The sensitivity to such drugs and the fact that the anatomical dispersion of the reward system corresponds with the dorsal and ventral boundaries of the dopaminergic cell groups of the ventral tegmental area and substantia nigra (Corbett and Wise, 1980; Wise, 1981) initially suggested that MFB brain stimulation was rewarding because it directly activated ascending dopaminergic projections. Against this possibility was the fact that the optimal stimulation frequencies for activating the dopamine system are much lower than the optimal frequencies for supporting the behavior (Wise, 1978). Subsequent parametric studies have confirmed that, because of their high threshold (Yeomans et al., 1988), few dopamine fibers are directly activated by the stimulation in most self-stimulation studies. Under the usual conditions of testing, the directly activated fiber population is characterized by short refractory periods and fast conduction velocities typical of large myelinated fibers and inconsistent with the small unmyelinated dopaminergic fibers of the MFB (Gallistel et al., 1981). Indeed, rewarding MFB stimulation appears to depend on at least two sub-populations of directly activated fibers; a cholinergic population with ultra-short (0.5-0.6msec) refractory periods and a second population, unidentified as to neurotransmitter or neurotransmitters, with somewhat longer (0.7-2.5msec) refractory periods (Gratton and Wise, 1985). Collision tests suggest that the bulk of the directly activated fibers descend the medial forebrain bundle (Bielajew and Shizgal, 1986) to the level of the ventral tegmental area (VTA) and substantia nigra and perhaps beyond (Boye and Rompré, 1996).

While MFB reward sites between the lateral hypothalamus and ventral tegmental area appear to involve the same fiber system, neither the origin nor the termination of that system is clearly established. While it was once thought that a single MFB system traversed the length of the hypothalamus, the fibers connecting the lateral preoptic area and the lateral hypothalamus appear to have more varied conduction velocities than those connecting the lateral hypothalamus with the ventral tegmental area (Bielejew et al., 2001). Moreover, while there is connectivity between lateral preoptic and lateral hypothalamic reward sites and between lateral hypothalamic and ventral tegmental reward sites, connectivity between lateral preoptic and ventral tegmental sites has been difficult to document (Bielajew et al., 2000). And while it was once suggested that the termination was at the dopaminergic cell bodies of the ventral tegmental area and substantia nigra (Wise, 1980; Yeomans, 1982), a more recent hypothesis is that the bulk of the directly activated MFB reward fibers project through the ventral tegmental area and substantia nigra to the cholinergic neurons of the pedunculopontine or laterodorsal tegmental nucleus, from which the reward signal is relayed back to the ventral tegmental area (Rada et al., 2000; Yeomans et al., 1993; Yeomans et al., 2000). Note that unless there is antidromic activation of this cholinergic pathway it cannot account for the cholinergic portion of the directly-activated MFB fibers.

Several MFB-related reward sites have been identified. Mu and delta opioids are self-administered into the VTA (Bozarth and Wise, 1981; Welzl et al., 1989; Devine and Wise, 1994; Zangen et al., 2002); these rewarding effects of mu opioids appear to be localized to the caudal VTA (Zangen et al., 2002). The rewarding effects of mu opioids in the VTA are thought to be due to disinhibition: mu opioids inhibit nearby GABAergic neurons that normally hold the dopamine under inhibitory control (Johnson and North, 1992). GABA_A agonists (Ikemoto et al., 1998) and the cholinergic agonist carbachol (Ikemoto and Wise, 2002) are also self-adminstered more readily into the caudal than the rostral VTA; the best sites for carbachol are in a thin band just dorsal to the interpeduncular nucleus (Ikemoto and Wise, 2002). GABA_A agonists, like opioids, are presumed to be rewarding because they disinhibit the dopamine system by inhibiting its GABAergic neighbors; self-administration of GABA_A agonists into the posterior VTA are antagonized by GABA_A antagonists in the posterior VTA (Ikemoto et al., 1998). Carbachol is thought to be rewarding because it activates the dopamine system directly (Blaha et al., 1996); VTA carbachol self-administration is attenuated by the D₁ dopamine antagonist SCH 23390 (Ikemoto and Wise, 2002). GABA_Aantagonists, on the other hand, are self-administered preferentially into the anterior VTA (Ikemoto et al., 1997), where they appear to diffuse to act at the supramammillary nucleus (Ikemoto, 2005); the rewarding effects of anterior VTA and supramammillary nucleus injections of GABA_A antagonists are blocked by anterior VTA and supramammillary injections of GABA_A agonists (Ikemoto, 2005; Ikemoto et al., 1997). GABA_A agonists and antagonists injected into the middle of the VTA can each be rewarding in the conditioned place preference paradigm (Laviolette and van der Kooy, 2001), where rate of diffusion from the injection site is not so critical.

