies for development of pharmacotherapeutics for addiction. 5-HT neurons originate in the raphe nuclei in the midbrain and project to numerous regions throughout the brain (Halliday and Tork, 1989), including a dense innervation of terminals to the VTA, NAc, PFC, amygdala, hippocampus and dorsal striatum (Halliday and Tork, 1989). The actions of 5-HT are mediated through at least 16 receptor subtypes (5-HTRs) grouped into seven families (5-HT1R–5-HT7R) according to their structural and functional characteristics, and include 13 distinct G-protein coupled receptors, coupled to various effector systems, and three ligand-gated ion channels (the 5-HT3R) (for reviews, see Hoyer et al., 2002; Green, 2006). The 5-HTRs therefore provide a diverse landscape of available signalling cascades and mechanisms unparalleled in any other neurotransmitter system. As such, a plethora of potential sites of action exist which may be integral for the integration of 5-HT, with signalling important to the impact of abused drugs on brain function.

The serotonin reuptake transporter (SERT) and the 5-HTRs are important sites of action for medications therapeutically effective in multiple psychiatric disorders (e.g. anxiety, depression, schizophrenia) and physiological disorders (e.g. migraine, irritable bowel syndrome) (for review, see Naughton et al., 2000; Jones and Blackburn, 2002). Growing evidence (Ait-Daoud et al., 2006; Bubar and Cunningham, 2006; Rothman et al., 2006; Sekine et al., 2006; El-Mallakh and Abraham, 2007; Hughes et al., 2007; Levin and Rezvani, 2007; Moeller et al., 2007; Tambour and Quertemont, 2007; Vocci and Appel, 2007) also supports the prospects of therapeutic gains for serotonergic medications in alcohol and drug abuse disorders. Much of this research has focused on the utility for treatment of psychostimulant addicts because there are currently no medications for successfully maintaining recovery from psychostimulant addiction. In particular, a large body of pre-clinical evidence exists that describes an integral role for 5-HT modulation of the neurochemical and behavioural effects of cocaine.

The psychostimulant cocaine, the alkaloid of Erythroxylum coca, binds to the SERT, inhibiting 5-HT reuptake and increasing synaptic 5-HT efflux in addition to its similar actions at DA and norepinephrine transporters (Koe, 1976). Pharmacological and genetic manipulations of 5-HT neurotransmission demonstrate roles for several of the 16 distinct 5-HTRs in the control of cocaine-induced behaviours (Cunningham and Callahan, 1994; Callahan and Cunningham, 1995, 1997; De La Garza et al., 1996, 1998; Walsh and Cunningham, 1997; McCreary and Cunningham, 1999; McMahon and Cunningham, 1999, 2001a; De La Garza and Cunningham, 2000; McMahon et al., 2001; Filip and Cunningham, 2002, Filip and Cunningham, 2003; Filip et al., 2004, 2006; Frankel and Cunningham, 2004; Szucs et al., 2005; Liu and Cunningham, 2006; Navailles et al., 2008). The 5-HT2R family is particularly interesting as a target for development of therapeutic medications (Higgins and Fletcher, 2003; De La Garza et al., 2005; Bubar and Cunningham, 2006; Muller and Carey, 2006). We will review the evidence in support of a role for the 5-HT2AR and 5-HT2CR based on pre-clinical studies.

Section snippets

Distribution of 5-HT2AR and 5-HT2CR

The 5-HT2R subfamily of seven transmembrane region G-protein–coupled 5-HTRs is composed of three proteins: the 5-HT2AR, 5-HT2BR and 5-HT2CR, derived from three different genes. The 5-HT2BR protein, expressed primarily in the periphery (Kursar et al., 1994; Bonhaus et al., 1995), is thought to play a negligible role in the central effects of drugs of abuse (Bankson and Cunningham, 2002; Fletcher et al., 2002a, Fletcher et al., 2002b; Filip et al., 2004, Filip et al., 2006) and, as such, will not

5-HT2AR and 5-HT2CR: functional regulation

The 5-HT2AR and 5-HT2CR display >50% overall amino acid sequence homology and >80% sequence homology within the transmembrane regions (Boess and Martin, 1994; Martin and Humphrey, 1994). Likewise, the 5-HT2AR and 5-HT2CR activate similar signalling pathways: each couple to Gαq/11 to activate the downstream effector phospholipase C (PLC), promoting the hydrolysis of membrane phospholipids and the production of inositol-1,4,5-triphosphate and diacylglycerol leading to increased intracellular Ca2+

