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Frontiers in Biology

Front. Biol.    2016, Vol. 11 Issue (5) : 376-386     DOI: 10.1007/s11515-016-1424-0
Phosphodiesterase 4 inhibitors and drugs of abuse: current knowledge and therapeutic opportunities
Christopher M. Olsen1,2(),Qing-Song Liu1,2()
1. Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
2. Neuroscience Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
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BACKGROUND: Long-term exposure to drugs of abuse causes an upregulation of the cAMP-signaling pathway in the nucleus accumbens and other forebrain regions, this common neuroadaptation is thought to underlie aspects of drug tolerance and dependence. Phosphodiesterase 4 (PDE4) is an enzyme that the selective hydrolyzes intracellular cAMP. It is expressed in several brain regions that regulate the reinforcing effects of drugs of abuse.

OBJECTIVE: Here, we review the current knowledge about central nervous system (CNS) distribution of PDE4 isoforms and the effects of systemic and brain-region specific inhibition of PDE4 on behavioral models of drug addiction.

METHODS: A systematic literature search was performed using the Pubmed.

RESULTS: Using behavioral sensitization, conditioned place preference and drug self-administration as behavioral models, a large number of studies have shown that local or systemic administration of PDE4 inhibitors reduce drug intake and/or drug seeking for psychostimulants, alcohol, and opioids in rats or mice.

CONCLUSIONS: Preclinical studies suggest that PDE4 could be a therapeutic target for several classes of substance use disorder. We conclude by identifying opportunities for the development of subtype-selective PDE4 inhibitors that may reduce addiction liability and minimize the side effects that limit the clinical potential of non-selective PDE4 inhibitors. Several PDE4 inhibitors have been clinically approved for other diseases. There is a promising possibility to repurpose these PDE4 inhibitors for the treatment of drug addiction as they are safe and well-tolerated in patients.