Several afferents to the dopamine system are also implicated. Nicotinic cholinergic receptors in the VTA appear to be important for nicotine's rewarding actions. Intravenous nicotine self-administration is attenuated by lesions of VTA dopamine neurons or by intraventricular treatment with the nicotinic antagonist chlorisondamine (Corrigall et al., 1992). Chlorisondamine is a nicotinic channel blocker that is taken up by dopaminergic neurons and concentrated in dopaminergic cell bodies for months (El-Bizri et al., 1995). It blocks nicotinic actions on the dopamine system for 10 weeks or longer and blocks the ability of nicotine to potentiate lateral hypothalamic brain stimulation reward for at least three weeks (Wise et al., 1998); this action of nicotine is thought to be mediated at the level of the dopamine cell body or dendrites. This interpretation is consistent with the finding that the rewarding effects of VTA carbachol are attenuated by co-infusion of the nicotinic antagonist dihydro-β-erythroidine (Ikemoto and Wise, 2002). Muscarinic input to VTA is also implicated in reward function (Yeomans et al., 1993). Muscarinic M5 receptors on VTA dopamine neurons are thought to be involved (Yeomans et al., 2000). Thus nicotinic and muscarinic receptor activation in the VTA each contributes to reward function (Yeomans and Baptista, 1997).

The rewarding action of posterior VTA muscimol is blocked by the GABA_A antagonist picrotoxin (Ikemoto et al., 1998), implicating GABA_A receptors in this region in reward function. Mu and delta opioid reward in the VTA (Devine and Wise, 1994) are proportional to their ability to activate the mesolimbic dopamine system (Devine et al., 1993). Few delta opioid receptors are expressed in the VTA. Nonetheless, delta opioids are rewarding there and are not rewarding—and are not effective in activating the dopamine system—when injected into the adjacent interpeduncular nucleus, where delta opioid receptor expression is dense (Devine et al., 1993). While the access of delta opioids to the dopamine system remains to be understood, it is thought that mu opioids are rewarding because they inhibit the same GABAergic neurons as are inhibited by GABA_A agonists in the VTA, disinhibiting the VTA dopamine system in parallel to the disinhibition of nigral dopamine neurons known to result from inhibition of nearby GABAergic neurons (Johnson and North, 1992; Tepper et al., 1995).

Recently we have found that drug-seeking behavior can be reinstated by footshock stress and by local infusion of corticotropin-releasing factor (CRF) into the VTA (Wang et al. 2004). While it has no such effect in cocaine-naïve animals, CRF causes glutamate and dopamine release in the VTA of cocaine-experienced animals. Footshock stress causes equal CRF release in the VTA of cocaine-naïve and cocaine-experienced animals; thus it appears that some aspect of cocaine exposure—and perhaps other stressors—gives neuronally released CRF access to brain reward circuitry.