5-HT2AR and 5-HT2CR modulation of DA neurotransmission

An important characteristic for establishing the 5-HT2AR and 5-HT2CR as targets for pharmacotherapeutic intervention for substance use disorders is the ability of these receptors to modulate DA neurotransmission within the limbic-corticostriatal circuit. Indeed, two recent reports have reviewed in detail how pharmacological manipulation of 5-HT2AR and 5-HT2CR alters DA neurotransmission (Alex and Pehek, 2007; Fink and Gothert, 2007). Extracellular single unit recordings of VTA DA neuron firing

5-HT2AR and 5-HT2CR modulation of psychostimulant-evoked DA neurotransmission

Ligands for the 5-HT2AR and 5-HT2CR have also been shown to modulate efflux of DA induced upon systemic administration of psychostimulants. Similar to the effects observed upon basal DA release, systemic administration of 5-HT2CR antagonists enhanced cocaine-evoked DA release in the NAc (De Deurwaerdere et al., 2004). In contrast, systemic administration of the non-selective 5-HT2A/2CR antagonist ketanserin or the selective 5-HT2AR antagonist SR 46349B reduced cocaine-evoked (Broderick et al.,

5-HT2AR and 5-HT2CR modulation of psychostimulant-evoked behaviours

A number of animal models are commonly utilized to examine the neurobiological mechanisms underlying the effects of drugs of abuse during various stages of the cycle of addiction (see Fig. 2). The largest volume of data suggesting that neurotransmission through the 5-HT2AR and 5-HT2CR may modulate the behavioural effects of psychostimulants exists from studies examining the effects of 5-HT2R ligands on the hypermotive, stimulus and reinforcing effects of cocaine in rodents (see Table 1 for

Cocaine and 5-HT2R pharmacotherapy in humans

A limited number of studies have addressed the potential for serotonergic ligands, and in particular selective 5-HT2R ligands, to serve as effective pharmacotherapeutic strategies in addiction. By and large, the majority of studies have utilized non-selective 5-HT2R antagonists that are clinically available for the treatment of psychosis. For example, studies using atypical antipsychotic drugs with a high 5-HT2AR/D2-like receptor affinity ratio, including risperidone (Risperdal®) and olanzapine

5-HT2AR and 5-HT2CR ligands available for medicine and research

The 5-HT2AR and 5-HT2CR are under investigation as potential therapeutic targets for psychiatric conditions, including schizophrenia, depression and anxiety, obsessive compulsive disorders, as well as sleep disorders and obesity. Active initiatives are underway to develop selective 5-HT2AR and 5-HT2CR ligands with the potential utility in treatment of these disorders. A number of recent reviews provide detailed descriptions of the variety of 5-HT2R compounds currently available for pre-clinical

Conclusions

The need for more effective medications for the treatment of psychostimulant use and dependence has encouraged researchers to identify novel targets towards which the development of pharmacotherapeutics may be directed. A plethora of pre-clinical data suggest that the 5-HT2AR and 5-HT2CR play important roles in modulating the in vivo effects of cocaine and other drugs of abuse, potentially via modulation of DA neurotransmission within the limbic-corticostriatal circuitry. In particular, cocaine

Abbreviations

    5-HT

    5-hydroxytryptamine, serotonin

    5-HTR

    5-HT receptor

    CPP

    conditioned place preference

    DA

    dopamine

    DOI

    1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane

    GABA

    γ-aminobutyric acid

    IF

    interfascicular nucleus

    mCPP

    meta-chlorophenylpiperazine

    MDMA

    3,4-methylenedioxymethamphetamine

    NAc

    nucleus accumbens

    PBP

    parabrachial pigmented nucleus

    PCP

    phencyclidine

    PCPA

    p-chlorophenylalanine

    PLA2

    phospholipase A2

    PLC

    phospholipase C

    PN

    paranigral nucleus

    SERT

    serotonin reuptake transporter

    SNPs

    single nucleotide polymorphisms

    SSRIs

    selective

Acknowledgements

We gratefully acknowledge the support from the National Institute on Drug Abuse: DA 00260, DA 06511, DA 07287, DA 13595, DA 15259, DA 020087 and DA 024157.

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