Role of Phosphodiesterase 4-Mediated Cyclic AMP ...

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Role of Phosphodiesterase 4-Mediated Cyclic AMP Signaling in Pharmacotherapy for Substance Dependence Rui-Ting Wen1, Wan-Yu Feng1, Jian-Hui Liang2* and Han-Ting Zhang3* 1 Pharmacy Department of Peking University People’s Hospital, Beijing, 100044, P.R. China; 2National Institute on Drug Dependence, Beijing, 100191, P.R. China; 3West Virginia University Health Sciences Center, Morgantown, WV 26506, USA

Abstract: The harmful effects caused by misuse of psychoactive substances have raised both medical and social problems. Substance dependence is a chronic relapsing disorder, which appears to involve neuroadaptive changes in cellular signaling and downstream gene expression. The unchanged consumption of present substances and increasing demand for new psychostimulants make the development of novel management/treatment strategies challenging. Emerging evidence has shown that the cyclic AMP (cAMP) signaling cascade plays a critical role in the initiation and development of dependence. Thus, phosphodiesterase 4 (PDE4), the primary hydrolytic enzyme for intracellular cAMP, is considered a potential target for future therapeutics dealing with prevention and intervention of substance dependence. This implication is supported by recent data from preclinical studies, and the rapid development of PDE4 inhibitors. Taken together, specific inhibitors of PDE4 and its subtypes possibly represent a novel class of pharmacotherapies for the prevention and abstinence of substance dependence. Here we discuss the modulatory role of cAMP signal transduction in the process of substance dependence and highlight recent evidence that PDE4 inhibitors might be a promising approach to substance dependence therapy.

Keyword: Psychoactive substance, dependence, addiction, drug abuse, cAMP, PDE4, therapies. 1. INTRODUCTION Psychoactive substances, including alcohol, nicotine, and other drugs of abuse, represent a great threat to individuals and society (Table 1) [1-4]. Misuse of these substances can not only lead to physical and mental damage to the users, but also cause great social harms, notably increased criminality, traffic accidents, family adversities, and health-care costs [2, 5-7]. Substance dependence, which refers to a similar concept with the term “addiction” [8-10], contributes as a major causal factor to the above harmful effects. This psychiatric disorder can be characterized by a compulsive pattern of substance seeking and taking behavior despite the adverse consequences, as well as multiple systematic symptoms indicating tolerance and withdrawal [8, 11]. Although specific regulatory measures have been performed to control licit and illicit drug use in most countries, the demand and consumption of addictive substances have not been substantially reduced at global levels, even with an increasing trend in the production and misuse of new psychoactive chemicals [12, 13]. On the other hand, legal substances such as alcohol have been assessed to cause more harmful effects than many illicit drugs (e.g. heroin, cocaine and amphetamine) [2, 5-7, 14]. Therefore, despite legislation and control systems, more reliable medical approaches for prevention and treatment of substance dependence are of particular importance. The development of physical and psychological dependence to addictive substances is a chronic and habit-forming process accompanied by persistent maladaptive memories obtained from normal learning procedures [10, 15, 16]. This process involves a series of neurobiological dysfunctions in the central nervous system (CNS). Our previous studies have shown that neuroadaptive changes can even occur at the first exposure to addictive substances [17-20]. Thus, elucidating the underlying molecular mechanisms for *Address correspondence to these authors at the National Institute on Drug Dependence, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, P. R. China; Tel: 86-10-82802452 (O); Fax: 86-10-62032624 (O); E-mail: [email protected] Department of Behavioral Medicine & Psychiatry and Physiology & Pharmacology, West Virginia University Health Sciences Center, 1 Medical Center Drive, Morgantown, WV 26506-9137, USA; Tel: +1-304-293-1488; Fax: +1-304-293-1634; E-mail: [email protected] /15 $58.00+.00

