Nucleus Accumbens Receptors

From an evolutionary perspective, reinforcement of natural stimulation that enhances survival or the perpetuation of genes (such as food and sex) would be beneficial to the continuation of the species. The system of conditioning through reward and gratification remains one of the most fundamental examples of such reinforcement. However, there is a small fraction of pharmacological substances that possess the ability to abnormally intensify this reward function in the brain, known as drugs of abuse, which include the psychostimulants (cocaine and amphetamine), the opiates (heroin and opioids), nicotine, ethanol, and marijuana (i.e., cannabis or cannabi-noids) (Hyman et al. 2006). These abused drugs act on specific receptors in the brain to mediate their actions, each resulting in distinct behavioral and physiological responses. While reasons for individual self-administration may differ, a major motivational factor may be to experience the euphoric sensations resulting from stimulation of the reward circuit of the brain. However, drugs of abuse differ from natural rewards as they have little survival value and may cause a state known as drug addiction, which is a complex affliction of the brain, where initial voluntary drug consumption leads to compulsive drug seeking, loss of self-control, and eventually habituation (Everitt and Robbins 2005).

Drug addiction had been traditionally viewed as the motivation of an addict to take drug results from the desire to experience the rewarding (e.g., hedonic) effects of the drug as well as from the desire to avoid the punishing (e.g., anhedonic or aversive) consequences of drug withdrawal. Intensive studies during the past decades have added new knowledge about the mechanisms of drug addiction.

Departments of Psychiatry and Cellular and Molecular Medicine, Institute of Mental Health Research, University of Ottawa, 1145 Carling Ave, Ottawa, ON, Canada, K1Z 7K4 e-mail: [email protected].

G. Di Giovanni et al. (eds.), 5-HT2C Receptors in the Pathophysiology of CNS Disease, The Receptors 22, DOI 10.1007/978-1-60761-941-3_16, © Springer Science+Business Media, LLC 2011

The current understanding of drug addiction is that repeated drug use abnormally stimulates neurons responding to natural reinforcers such as food and sex, leading to long-lasting adaptation changes of brain reward pathways (Koob and Moal 1997; Nestler 2004) and aberrant learning processes (Robbins and Everitt 1999, 2002). Drug addiction has many phases, including initiation or euphoria phase (i.e., drug-induced rewarding or reinforcing effects), maintenance or dependence phase (i.e., compulsive drug taking), tolerance, withdrawal episodes, protracted abstinence, and craving and relapse (or reinstatement). The latter stages are characterized by lasting neural adaptations in the brain, promoting obsessive drug-seeking behavior via decreased value of natural rewards and impaired cognitive control (Kalivas and Volkow 2005). Although initial mechanisms for various drugs may differ, the underlying reward mechanism is of integral importance since it serves as a common pathway for virtually all abused drugs. Hence, numerous studies have focused on understanding drug-induced rewarding effects and the brain structures associated with them.

The main system in the brain that mediates natural and drug-induced reward effects is known as the mesolimbic dopamine pathway, which consists of dopamine neurons in the ventral tegmental area (VTA), a mammalian midbrain region, projecting nerve fibers (i.e., axons) to innervate the nucleus accumbens (NAc), a neuronal cluster in the forebrain (Alex and Pehek 2007; Laviolette and van der Kooy 2004). The VTA is populated by dopamine, serotonin (5-hydroxytryptamine, 5-HT), gamma-aminobutyric acid (GABA), and glutamatergic neurons (Bubar and Cunningham 2006; Yamaguchi et al. 2007). Stimulation of the VTA dopamine neurons leads to increased release of the neurotransmitter dopamine in the NAc, resulting in the acute sensations of euphoria or reward known to initiate drug addiction.

Since dopamine is crucial for the onset of addiction, the regulation of dop-amine neural processes is of particular interest. The 5-HT neurons from dorsal raphe (DR) nucleus densely innervate the VTA and NAc, thereby making them well situated to exert influence on the mesolimbic dopamine pathways (Bubar and Cunningham 2006; Halliday and Tork 1989). Although it is well known that 5-HT has the ability to mediate dopamine neurotransmission (Fletcher et al. 2004), the direction of modulation differs according to different subtypes of the 5-HT receptor population that are stimulated (Fletcher et al. 2004). The 5-HT2 receptor family in particular is linked to the control of central dopaminergic activity (Di Matteo et al. 2000). It has been established that 5-HT2C, one of the three subtypes of the 5-HT2 receptor, plays a prominent role in inhibiting dopamine neurotransmission in the midbrain (Di Matteo et al. 2002; Fletcher et al. 2004). Studies using the 5-HT2C agonist R0600175 displayed a reduction in the firing rate of VTA dopamine neurons, resulting in decreased levels of dopamine release in the NAc and frontal cortex. The 5-HT2C antagonist, SB 242084, reversed this effect (Di Matteo et al. 2000; Fletcher et ail. 2004). When administered alone, SB 242084 resulted in an increase of the basal firing rate of VTA dopamine neurons (Di Matteo et al. 2000; Fletcher et al. 2004). These results support that 5-HT2C