Keywords PDE4      PDE4 inhibitors      VTA      nucleus accumbens      drug addiction     
Corresponding Authors: Christopher M. Olsen,Qing-Song Liu   
Online First Date: 17 October 2016    Issue Date: 04 November 2016
 Cite this article:   
Christopher M. Olsen,Qing-Song Liu. Phosphodiesterase 4 inhibitors and drugs of abuse: current knowledge and therapeutic opportunities[J]. Front. Biol., 2016, 11(5): 376-386.
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Christopher M. Olsen
Qing-Song Liu
Locomotor sensitization
(Pierce and Kalivas, 1997; Robinson and Berridge, 1993,2008)
Locomotor sensitization is a phenomenon where the locomotor response to a drug (e.g., amphetamine) is increased in animals with a history of repeated drug exposure. Previous studies have observed this increase for up to one year following cessation of drug treatment. The basis for this test is that locomotor sensitization may reflect long-lasting neuroadaptations and behavioral changes following repeated drug exposure, such as increased craving following exposure to drug cues.
Conditioned place preference
(Bardo and Bevins, 2000; Tzschentke, 2007;Olsen et al., 2010;Liu et al., 2014)
The conditioned place preference (CPP) test is a behavioral test that measures an animal’s preference for a place that is associated with previous exposure to a reward.
CPP protocols are typically divided into three phases: a pre-test, a conditioning phase, and a post-test. In the pre-test, a drug naïve animal is allowed to explore the entire CPP apparatus (typically composed of two or three distinct, but connected chambers). During the conditioning phase, the animal spends time confined to each of the chambers, however one chamber is paired with a reward (e.g., cocaine), while the other chamber is not (e.g. saline). After several of these pairing sessions, the animal undergoes the post-test in which the animal again is allowed to explore the entire CPP apparatus in a drug free state. The conditioned place preference is typically measured in one of two ways: 1) the difference in time spent in the reward paired chamber between the pre-test and post-test or 2) the difference in the post-test time spent in the reward paired chamber and the non-reward paired chamber. These outcome measures are collected while the animal is in a drug-free state.
Intravenous drug self-administration
(Thomsen and Caine, 2005;Olsen and Winder, 2006;Allain et al., 2015; Muelbl et al., 2016)
Intravenous drug self-administration is a measure of the reinforcing properties of a drug. The basis of this test is that a positive outcome associated with a response will increase the likelihood of the response in the future. Thus, intravenous drug self-administration is a type of operant (instrumental) conditioning that uses intravenous infusion of a drug as the reinforcer.
An animal with a chronic venous catheter is placed into an operant conditioning chamber, where it learns that a response on the “active” manipulanda (e.g., a lever) results in a drug infusion, whereas a response on the “inactive” manipulanda has no consequence. Drug self-administration is considered to be acquired when there is selectivity in responses on the active manipulanda relative to the inactive one. The effects of treatments on drug self-administration are typically measured as a change in drug self-administration relative to previously stabilized intake. This outcome measure is collected while the animal is under the influence of the drug of abuse.
Reinstatement of drug seeking
(Shaham et al., 2003; Conrad et al., 2013; Mantsch et al., 2016)
Reinstatement of drug seeking is a measure of drug seeking that is evoked by a stimulus. The basis of this test is that drug seeking (either using the CPP or the operant response in a drug self-administration test) is first extinguished by dissociating the connection between the drug and the drug conditioned response through repeated testing without the drug, then reinstated with a stimulus. Stimuli that are commonly used to reinstate drug seeking include drug-associated cues, stress, or a priming dose of the drug itself. These stimuli are known to also elicit craving in human drug users. The outcome measures are active and inactive manipulandum responding or time spent in the drug and nondrug paired sides (depending on if this is a self-administration or CPP test respectively). These measures are collected while the animal is in a drug-free state (unless drug priming is used to reinstate drug seeking).
Two bottle choice test for alcohol drinking
(Rodd et al., 2004; Crabbe, 2014; Lim et al., 2015; Muelbl et al., 2016 )
The two bottle choice test is a measure of voluntary alcohol intake and preference. In this test, alcohol is concurrently available with water and food, so alcohol intake is driven by hedonic processes as opposed to metabolic need. Outcome measures are total alcohol intake and preference (% of total fluid intake that is alcohol), and are collected while the subject is under the influence of the drug.
Intracranial self-stimulation
(Carlezon and Chartoff, 2007; Britt et al., 2012; Ikemoto and Bonci, 2014; Negus and Miller, 2014)
Intracranial self-stimulation measures the reinforcing properties of electrical or optogenetic stimulation of brain reward circuitry. The basis of this test is that direct stimulation of some brain regions (e.g., ventral tegmental area) or specific pathways (e.g., ventral hippocampus to nucleus accumbens) is innately reinforcing. Thus, operant conditioning is performed using stimulation as the primary reinforcer. Data from intracranial self-stimulation experiments are commonly represented as response rates across a series of stimulus intensities (or frequencies), and treatments that enhance brain stimulation reward will produce a left-shift in this intensity-response curve. These outcome measures are collected while the animal is in a drug-free state, unless a treatment is tested for its ability to modulate drug-enhanced brain stimulation reward.
Drug discrimination
(Young, 2009; Stolerman et al., 2011)
Drug discrimination is a test that measures the discriminative stimulus effects of a drug. Psychoactive drugs produce subjective feelings, which can be used to signal that a specific behavioral response is required to earn a reward. For example, an animal can be trained that after a saline infusion, pressing the left lever in an operant conditioning chamber will deliver a food pellet. However, after a cocaine infusion, only presses on the left lever deliver a food pellet. Test sessions occur in the absence of food reward, and the outcome measure is the percentage of cocaine- or saline-appropriate responses after each treatment.
There are two main types of drug discrimination tests: stimulus antagonism and stimulus generalization. A stimulus antagonism drug discrimination test can be used to measure the ability of a different drug to reduce the discriminative stimulus properties of the comparator drug. For example, pretreatment with flumazenil (an antagonist of the benzodiazepine binding site of the GABA-A receptor) reduces the percentage of diazepam-appropriate responses in rats trained to discriminate diazepam from saline. A stimulus generalization drug discrimination test assesses the ability of a drug to generalize to another comparative drug. For example, treatment with amphetamine will produce cocaine-appropriate responding in animals trained to discriminate cocaine from saline. Data are collected while the animal is under the influence of the drug.
Tab.1  Behavioral tests commonly used in the study of drugs of abuse
Fig.1  Selective PDE4 inhibitors rolipram and Ro 20-1724 blocked I-LTD in VTA dopamine neurons. (A) The presence of cocaine (3 µM; indicated by horizontal bar) during the 10 Hz stimulation (indicated by arrow “↑”) induced I-LTD in VTA dopamine neurons (n = 6). This I-LTD was blocked by PDE4 inhibitors rolipram (1 µM; n = 8; p<0.05 vs. control) and Ro 20-1724 (200 µM; n = 8; p<0.05 vs. control). The PDE4 inhibitors were present throughout the whole-cell recordings. Sample IPSCs before (indicated by “1”) and after (indicated by “2”) the 10 Hz stimulation are shown on the top. (B) The presence of D2 receptor agonist quinpirole (1 µM) during the 10 Hz stimulation induced I-LTD in VTA dopamine neurons (n = 7). This I-LTD was blocked by rolipram (1 µM; n = 8; p<0.05 vs. control) or Ro 20-1724 (200 µM; n = 7; p<0.05 vs. control). Error bars indicate SEM (used with the permission of Neuropsychopharmacology).
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