substance use may produce novel strategies for abstinence and antirelapse treatment. Emerging evidence indicates that the initiation and maintenance of substance dependence is closely related to altered post-receptor signal transduction, gene expression, and neuronal plasticity. The modulatory role of cell signal systems in substance consuming behaviors has become a researching focus in recent neuroscience studies. Cyclic adenosine 3', 5'-monophosphate (cAMP), the firstdiscovered intracellular second messenger, plays a critical role in the modulation of various neurobiological processes including learning and memory [21, 22]. Intracellular cAMP is functionally coupled to multiple membrane neurotransmitter receptors via guanine nucleotide binding proteins (G protein). Elevated cAMP levels ultimately influence cAMP-inducible gene transcription patterns through phosphorylation of cAMP responsive element binding protein (CREB) by protein kinase A (PKA) [23]. These impacts make cAMP signaling a critical modulator in experience-based neuroadaptations [24]. It has been well established that the activity of the cAMP signal cascade is critically involved in the genetic predisposition, systematic intoxication, rewarding properties, and relapsing features of most addictive substances [23-28]. Thus, key steps in this signal cascade may represent potential targets for the development of interfering manipulations for substance dependence. As the trigger point of the cAMP signal system, intracellular cAMP levels are regulated via synthesis and degradation, catalyzed by adenylate cyclase (AC) and cAMP-specific phosphodiesterases (PDEs), respectively. AC is an effector enzyme of G protein and catalyzes cAMP generation. To date, ten different isoforms of AC (AC 1-10) have been identified and categorized by their structural features and regulation mechanisms [29-31]. On the other hand, PDEs represent a superfamily of hydrolytic enzymes, catalyzing the degradation of both cAMP and cyclic GMP (cGMP). This enzyme super family consists of eleven different families (PDE1-11), which can be divided into three groups based on their specific substrate: cAMP-specific PDEs (e.g., PDE4, PDE7, and PDE8), cGMPspecific PDEs (e.g., PDE5, PDE6, and PDE9), and dual substrate PDEs, which hydrolyze both cAMP and cGMP (e.g., PDE1, PDE2, PDE3, PDE10, and PDE11) (reviewed in [32-34]). Previous re-

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Table 1.

Wen et al.

Psychoactive substances: category, dependent potential and harm scores [1-4].

Category

Dependent potentiala

Harm scoresb

Amphetamine

2.0

23

Methamphetamine

1.67

33

Psychoactive substances

Primary action target

Stimulants Cocaine

Dopamine transporter

2.39

27 (55 for crack cocaine)

Nicotine

N-AChR

2.21

26

Alcohol

GABA/glutamate receptor

2.3

72

Benzodiazepines

GABA receptor

1.7

15

GHB

GABA receptor

1.19

19

Morphine

Mu opioid receptor

Codeine

Mu opioid receptor

Heroin

Mu opioid receptor

3.00

55

Buprenorphine

Mu opioid receptor

2.0

7

Methadone

Mu opioid receptor

2.08

14

Cannabis

CB1 receptor

1.9

20

Ketamine/PCP

NMDA receptor

1.54

15

LSD

5-HT2 receptor

1.3

7

Ecstasy

5-HT transporter

1.5

9

Sedatives

Opiates

Hallucinogen CB1 receptor: cannabinoid receptor type 1; GABA: -aminobutyric acid; GHB: gammahydroxybutyrate; LSD: Lysergic acid diethylamide; N-AChR: Nicotinic acetylcholine receptor; NMDA: N-methyl-d-aspartate; PCP: phencyclidine. a. The evaluated scores are based on four-point ratings (0 = no risk, 1 = some risk, 2 = moderate risk, and 3 = extreme risk). b. The scoring process is based on 0–100 ratio scales, with zero representing no harm. (Adapted from a series studies of Lingford-Hughes and Nutt D 2003; and Nutt et al., 2007, 2010 [1-3])

search suggests that inhibition of cAMP-specific PDEs may exhibit more potent and stable effects in increasing cAMP concentrations than stimulation of AC [35]. Among cAMP-specific PDEs, PDE4 is widely expressed in the CNS, rendering it a potential interfering target for many neuropsychological disorders. Current preclinical studies indicate that pharmacological inhi-bition of PDE4 by its selective inhibitors may produce therapeutic effects on a variety of CNS disorders, such as Alzheimer’s disease [36-39], Parkinson’s disease [40, 41], brain tumors [42], ischemic stroke [43, 44], depression [45-48], anxiety [49, 50], and schizophrenia [51-53]. Given the extensive engagement of PDE4 in neurobiological processes, scientists began to explore its role in behavioral and neuronal responses to short- and long-term substance exposure. Recent studies have demonstrated the role of PDE4 in the initiation and development of dependence to several substances in animal models [5459]. These progresses coincide with the rapid development and clinical evaluation of selective PDE4 inhibitors [60-62], which may represent a promising class of pharmacotherapy for substance dependence. In this review, we will first summarize the neural basis for substance dependence (section 2), and then focus on the evidence that implicates a regulatory role for the cAMP signal cascade and PDE4 in specific brain regions (section 3 and 4). Finally, we will discuss the current challenges we have with PDE4 as a therapeutic target. 2. IMPORTANT NEURAL CIRCUITRY AND BRAIN REGIONS IN SUBSTANCE DEPENDENCE Although psychoactive substances differ in their actions on CNS (Table 1), common mechanisms are likely to be implicated in their rewarding property and dependent process [63, 64]. It is gen-