While lateral hypothalamic electrical stimulation can induce dopamine-dependent feeding in sated animals (Phillips and Nikaido, 1975), it appears that this system plays a stronger role in reinforcement than in motivation. Indeed, it has been argued that the stimulation motivates feeding only after animals have learned, through trial and error, that the stimulation makes food reinforcing even under conditions of satiety (Coons et al., 1965; Mendelson, 1966). Thresholds for stimulation-induced feeding decrease with experience (Wise, 1968), but even in experienced animals, it takes stronger levels of stimulation to motivate consummatory responding than to reinforce behavior. With current intensity at the same level, stimulation-induced reward requires longer stimulation trains (Ball, 1970) and somewhat higher stimulation frequencies (Gratton and Wise, 1988b) than does stimulation-induced feeding. This is consistent with the fact that free-feeding is more difficult to disrupt with neuroleptics (Wise and Raptis, 1986) or with dopamine-depleting lesions (Aberman and Salamone, 1999) than is food-rewarded lever-pressing (Aberman and Salamone, 1999; Wise et al., 1978a).

In assessing the relative contributions of reinforcing and motivational effects of dopamine, it must be remembered that severe depletion of forebrain dopamine (Stricker and Zigmond, 1985; Robinson et al., 2005) or large lateral hypothalamic lesions (Teitelbaum and Epstein, 1962) cause profound deficits in arousal and motor function. Thus discussions of the motivational effects of the dopaminergic component of motivational circuitry properly revolve around studies involving lesions or doses of dopamine antagonists that leave arousal and motor function relatively intact or preparations where arousal is provided by some experimental manipulation (Robinson et al., 2005). Even in the case of moderate levels of dopamine blockade, however, it has recently been suggested that moderate doses of dopamine antagonists interfere with the motivation to seek a reward rather than with the effectiveness of the reward once earned, that, in lay language, animals with impaired dopamine function no longer want the reward but still like it when they happen to get it (Berridge and Robinson, 1998).

This view is falsified by a number of experiments showing that the deterioration of motivation that develops in animals tested under conditions of moderate dopamine receptor blockade is a consequence of the devalued effectiveness of the reward in this condition. Most telling is the fact that dopamine antagonists disrupt reward-seeking behavior only after they disrupt the reinforcing effects of the reward. This is most evident in studies in which approach and consummatory responses are assessed in discrete trials (Fouriezos et al., 1978; McFarland and Ettenberg, 1995). For example, in a task where animals traversed a runway for a single intravenous heroin injection each day, running speed was normal on the day haloperidol was given, but was slow on the following day. Thus haloperidol disrupted the reinforcing effect of heroin but not the response habit or the response-eliciting effectiveness of the runway cues in trained animals that had never had haloperidol before (McFarland and Ettenberg, 1995); similar effects are seen with food reward (McFarland and Ettenberg, 1998. The ability of dopamine antagonists to impair free-feeding (Wise and Raptis, 1986) or lever-pressing for food (Wise et al., 1978a) increases progressively, both within and across test days, as the animal experiences the food under the antagonist. Thus the devaluation of reward by the antagonist is remembered and the memory of reward under dopamine blockade is what degrades subsequent motivation. Neuroleptics degrade the remembrance of value of rewards past before they degrade the acceptance of rewards present.

Thus the importance of the dopamine system and its afferents for motivation is complex. Motivation is strongly influenced by situational cues in the case of well-learned habitual behavior. For example, sated animals that were trained to respond for food under conditions of hunger will continue to respond normally for food and to eat it, for a considerable period, when subsequently tested when sated (Kimble, 1951; Koch and Daniel, 1945). Indeed, animals trained to work for food will continue to work for it despite the availability of free food (Jensen, 1963; Morgan, 1974). Thus motivation of response habits is strongly influenced not only by internal states but also by external stimuli. The immediate motivating effects of external reward-predictive stimuli appear to be largely dopamine-independent so long as the arousal and motor function are not impaired and so long as the animal has not yet had experience with the reward in the dopamine-antagonized condition (McFarland and Ettenberg, 1995; McFarland and Ettenberg, 1998). Reward-predictive stimuli begin to lose their effectiveness, however, as the animal gains experience with the reward under conditions of dopamine blockade (Fouriezos et al., 1978; Fouriezos and Wise, 1976; McFarland and Ettenberg, 1995; Wise and Raptis, 1986; Wise et al., 1978a).