exerts tonic inhibitory control over the mesolimbic dopamine system, the reward center of the brain. Thus, it is plausible that 5-HT2C influences drug addiction. Research exploring this relationship discovered that treatment with R0600175 attenuated drug-induced activity and self-administration of both cocaine and nicotine, effects that were reversed by SB 242084 (Grottick et al. 2000, 2001). Further evidence demonstrated that administration of R0600175 could also dampen self-administration of food, supporting the generality of 5-HT2C in regulating the reward pathway of the brain (Grottick et al. 2001). The 5-HT2C receptor belongs to a superfamily of a G-protein-coupled receptor (GPCR) consisting of seven transmembrane domains, one extracellular N-terminal, one intracellular C-terminal, three extracellular loops, and three intracellular loops. The 5-HT2C receptor is involved in phosphatidylinositol hydrolysis (Muller and Carey 2006). The three intracellular loops of the 5-HT2C receptor contain phosphorylation sites that may be activated by serotonin or agonists such as R0600175 (Fletcher et al. 2004). Phosphorylation of 5-HT2C receptor prevents receptor desensitization, enhances resensitization, and is necessary for efficient signaling (Backstrom et al. 2000; Muller and Carey 2006). Therefore, by regulating the phosphoryla-tion of 5-HT2C receptors, it may be possible to exert control over the mesolimbic pathway (Fig. 16.1).

The phosphorylation state of receptors can be modulated by phosphatases, enzymes that hydrolyze phosphate groups from their substrates. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a dual lipid-protein phosphatase that functions as a tumor suppressor involved in cell cycling, translation, and apoptosis (Simpson and Parsons 2001). PTEN utilizes its lipid phosphatase activity to dephosphorylate PtdIns-3,4,5-P3, opposing the phosphatidylinositol 3-kinase/Akt pathway involved in cellular survival and proliferation (Leslie and Downes 2004; Simpson and Parsons 2001). Moreover, the protein phosphatase activity of PTEN allows it to modulate the mitogen-activated kinase pathway, which plays a similarly vital role to the Akt pathway in regulating proliferation and differentiation (Waite and Eng 2002). It was discovered that PTEN is widely expressed in the brain where it is involved in neuronal development and adult neuronal function (Lachyankar et al. 2000). In addition, we recently found that PTEN regulates hippocampal extrasynaptic signaling through direct protein-protein interaction with the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors (Ning et al. 2004). The significance of interaction of PTEN with other proteins in the brain, the phosphatase ability of PTEN, and the wide distribution of PTEN in most brain neurons, if not all, suggest that PTEN may play prominent roles in various brain functions through its ability to interact with other proteins and protein phosphorylation. Thus, considering that the phosphorylation state of 5-HT2C receptor may impact the activity of the mesolimbic dopamine system as described above, we initially hypothesized that PTEN may directly interact with 5-HT2C receptor in VTA dopamine pathway so as to govern the phosphorylation of 5-HT2C receptor, indirectly controlling the reward pathway of the brain (Fig. 16.1).

Nucleus Accumbens Receptors

Fig. 16.1 PTEN modifies 5-HT2C-receptor function in the ventral tegmental area (VTA), and disruption of PTEN-5-HT2C receptor coupling reduces drug-of-addiction-induced DA activity increases in the nucleus accumbens (NAc). 5-HT2C receptors are found in the VTA in gamma-aminobutyric acid (GABA) and, possibly, DA neurons. (a) Low-level activation of 5-HT2C receptors in VTA GABA-containing neurons causes only a small inhibition of frontal cortex (FC) glutamate-containing (Glu) neurons and of VTA DA-containing neurons (thin lines), resulting in a high level of DA activity in the NAc. (b) High-level activation of 5-HT2C receptors in VTA GABA-containing neurons causes an increase in GABA activity in the VTA and FC (thick lines) that suppresses the firing of DA neurons in the VTA directly or by reduced activation of FC projections. This results in reduced NAc DA activity. (c) 5-HT2C receptors associate with Gq and activate PLC activity. PLC catalyses PIP breakdown, resulting in formation of the second messengers inositol trisphosphate (IP3) and diacylglycerol (DAG). Phosphorylation (P) of the 5-HT2C receptor prevents receptor desensitization after 5-HT or agonist binding. The protein-protein association of PTEN-5-HT2C receptor causes receptor dephosphorylation and, thereby, inactivation. (d) Prevention of PTEN-5-HT2C receptor coupling by the peptide Tat-3L4F increases 5-HT2C receptor (Reprinted from Muller and Carey 2006. With permission from Elsevier Science)

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