erally recognized that the limbic cortico-striatal circuitry, which is conserved across species (humans, primates and rodents), represents the key neural system in substance dependence. This circuitry consists of limbic cortical brain regions involved in motivation, reward, learning and memory, such as basal ganglia (striatum and pallidum), neocortical areas (especially the prefrontal cortices), the amygdala, and the hippocampus [10]. Among them, the ventral striatum, the amygdala, and the orbitofrontal cortex are of most importance to reward and motivated behaviors. Nearly all addictive substances cause an increase in synaptic dopamine (DA) levels via different actions [3, 10]. These primary effects ultimately lead to stimulation of the mesolimbic dopaminergic pathway, especially the neural circuit from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), which represents the primary regulator of reward properties for most psychoactive substances [15, 65, 66]. For example, morphine acts at opiate receptors and has its most rewarding actions in the VTA; nicotine binds to nicotinic acetylcholine receptors (nAChR) and causes DA release in both VTA and NAc, while cocaine and amphetamine increase DA concentrations in the NAc by interacting with cell membrane transporters that remove dopamine and other monoamines [16]. The NAc, together with caudate putamen and the striatal parts of the olfactory tubercle, represents the ventral-striatal complex, of which the NAc is a prominent component [67, 68]. The NAc is not a homogeneous structure but can be subdivided into core (NAcC) and shell (NAcSh) subregions, which differ in their connection and function [69]. The NAcSh is an atypical area of the striatal structure [68], but shows similar neurochemical modulation and afferent projections with the central nucleus of the amygdale (CeA). As a result, NAcSh is included in the brain structure of ‘extended

Role of Phosphodiesterase 4-Mediated Cyclic AMP Signaling in Pharmacotherapy

amygdale’ (EA), which was originally described by Johnston and represents an importance circuitry for reward, motivation and reinforcement [70, 71]. The core structures of the NAc are linked to the caudate putamen and substantia nigra, which are mainly related to motor behaviors [72, 73]. Furthermore, the NAc can exhibit neuroadaptational changes following substance consumption, particularly occurring at glutamatergic signaling [74, 75]. Thus, the function and connection of neural circuits from the VTA to the NAc may account for the euphoric and rewarding states for addictive substance exposure, leading to the initial reinforcement and habitforming patterns of substance use. On the other hand, the pre-existing anhedonic or dysphoric state and withdrawal symptoms are purported to be negative reinforcers in perpetuating substance dependence [76-78]. The dysphoric status is considered as an important factor in declination and persistence of substance use for self-medication. Amygdaloid brain regions, particularly the central and medial nucleus of amygdala (CeA and MeA), appear to be associated with the innate and withdrawalinduced dysphoric reactions, especially closely related to the promotion of anxiety-like behaviors [28, 79]. A set of afferent pathways from these amygdaloid nuclei projects to anatomical targets in midbrain, hypothalamus, and lower brain stem, which are important in the modulation of visceral functions related to emotional stimuli [28, 80]. Moreover, disordered cell functions in CeA and MeA can offer genetic predisposition for the vulnerability to substance use disorders [81-83]. Taken together, both NAc and amygdaloid nuclei as well as their anatomical neural connections produce a promoting effect on the initiation and maintenance of substance dependent process. 3. ROLE OF cAMP SIGNAL CASCADE IN SUBSTANCE DEPENDENCE As described above, the post-receptor cAMP/PKA/CREB signaling cascade transmits extracellular information initiated by cell stimuli to the cell nucleus, leading to altered gene expression patterns and further neuronal functions. This signal transduction pathway has been considered to play a central role in the process of substance dependence and possibly underlie a common route for brain adaptational responses to multiple addictive chemicals [28, 84, 85]. In this signal system, the generation of cAMP can be triggered by activation of AC via coupled G protein and G proteincoupled receptors (GPCRs), inducing the phosphorylation of the gene transcription factor CREB via cAMP-dependent PKA [73]. CREB acts as a convergence point for several intracellular signaling cascades, including Ca2+ and mitogen activated protein kinase (MAPK) signaling [86]. Phosphorylated CREB (p-CREB) interacts with CREB binding protein (CBP) and regulates the expression of downstream cAMP-inducible genes at the cAMP-responsive element (CRE) promoter region. The important CREB target genes include neuropeptide Y (NPY), corticotrophin-releasing factor (CRF), brain-derived neurotrophic factor (BDNF), and activityregulated cytoskeleton-associated protein (Arc), which plays a role in the regulation of dendritic spine morphology [24, 87, 88]. 3.1. Impact of Psychoactive Substances on cAMP Signaling Psychoactive substances enter the brain and perform their initial actions by interacting with endogenous chemical receptors or other functional sites. Some of the receptors belong to the GPCR superfamily, such as the opioid and cannabinoid receptors, which can result in activation or inhibition of cAMP signaling though stimulatory or inhibitory G-protein. However, substances with their main action at other receptors or targets, such as alcohol, cocaine, and amphetamine, are also proven to cause functional changes in cAMP signaling. These facts make the cAMP signaling cascade a common modulator of the post-receptor action of multiple addictive substances.

