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B~HAVIORAL FUNCTIONS OF NUCLEUS ACCUMBENS DOPAMINE 351 d lab chow (44,45,198). DA depletions in the medial striatum did not significantly affect lever pressing or chow consump- tion, and the nucleus accumbens is the only site at which DA depletions mimic the effects of administration of low doses of systemic neuroleptics. Thus, depletions of nucleus accumbens DA do not produce a general reduction in food motivation, although accumbens DA depletions do decrease instrumental lever pressing for food when alternative food sources are available (44). Depletions of DA in the ventrolateral neostdatum (VLS) reduced both lever pressing for food and chow consumption (44). Based only upon this result, it may appear superficially that the VLS is the long sought "reward center" for food. Yet such a statement is without any basis in fact; there is no evidence whatsoever that VLS has any "reward" functions related to food, and there is an enormous body of evidence demonstrating that the VLS is involved in skilled motor usage of the forepaw and head regions. In an initial study, (110), it was observed that DA depletions in the VLS produced profound feeding deficits, and also produced tremulous oral movements. In a subsequent study, 6- OHDA was injected into the nucleus accumbens, antero- ventromedial striatum, and VLS. Detailed behavioral observations demonstrated that the 6ritical region in which DA depletions disrupt feeding is the VLS; rats with VLS DA depletions have pronounced deficits in food intake, feeding rate and forepaw usage during feeding (197). Thus, these results indicate that a classic result of striatal DA depletion (i.e. feeding deficits (60,146,219,232) can be localized to a particular striatal subregion, i.e. the VLS). Rats With VLS DA depletions are directed towards food consumption; most of these rats will vigorously consume wet mash, will attempt to eat large dry pellets, and will attempt to grasp small food pellets (184,197). Yet, rats with VLS DA depletions have severe motor/sensorimotor impairments that interfere with their ability to reach, grasp, handle and chew pellets (197). This conclusion is consistent with previous work demonstrating that severe impairments in reaching and grasping with the contralateral forepaw are produced by DA depletions in lateral striatum (66,237) or, more specifically, the VLS (184). Also, these results are consistent with anatomical data showing that the lateral neostriatum receives massive projections from sensorimotor neocortex (36,154). Additional experiments have been conducted to characterize the effects of local DA depletions on the microstructure of operant responding. Computerized behavioral analyses were conducted to obtain various measures of instrumental responding, includ- ing the interresponse time (IRT) for each operant response. Each IRT represents the reciprocal of the local response rate. As noted above, accumbens DA depletions produced a slight decrease in FR5 lever pressing and a modest slowing of the IRT distribution. In contrast, VLS DA depletions produced profound motor deficits that resulted in substantial and persistent reductions in lever pressing and a dramatic slowing of the IRT distribution (196). Subsequent work has shown that VLS DA depletions alter both the initiation and duration of lever pressing responses (46). Thus, VLS DA depletions clearly produce profound deficits in skilled motor usage, which affect the ability of rats to eat large food pellets or press levers to obtain food. In contrast, the effects of accumbens DA depletions are much more subtle. Accum- bens DA depletions do not impair chow intake, and only slightly affect lever pressing on CRF or FR5 schedules. Nevertheless, when chow is available concurrently along with lever pressing on FR5 schedules, accumbens DA depletions alter the path that the animal uses to obtain food, such that lever pressing is decreased and chow con- sumption is increased. One of the major goals of this research was to determine whether accumbens DA depletions caused a decrease in lever pressing and an increase in chow consumption because of motor deficits that set an absolute limit on the number of lever presses that could be emitted. In a recent study (45), rats were tested on days 1, 3, and 5 of a 5-day test week using the concurrent FR5/feeding procedure. On days 2 and 4 of each week lab chow was not concurrently available, and rats could only lever press on the FR5 schedule for pellets to obtain food. DA depletions produced by intra-accumbens injections of 6-OHDA produced dramatic decreases in lever pressing and increases in chow consumption on days when lab