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Opioid agonists such as heroin and morphine activate midbrain dopaminergic neurons and elevate extracellular levels of DA in striatal regions. The rewarding effects of opioids may depend in part on dopaminergic systems, although there is clear evidence of DA-independent mechanisms as well (Laviolette et al. 2002; Pettit et al. 1984; van Ree et al. 1999). The indirect dopaminergic effect of opioids can be altered by 5-HT2C receptor ligands. The agonist MK212 inhibited the increase in extracellular levels of DA in the nucleus accumbens induced by morphine (Willins and Meltzer 1998). The 5-HT2B/2C antagonist SB 206553 enhanced the ability of morphine to increase the firing rate of midbrain DA neurons and to increase levels of DA in the nucleus accumbens (Porras et al. 2002). Consistent with this latter result, SB 242084 produced a modest potentiation of the ability of morphine to stimulate locomotor activity in rats (Fletcher et al. 2006). We are not aware of any published studies of the effects of 5-HT2C receptor ligands on reward-related behavioral effects of opioids.

In summary, these results show that multiple behavioral effects of cocaine, nicotine, and ethanol are reduced or attenuated by 5-HT2C receptor agonists. Under certain experimental conditions the effects of these drugs can be enhanced by blocking 5-HT2C receptors, suggesting some endogenous tonic control over these behaviors by 5-HT2C receptor-mediated neurotransmission.

15.4 Effects of 5-HT2C Receptor Ligands on Brain Stimulation Reward

Rats will readily self-administer brief trains of electrical stimulation to specific brain regions such as the lateral hypothalamus or VTA. Measuring changes in brain stimulation reward (BSR) can be used as a technique for investigating the circuitry of the brain's reward systems and for determining the effects of drugs on that circuitry (Carlezon and Chartoff 2007; Wise 2002). Manipulations of brain 5-HT function have long been known to modulate BSR (Redgrave 1978; van der Kooy et al. 1977). Greenshaw and colleagues have recently examined the effects of 5-HT2C receptor ligands on BSR via electrodes placed in the VTA (Hayes et al. 2008). Using a rate-frequency threshold analysis, it was found that systemic administration of the 5-HT1A/1B/2C agonist trifluromethylphenylpiperazine (TFMPP) and the selective 5-HT2C agonist WAY 161503 increased rate-frequency thresholds without altering maximal response rates. The effect of TFMPP was blocked by SB 242084 indicating that 5-HT2C receptor activation is the critical pharmacological action of this drug. By itself, SB 242084 did not alter rate-frequency thresholds. The profile of behavioral change induced by TFMPP and WAY 161503 suggests that 5-HT2C receptor activation reduces the rewarding effects of electrical stimulation of the VTA without affecting the capacity to respond. These results show that while the rewarding effects of brain stimulation can be reduced by pharmacological activation of 5-HT2C receptors, 5-HT acting via 5-HT2C receptors likely does not play a tonic role in the expression of brain stimulation reward.

15.5 Effects of 5-HT2C Receptor Ligands on Impulsive Behavior

Impulsivity is a characteristic of normal everyday behavior, but excessive impulsiv-ity may take on a pathological nature that is exhibited in a diversity of psychiatric disorders including aggression, attention deficit hyperactivity disorder (ADHD), drug abuse, and eating disorders (Hollander and Rosen 2000; Moeller et al. 2001). Impulsivity is not a unitary construct and encompasses a variety of different types of behavior, which may well be independent of each other (Evenden 1999). Two forms of impulsivity have been especially well studied in animal models. Impulsive action, which refers to the tendency to make premature responses in anticipation of an expected event, reflects a loss of inhibitory control over behavior. Impulsive choice is a description of the situation in which individuals prefer a small reward that is available immediately to a larger reward that is available after a delay. Operationally, this is studied in animals tests by allowing subjects to choose between one food pellet that is immediately contingent on making an operant response, or three or four pellets that are made available some time after the operant response. It has been argued that the type of delay discounting that underlies choice behavior in this type of situation is reduced in drug abuse (Perry and Carroll 2008; Perry et al. 2005). In other words, the immediate effects of a taking a drug (e.g., euphoria) are valued over the long-term benefits of drug abstinence (e.g., good health, successful interpersonal relationships, or steady employment).