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A series of studies by Dr. Yoshimura et al. reveal the reaction characteristics of the cAMP signal pathway to short-term alcohol exposure. In the human embryonic kidney cell line HEK 293 that expresses each AC isoform (AC 1-3, 5-9), alcohol exposure can enhance the stimulatory G protein (Gs)-stimulated AC activity in an isoform-specific manner. Stimulation of cAMP generation by AC7 was at least 2-3 fold greater than that observed in the other AC isoforms after alcohol exposure [89, 90]. This enhancement of cAMP accumulation in HEK 293 cells expressing AC7 can be observed at an alcohol concentration of 20 mM, and can be facilitated with increasing concentrations of alcohol [89]. These data indicate that pharmacologically relevant concentrations of alcohol can activate cAMP generation and might also trigger its downstream signaling transduction. In the subsequent real-time detection of alcohol effects on cAMP concentrations, scientists confirmed the previous results that alcohol can activate cAMP generation in a similar manner to DA, of which the receptor is GPCR. However, when cells are firstly stimulated with DA, the following alcohol exposure causes decreases in cAMP concentrations. Thus, the effects of alcohol on cAMP is not only determined by AC isoforms, but also related to the duration of its exposure [91]. This result is consistent with in vivo studies that show decreased cAMP transduction in animal brains after chronic alcohol exposure [92, 93]. Yang and colleagues demonstrated rapid increases in p-CREB levels in the cerebellum and striatum of rats in response to acute alcohol exposure, which was attenuated by chronic alcohol treatment [94-96]. Voluntary ethanol intake causes decreases in CREB phosphorylation in the NAcSh, but not NAcC, in rats [97, 98]. However, CRE-DNA binding ability and p-CREB levels are not affected by chronic alcohol exposure, but are decreased in cortical brain regions in response to alcohol withdrawal [99, 100]. The pCREB levels are decreased further during 24- and 72-h ethanol withdrawal periods, but are shown to increase to normal levels after 7 days [97]. These changes in CREB signal transduction reveal adaptive reactions of this signal cascade, which appears to transfer from one balance state to another. The regulation of the cAMP signaling pathway in the brain stands as the best established molecular adaptation associated with acute and chronic opiate exposure [101]. Acute opiate exposure inhibits AC activity in many types of neurons in the brain [102, 103], whereas a compensatory up-regulation of cAMP signaling is detected by chronic opiate treatment in specific brain regions [103, 104]. Via implantation of morphine pellets in rodent brains, scientists have found chronic treatment of morphine leads to enhanced G protein-mediated AC activity and intracellular cAMP levels in the striatum of both opiate-dependent (72 h after implantation), and opiate withdrawing (1 h post-naloxone precipitation) mice [103]. However, the increase in AC activity is only detected in the locus coeruleus of rats after 5-day implantation of morphine pellets, but not in the frontal cortex and neostriatum [105]. The three types of opioid receptor, -, -, and -opioid receptor are all functionally coupled to G protein. Although they share common mechanisms in actions on cell signaling systems, differences exist in many of their pharmacological effects. To determine which type of opiate receptor is responsible in the post-receptor cAMP signal transduction associated with opiate treatment, genetargeted mice lacking -, -, or -opioid receptors were utilized for investigation. Decreased cAMP signaling is observed in the cortex and/or striatum of -, or -opioid receptor knockout (KO) mice, but not in -KO mice [101]. This result suggests that endogenous opioid activates cAMP signaling transduction in the brain by acting on - and -receptors. However, the manipulation of chronic morphine treatment reveals paradoxical results. Unchanged cAMP signal activity is found in wide-type, -KO, and -KO mice, while KO mice show an upregulation of cAMP signaling activity in the cortex and/or striatum, indicating the involvement of heterologous receptor adaptations in -KO mice.


The profound effects of cannabis derivatives are mediated by the endogenous cannabinoid (CB) receptors, including CB1, CB2 receptor, and even GPR55, one of the novel CB receptors [106108]. All these receptors belong to GPCRs and have seven transmembrane regions in their structures [109]. Upon ligands binding, cannabinoid receptors negatively regulate AC activity and inhibit cAMP generation via a toxin sensitive inhibitory G protein (Gi). CB1 (brain type) receptors are most abundantly expressed in the CNS, mainly in the basal ganglia, the hippocampus, and the cerebellum, indicating its fundamental role in cannabis dependence. In contrast, CB2 (peripheral type) receptors are mainly located in leukocytes of peripheral tissues, with little expression in the brain. Being mainly confined to the presynaptic terminals, CB1 receptors following activation usually lead to inhibition of neurotransmitter release. The reduction of inhibitory neurotransmitters, such as aminobutyric acid (GABA), is critically responsible for stress and reward mechanisms. Although stimulants such as cocaine and nicotine don’t directly act at GPCRs, altered cAMP signal transduction are also found in neurons exposed to these two drugs. In contrast to sedatives like alcohol, chronic cocaine treatment stimulates AC activity and downstream signaling in NAc neurons of rats [110]. However, by continuous intracerebroventricular infusion of cocaine, phosphorylation of CREB is significantly decreased in the rat caudate putamen [111], indicating that the modulatory effect of cocaine on cAMP signaling appears to be brain region-specific. Similarly, repeated or chronic nicotine exposure can lead to a desensitized state of nAChR in the rat brain. This status of nAChR is associated with decreased PKA activity, whereas the activated nAChR by acute nicotine administration results in an unchanged status of PKA activity, suggesting that inhibited PKA signaling by nAChR desensitization may be responsible for nicotine tolerance and dependence [112]. 3.2. cAMP Signaling Mediates Intoxication to Substance Use Physiological responses to short- and long-term substance abuse contribute as a major harmful aspect despite the psychological toxicity. Evidence shows that, the multiple intoxication of alcohol use, such as ataxia, sedation, and neuron death, can be modulated by the activity of cAMP signal transduction. As the earliest and most well recognized effect of alcohol consumption in human and laboratory animals, cerebellar ataxia has been shown to be associated with the development of alcoholism [113] and closely relates to the modulation of the cerebellar cAMP signaling system [114]. The adenosine A1 receptors, which are negatively coupled to AC-cAMP signaling, stand as the main adenosine receptors responsible for the modulation of ethanol-induced ataxia [115, 116]. Using intracerebellar microinfusions, Dar has demonstrated that cAMP and its analogue 8-(4-chlorophenylthio)-cAMP (cpt-cAMP) produce a dose-dependent and sustained attenuation of ethanol-induced ataxia; forskolin and Sp-cAMP (an activator of PKA) attenuates ethanol-induced ataxia; and Rp-cAMP (an inhibitor of PKA) exhibits an opposite effect [117, 118]. Taken together, the above results support the primary role of the cerebellar cAMP signalign system in the expression of ethanol-induced ataxia. Recent studies on the sedative effects of alcohol show that, in rats selectively bred for high (HAD) and low (LAD) alcohol drinking, higher sensitivity to the sedative effect of alcohol is observed in LAD rats, while more rapid tolerance to this effect is established in HAD rats. Immunoblot analyses reveal that rats with the higher Gs levels in the frontal cortex and hippocampus are more rapidly affected by the sedative properties of alcohol than rats with lower Gs levels. The subsequent G protein expression and AC activity in the frontal cortex, hippocampus, cerebellum, and NAc are also involved in this process, indicating the role of AC signal transduction in mediating sensitivity and tolerance to alcohol-induced sedation.

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Neuronal loss is a key component in the pathophysiology of fetal alcohol syndrome (FAS), which is linked to dyscoordination and has gained a major public health concern. Alcohol can increase cellular apoptosis in developing neurons via the direct effects of oxidative stress on neurons, and via increasing production of microglia-derived factors. Activated gene transcription factor CREB has been strongly linked to the survival of multiple cell types, including neurons [119-121]. Forskolin, an activator of the cAMP pathway, is found to be protective against alcohol’s toxic effect on cultured cerebellar granule neurons [122]. Furthermore, the dibutyryl cAMP (dbcAMP), known as a PKA activator, also ameliorates alcohol-induced neuronal oxidative status and apoptosis in hypothalamic neuronal cells in primary cultures. These facts indicate that activated cAMP signal transduction may represent a protective factor against the physiological toxicity caused by exposure to alcohol. Cocaine exposure during the fetal period can produce longlasting changes in brain structure and function. It has been detected that increased basal cAMP levels in the striatum and cerebral cortex is associated with cocaine exposure. By blocking the adenosine A2a receptor, the basal cAMP levels in the cocaine-exposed brain is downregulated to physiological levels, suggesting the involvement of adenosine receptors in mediating cocaine’s effects on the embryonic brain [122]. This finding coincides with the previous result that basal AC activity is significantly reduced following prenatal exposure to cocaine. Moreover, the ability of forskolin in stimulating AC transduction is attenuated following cocaine exposure [123]. 3.3. Role of cAMP Signal Transduction in Substance Dependence and Withdrawal As is involved in various aspects of CNS function, cAMP signaling has been proposed to act as a genetic factor for the predisposition and modulation of tolerance and dependence to psychoactive substances. By utilizing samples from clinical alcoholic patients, Sohma and co-workers demonstrated that levels of Gs and AC1 were reduced in postmortem brains of alcoholics [124]. With the technique of reverse transcription-polymerase chain reaction (RTPCR), scientists also found that the mRNA levels of Gs, AC1, and AC8 in blood cells are lower in family history-positive alcoholics than those in family history-negative alcoholics, indicating that the cAMP signaling system may play a role in genetic predisposition to alcohol dependence [23, 124]. A series of studies by Pandey and colleagues reveal the role of cAMP signaling in alcohol dependence and withdrawal process. By comparing with alcohol preferring (P) and non-preferring (NP) rats, they demonstrated that levels of CREB, p-CREB, NPY, and CREDNA binding ability are innately lower in the CeA and MeA, but not the basolateral amygdala (BLA), in P rats relative to NP rats. The brain-region specific pattern of decreased CREB function and downstream signaling correlates with higher baseline of alcohol preference and anxiety-like behavior in P rats [125, 126]. Ethanol injection or voluntary intake attenuates CREB dysfunction and the high anxiety-like behavior in P rats, but produces no changes in NP rats. Pharmacological activation of CREB signal transduction in the CeA by the PKA activator Sp-cAMP or NPY decreases both anxiety levels and ethanol consumption in P rats. In contrast, infusions of the PKA inhibitor Rp-cAMP into the CeA inhibit CREB phosphorylation, increase anxiety levels, and provoke ethanol-drinking behavior in NP rats [125]. These results suggest that the function of PKA, CREB, and subsequent downstream signal transduction may represent a genetic predisposition for anxiety and alcohol-drinking behavior. This implication is supported by the evidence that mice with partial deletion of the CREB gene and subsequent decreased expression of CREB, p-CREB, NPY, and BDNF exhibit higher preference for ethanol than wild-type littermates [127]. Consistent with this, as demonstrated by examination of innate expression and phosphorylation of CREB in various brain structures in parallel