Impulsiveness and a propensity to drug abuse are related to each other in several ways. Evidence suggests that impulsiveness may lead to drug abuse; that drug abuse itself may lead to impulsivity; and that impulsivity and drug abuse are linked through a variety of common other factors such as reactivity to rewarding stimuli, sex, and early experience (Perry and Carroll 2008). Using nicotine as an example, studies in animals have shown that impulsive choice and impulsive action differentially predict acquisition and maintenance of nicotine self-administration, as well as reinstatement of nicotine (Diergaarde et al. 2008) and perhaps alcohol seeking (Le et al. 2008). A recent study indicates that adolescent exposure to nicotine enhances impulsive action in adulthood (Counotte et al. 2009). In humans, high impulsivity may be associated with increased sensitivity to the reinforcing effects of nicotine and may predict a more rapid relapse to smoking following a period of abstinence (Doran et al. 2004; Mitchell 2004; VanderVeen et al. 2008; Perkins et al. 2008). Individual differences in impulsive choice in rats may predict subsequent acquisition of cocaine self-administration (Perry et al. 2005). Finally, a history of drug self-administration in rats may enhance impulsive action, although the magnitude and duration of this effect differs across different drugs (Dalley et al. 2005a, b).

Serotonin has long been linked to impulsivity. Early work in this area, typically involving nonselective generalized manipulation of brain 5-HT function, suggests that low 5-HT activity is linked to impulsivity (Soubrie 1986). It is now apparent that the relationship between 5-HT and impulsive behavior is much more complex depending on the type of impulsivity, the specific 5-HT receptor, and the brain region involved. A number of studies have now shown that altering 5-HT2C receptor-mediated function has an inhibitory effect, particularly on impulsive action.

On a differential reinforcement of low rate of responding (DRL) schedule animals are reinforced for spacing their responses a specified minimum time period apart. Responses occurring earlier than the schedule value are not reinforced, and the schedule clock is reset. For example, on a DRL24s schedule responses are reinforced only if they occur at least 24 s after the previous response. Blocking 5-HT2C receptors with SB 242084 disrupted responding on a DRL24s schedule by increasing the likelihood that responses were made earlier than the 24-s value (Higgins et al. 2003). The exact behavioral processes affected by SB 242084 are not clear, but this profile of behavior is consistent with impaired behavioral inhibition. More direct evidence that impulsive action is increased by SB 242084 comes from studies using the five-choice serial reaction time (5-CSRT) test. This test is primarily used to measure visual attention and requires animals to detect and respond to brief light stimuli (Robbins 2002). Poor response inhibition in this test is observed as an increase in premature responses, occurring before the onset of stimulus presentation. SB 242084 produced a significant increase in premature responding without consistently affecting accuracy of performance (Higgins et al. 2003; Fletcher et al. 2007; Winstanley et al. 2004). This effect was seen under standard baseline conditions when levels of premature responding were quite low, as well as under conditions where premature response rate was elevated by manipulating the rate and predictability of trials. The increase in impulsive action was also seen in both rats and mice (Fletcher et al. 2007). Selective destruction of brain 5-HT neurons achieved through intracerebral infusions of the neurotoxin 5,7-dihy-doxytryptamine produce the same effect (Fletcher 1995; Harrison et al. 1997; Wogar et al. 1992). The results with SB 242084 imply that loss of 5-HT2C receptor-mediated neurotransmission is the main mediator of this effect. In contrast to the effects of SB

242084, activating 5-HT2C receptors using Ro60-0175 (Quarta et al. 2007; Fletcher et al. 2007) and WAY 163909 (Navarra et al. 2008) reduced premature responding under basal conditions and when premature responding was elevated through unpredictable or long ITIs. In general, the reductions in premature responding induced by 5-HT2C receptor agonists were not accompanied by consistent changes in other behaviors such as accuracy of responding. Indeed, Quarta et al. (2007) explicitly concluded that the ability of Ro60-1075 to reduce premature responding could not be explained by a sedative action of this drug.

The results from these tests show consistently, across different laboratories, that 5-HT2C receptor agonists reduce while 5-HT2C receptor antagonists enhance impulsive responding. This bidirectional modulation of impulsive action by 5-HT2C receptor ligands is similar to that observed for aspects of the behavioral effects of cocaine, including cocaine reinforcement and reinstatement for responding. Thus, manipulation of 5-HT2C receptor function produces a consistent spectrum of behavioral changes that encompasses aspects of both drug-abuse-related behavior and impulsivity.