studies using alcohol-preferring C57BL/6 (C57) and non-preferring DBA/2 (DBA) mice, the levels of CREB, p-CREB and NPY are lower, specifically in the NAcSh, in C57 mice than that of DBA mice. It is noted that this dysfunction in CREB and its target gene expression correlates with the high alcohol preference and consumption in C57 mice, but not the anxiety levels. Results from these two control strains indicate a different mechanism for alcohol drinking behavior from that of P/NP rats, which may involve altered brain rewarding properties of alcohol. The dysphoric reactions including anxiety that appear during the early stage of alcohol withdrawal promote continued alcohol use in alcoholics [128, 129]. CREB-mediated signaling is not only responsible for innate anxiety-like behaviors in alcohol-preferring animals, but also involved in the increased anxiety levels related to alcohol withdrawal. It has been shown that levels of p-CREB and NPY are decreased in amygdaloid (CeA and MeA, but not BLA) and cortical structures in rats enduring alcohol withdrawal after chronic drinking behavior [130, 131]. However, with Sp-cAMP directly infused into the CeA structure, p-CREB and NPY expression are increased to normal levels, leading to the prevention of the development of anxiety-like behaviors during alcohol withdrawal. In contrast, decreased CREB function via infusions of a PKA inhibitor into the CeA provoked anxiety-like behaviors and increased ethanol intake in normal animals [130, 131]. Taken together, the above results suggest that decreased PKA/CREB signaling in the NAc or amygdala, either innately or due to withdrawal after ethanol exposure, may be involved in the alcohol preference and dependence process; improving these deficits to normal levels appears to be an interfering manipulation for anxiety status and alcohol drinking behavior. The cAMP signal system has also been implicated in the development of opiate tolerance and dependence process via mediating opioid receptor desensitization, opiate rewarding properties, and the withdrawal symptoms after chronic opiate exposure. Phosphorylation of GPCRs by cAMP-dependent protein kinase stands as an important mechanism in rapid receptor desensitization. Using a reconstituted in vitro system, activated cAMP-dependent kinase has been shown to disrupt the coupling of -opioid receptor to Gi [132, 133]. With the treatment of forskolin and the cAMP-dependent kinase inhibitor H8, it is found that cAMP-dependent kinase is involved in the development of tolerance to morphine at the -opioid receptor level, but through different mechanisms from that induced by morphine [134], indicating the role of cAMP signaling in chronic exposure to morphine. Animal models of drug discrimination have been used to examine the reinforcing effects of addictive substances. With the use of instrumental drugs increasing or decreasing cAMP levels in vivo, scientists have found that all these drugs inhibit the discriminativestimulus effects of methamphetamine, while drugs activating cAMP signaling attenuate the discriminative-stimulus effects of morphine. These findings suggest the critical involvement of cAMP signal cascade in discriminative-stimulus effects of methamphetamine and morphine. Agmatine, an endogenous amine derived from arginine, is reported to block symptoms of naloxone precipitated morphine withdrawal in vitro and in vivo [135-137]. It is found that cAMP levels are markedly increased in naloxone incubated rat brain with chronic morphine exposure, which correlates with morphine withdrawal syndromes; naloxone-induced withdrawal symptoms are decreased by agmatine treatment along with morphine and the increased cAMP levels are significantly reduced in rat brain [138]. These results indicate that the inhibitory effect of agmatine on the development of dependence to morphine is probably mediated by the decreased cAMP signaling pathway during chronic morphine exposure.


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4. PDE4 AND SUBSTANCE DEPENDENCE As is described above, the intracellular cAMP signal system plays a critical role in the short-term and long-term neuroadaptive changes induced by addictive drugs and represents a common molecular basis for the development of substance dependence. It has been proposed that, key steps in the cAMP signal cascade may be potential targets for developing abstinence and anti-relapsing pharmacotherapies. PDE4, the enzyme that catalyzes cAMP degradation and abundantly distributes in CNS, is considered as a promising therapeutic target for multiple CNS disorders including substance dependence. To date, there are four genes (PDE4A, PDE4B, PDE4C, PDE4D) that encode over 25 different splice variants of this enzyme (reviewed in [33]). These four subtypes of PDE4 differ in their distribution and neuronal function (Table 2) [37, 48, 140]. 4.1. PDE4 Subtypes in Mammalian Brains All PDE4 variants can be divided into four categories: long form, short form, super-short form, and dead-short form PDE4s (Table 2), which mainly differ in their upstream conserved regions (UCR) in the variant-specific N-terminal region. However, the catalytic domains of all the variants stay highly conserved in the subtype specific C-terminus (reviewed in [33]). All PDE4 variants except for PDE4As contain an extracellular signal-regulated kinase (ERK) phosphorylation site in the catalytic domain, which regulates hydrolytic activity of PDE4 variants in a variant-specific pattern. ERK phosphorylation inhibits activity of long form PDE4s, weakly inhibits or does not alter activity of super-short form PDE4s, and increases that of short form PDE4s (reviewed in [139]). These different patterns of ERK phosphorylation effects on PDE4 variants together with their distinct molecular structures suggest PDE4 subtypes and variants may be responsible for different CNS functions. The distribution patterns of PDE4 subtypes in the CNS are similar among various mammals such as rats, monkeys, and humans [140]. However, brain expressions of the four PDE4 subtypes are found to differ from each other by histochemistry and autoradiography techniques (Table 2) [48, 140]. PDE4A, PDE4B and PDE4D are widely distributed in the brain, with the two latter appearing more abundant. In contrast, PDE4C is predominantly distributed in peripheral tissues. PDE4A and PDE4D share the similar distribution pattern and are implicated in the mediation of antidepressant activity and memory. PDE4B, by contrast, is the predominant PDE4 subtype in brain regions that involved in dopamineassociated and emotion-related processes, especially the NAc. Thus, PDE4B is more likely involved in drug dependence and abuse as well as other psychiatric disorders including schizophrenia and anxiety. 4.2. PDE4 and Alcohol Dependence To our best knowledge, the recent published studies from our laboratories are the first reports to investigate the role of PDE4 in alcohol-drinking behavior. By using alcohol-preferring C57 mice, we have demonstrated that inhibition of PDE4 by its selective inhibitor rolipram or Ro 20-1724 reduces alcohol consumption without gastrointestinal or sedative side effects [54]. This finding was verified by subsequent research in alcohol-preferring Fawn-Hooded (FH/Wjd) rats, which showed inhibitory effect of rolipram on both alcohol self-administration and chronic consumption models [57]. Consistent with these, ibudilast, a dual PDE3/PDE4 inhibitor, reduces ethanol drinking and relapse in P rats, high-alcohol drinking (HAD1) rats, and C57 mice using 2-h ethanol two-bottle choice and/or chronic intermittent ethanol (CIE) vapor exposure paradigms [141]. These findings suggest that PDE4 plays an important role in alcohol seeking and consumption behavior. Drugs interfering with PDE4 may be a potential pharmacotherapy for alcohol dependence.


Table 2.

Wen et al.

Brain distribution, molecular structure and possible therapeutic indications of PDE4 subtypes [37, 48, 140].