15.6 Effects of 5-HT2C Receptor Ligands on Feeding Behavior

It has long been known that manipulation of 5-HT function alters feeding behavior and body weight gain in both rodents and humans. For example, many drugs that indirectly elevate 5-HT function, including the 5-HT releaser fenfluramine, reduce food intake and body weight gain (Halford et al. 2007). Indeed, fenfluramine was used clinically for many years as an appetite suppressant and in the treatment of obesity, before its withdrawal in 1997 because of risks of pulmonary hypertension and cardiac valvulopathy. In contrast, under some conditions, lowering 5-HT activity led to increased food intake (Dourish et al. 1985; Fletcher 1988). A number of studies showed that the ability of fenfluramine to reduce food intake is dependent upon 5-HT1B and 5-HT2C receptors (Lee et al. 2004b; Neill and Cooper 1989; Vickers et al. 2001).

The importance of the 5-HT2C receptor in the control of food intake is further shown by the fact that 5-HT2C receptor agonists reliably reduce food intake and body weight gain. This has been demonstrated numerous times for the nonselec-tive agents mCPP and TFMPP, as well as for more selective compounds including Ro60-0175, Org 12962, VER 23779, BTV-933, YM348, WAY 161503, and lorca-serin (APD356) (Bickerdike 2003; Clifton et al. 2000a; Dalton et al. 2006; Hayashi et al. 2005; Kennett and Curzon 1988; Rowland et al. 2001; Schreiber and De Vry 2002; Somerville et al. 2007; Lam et al. 2008; Rosenzweig-Lipson et al. 2006). Indeed this latter compound has entered phase III clinical trials for the treatment of obesity.

Some evidence suggests that serotonergic drugs act specifically on the process of satiation. As satiety develops, animals show a characteristic behavioral profile that is termed the behavioral satiety sequence (Blundell et al. 1985). In this sequence, feeding gives way to a period of activity, then grooming, and finally a period of rest or inactivity. In the cases of fenfluramine and some 5-HT2C receptor agonists food intake reduction is characterized by an earlier onset of the behavioral sequence of satiety (Somerville et al. 2007; Halford et al. 1998; Vickers et al. 1999; Hewitt et al. 2002). The finding that the temporal sequencing of behavior is intact under the influence of these drugs implies that their ability to reduce feeding is through a specific alteration of motivational processes rather than some nonspecific sedative or disruptive action.

A dominant view in this field is that serotonergic systems influence feeding through part of the normal regulatory physiological mechanisms related to energy expenditure (Currie and Coscina 1997; Leibowitz and Alexander 1998). It has been specifically suggested that 5-HT2C receptor agonists influence feeding via an interaction with hypothalamic melanocortin mechanisms (Lam et al. 2008). Several earlier papers raised the possibility that drugs such as fenfluramine and fluoxetine may also act to alter rewarding properties of food (Gray and Cooper 1996; Hoebel et al. 1988; Leander 1987; Schwartz et al. 1989). Given the similarity in behavioral effects between fenfluramine and 5-HT2C receptor agonists and the involvement of 5-HT2C receptors in mediating some of the effects of fenfluramine, it is possible that 5-HT2C receptor agonists may reduce feeding by influencing food reward. To the best of our knowledge, this has not yet been tested. However, one study has found that the 5-HT2C receptor agonist VER23779 reduced responding for food on a second-order schedule of reinforcement (Somerville et al. 2007). In mice, mCPP dose-dependently reduced responding for palatable food on a progressive ratio schedule; interestingly, mCPP acted synergistically with the CB1 receptor antagonist rimonabant to reduce responding (Ward et al. 2008). All of these findings suggest that 5-HT2C receptor stimulation can reduce appetitive as well as consummatory aspects of feeding.

The finding that 5-HT2C receptor agonists reduce food intake has been confirmed many times, but the situation with 5-HT2C receptor antagonists is much less clear. At first sight the fact that 5-HT2C receptor knockout mice show an increase in daily food intake and become overweight in comparison to their wild-type littermate controls (Tecott et al. 1995) is consistent with the effects of 5-HT2C receptor agonists to reduce feeding. However, these mice do not show reliably enhanced food intake in short palatability-induced feeding tests, which are sensitive to the effects of 5-HT2C agonists (Dalton et al. 2006). These mice also do not show an enhanced motivation to seek food, as shown by the fact that they respond no differently than controls on a food reinforced progressive ratio schedule (Rocha et al. 2002). Similarly, the 5-HT2C receptor antagonist SB 242084 does not increase food intake in short feeding tests (Vickers et al. 1999; Hewitt et al. 2002; Clifton et al. 2000b). Although, another 5-HT2C receptor antagonist, RS102221, increased food intake (Bonhaus et al. 1997a), the fact that this compound failed to reverse motor effects of mCPP and appears to have limited brain penetration (Bonhaus et al. 1997b) casts doubt on this effect being mediated by central 5-HT2C receptors.

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