PDE4 subtypes

PDE4A

PDE4B

PDE4C

PDE4D

Striatum Cerebral cortex Brain distribution

Olfactory bulb Hippocampal structure Brain stem

Amygdala

Cerebral cortex

Hypothalamus Thalamus

Peripheral tissues

Frontal cortex

Olfactory bulb Hippocampal structure Brain stem

Olfactory bulb White matter (only) Long form

4A4/5, 4A8, 4A10, 4A11

4B1, 4B3, 4B4

Short form Super-short form

4A1

Dead-short form

4A7

Therapeutic indications

Depression Brain tumor

4C1, 4C2, 4C3

4D3, 4D4 , 4D5, 4D7, 4D9

4B2

4D1, 4D2

4B5

4D6, 4D10, 4D11

Anxiety Schizophrenia

Depression Alzheimer’s disease

Substance dependence

4.3. PDE4 and Morphine Dependence In earlier studies, the role of PDE4 in morphine dependence process has been mainly studied via withdrawal process to chronic morphine exposure. It has been demonstrated that chronic coadministration of PDE4 inhibitor rolipram and morphine could attenuate the withdrawal symptoms precipitated by naloxone in morphine dependent animals [142-145]. As morphine withdrawal symptoms are considered to attribute to elevated cAMP levels and c-Fos expression in the brain, the alleviating effect of rolipram may be related to the prevention of the up-regulation of the cAMP pathway in morphine-withdrawn animals. 5. CHALLENGES AND FUTURE PERSPECTIVES The critical involvement of cAMP signaling in substance dependence processes promoted the possibility that key steps in this signal cascade may represent therapeutic targets for the treatment of substance dependence. Expression and functional studies of PDE4 provide a strong rationale for targeting this enzyme in abstinence and anti-relapsing treatment. Drugs interfering with PDE4 activity may be a novel class of pharmacotherapies for this disease. The PDE4 targeting therapeutics discovered earlier in inflammatory diseases, such as asthma, chronic obstructive pulmonary disease (COPD), arthritis, and multiple sclerosis, has promoted the development of multiple PDE4 inhibitors. However, among the several generations of PDE4 inhibitors, only roflumilast has been approved by the Food and Drug Administration (FDA) as a pharmacotherapy for COPD. Other chemicals, including the first generation inhibitor rolipram were terminated from clinical evaluations primarily due to the remarkable side effects such as emesis. Thus, the development of novel PDE4 inhibitors should specify the therapeutic effect and minimize the side effects. Considering this desire, the following challenges need to be addressed on. First, the gastrointestinal side effects remain the main obstacle in developing future PDE4 inhibitors. Almost all available PDE4 inhibitors are emetic to a certain degree; the emetic response is considered attributed to cAMP elevation in emetic centers. PDE4D, with high expression in the area postrema and nucleus of solitary tract, is considered as the main PDE4 subtype that mediates the

emetic responses [48]. Thus, the highly specific PDE4B inhibitors may be a promising manipulation to achieve more selective therapeutic effect on substance dependence by avoiding side effects related to PDE4D. However, the highly conserved catalytic site within the PDE4 subfamily makes this goal difficult to attain using catalytic-site-directed competitive antagonists. Recent designs to modulate PDE4 activity via UCR result in a novel class of allosteric inhibitors with PDE4D specificity [146]. This finding makes it possible for designing peptides and other compounds that target the unique amino-terminal domains of each isoenzyme [42]. On the other hand, PDE4 is characterized by two conformers (apoenzyme and holoenzyme) that bind inhibitors differentially [147]. The interaction of PDE4 inhibitors with high affinity rolipram binding site (HARBS), which is the active site of holoenzyme, may partly account for nausea and emesis [148]. In contrast, PDE4 inhibitors bind weakly to the low affinity rolipram binding site (LARBS) of apoenzyme. With the exclusive expression in the CNS, the holoenzymes with HARBS are more critically involved in the central function mediated by PDE4 than apoenzymes, which are present in both central and peripheral tissues and responsible for the peripheral activity, such as anti-inflammatory reactions [48]. PDE4 inhibition as treatment for substance dependence may desire high affinity to the holoenzyme just as do other CNS diseases [48]. Therefore, it remains a contradictory problem to deal with both therapeutic and side effects mediated by HARBS. Some scientist proposed the use of ion-chelating motifs within inhibitors to improve their affinity to PDE4 isoforms [149]. This idea provides a possibility to design PDE4 inhibitors with specific binding to LARBS and improved affinity. In summary, the critical modulatory role of cAMP signaling in substance dependence makes PDE4 a promising therapeutic target for this CNS disorder. By analyzing the distribution and function of each PDE4 isoform, PDE4B may be the one most likely related to drug abuse and dependence. Overcoming the side effects of PDE4 inhibitors by refinement and developing allosteric and isoformspecific inhibitors will increase the possibility for PDE4 inhibitors to be a novel class of pharmocotherapies for substance abuse and dependence.


CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS This work was supported by research grants from US NIH/NIAAA (AA020042, to HTZ), National Nature Science Foundation of China (30870894; to JHL), National Basic Research Program of China (2009CB522000; to JHL), National Key Technology R&D Program of China (2011BAK04B08; to JHL). ABBREVIATIONS AC = Adenylate cyclase Arc = Activity-regulated cytoskeleton-associated protein BDNF = Brain-derived neurotrophic factor BLA = Basolateral amygdala cAMP = 3', 5'-Cyclic adenosine monophosphate CeA = Central nucleus of amygdala CNS = Central nervous system CBP = CREB binding protein CRF = Corticotrophin-releasing factor CREB = Cyclic AMP-responsive-elementbindingprotein G protein = guanine nucleotide binding proteins GPCR = G protein-coupled receptor Gi = Inhibitory G protein Gs = Stimulatory G protein HARBS = High affinity rolipram binding site LARBS = Low affinity rolipram binding site MAPK = Mitogen activated protein kinase MeA = Medial nucleus of amygdala PDE = Phosphodiesterase PKA = Protein kinase A NAc = Nucleus accumbens NPY = Neuropeptide Y VTA = Ventral tegmental area

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Received: April 2, 2014

Accepted: August 25, 2014

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