chow was available. Yet, lever pressing was not sig- nificantly reduced in DA-depleted rats on days when chow was not available, although there was a significant correla- tion between lever pressing and accumbens DA levels. These results again suggest that accumbens DA depletions do not produce a general deficit in food motivation, ankl also indicate that accumbens DA does not appear J~o be critical for the execution of individual motor acts involved in lever pressing. Therefore, the shift from lever pressing to chow consumption following accumbens DA depletions is not due to a motor deficit that sets an absolute ceiling on the number of responses that the rats could emit. Rather, these results are consistent with the notion that accumbens DA regulates the higher-order processes that are involved in response allocation relative to a variety of motivational stimuli. 5.4. A T-maze versiori of the cost~benefit procedures: involvetnent of accumbens DA in crossing energy barriers Although many studies have been performed using the instrumental FR5/chow feeding procedure, several impor- tant questions remain. Possibly, the shift from lever pressing to chow consumption that was produced by accumbens DA depletions could have occurred because these DA deple- tions selectively affect only "instrumental" behaviors such as lever pressing, but do not'affect "consummatory" behavior. In considering this question, it should of course be emphasized that food consumption also relies upon simple instrumental responses such as approaching and remaining in proximity to food (198,252). Yet despite such considera- tions, it is important to investigate cost/benefit procedures under conditions in which explicit instrumental responses are being selected. To address these concerns, a novel T- maze version of the cost/benefit paradigm was developed (192). For this task, one arm of the T-maze contains an alleyway that leads to two food pellets, whereas the other arm contains a 44 cm wire barrier that must be climbed in order to reach four food pellets (see Fig. 3). Well-trained rats continue to cross the barrier to receive four pellets. A low dose of haloperidol caused animals to shift away from the arm with the barrier, and towards the no-barrier arm that had a lower magnitude of reinforcement. However, this dose of haloperidol did not cause a shift away from the arm with four pellets if there was no barrier present. Accumbens DA depletions also decreased selection of the arm that contained

352 Top view Barrier ~ FIG. 3. Top view of the T-maze apparatus descibed in the text is shown. The start arm of the maze was a box 29 × 21 × 21 era. The test arm ar~.a was a box 99 x 32 X 59 cm, which was constructed of wooden walls and a wire mesh floor. The connection between the start arm and the test arms was a sliding aluminium door. The barrier (shown here on the left) was 44 cm high and was made from a metal grating with parallel bars 2.5 cm apart. the barrier, and increased selection of the no-barrier arm that contained only two pellets. Yet accumbens DA depletions did not alter selection based on reinforcement magnitude when there was no barrier present in either ann. These results closely resemble those obtained from the operant procedure, and indicate that the shift away from the arm with the barrier is not due to a loss of preference for the higher reward magnitude (192). Halopeddol-treated and DA depleted rats remain directed towards food acquisition and consumption, yet these animals altered their behavior to select the less effortful path to obtain food. A subsequent study was also performed using the T-maze barrier task (43). Under one test condition, one ann of the maze contained a high reinforcement density (four × 45 mg Bioserve pellets) and the other arm contained a low rein- forcement density (two × 45 mg pellets). The barrier was placed in the arm that contained the high density of food reinforcement. In the second test condition, a separate group of rats was trained in the same T-maze, in which there were four food pellets in the arm that was obstructed by the barrier, yet there were no food pellets in the unobstructed arm. After training rats received intra-accumbens of injec- tions 6-OHDA or ascorbate vehicle. Accumbens DA deple- tions substantially decreased the number of selections of the obstructed arm with the high reinforcement density when the unobstructed arm also contained two food pellets. DA- depleted rats in this condition showed increased selection of the no-barrier arm as well as decreased entry into the arm that contained the barrier. These effects persisted through- out the three weeks of post surgical testing. Nevertheless, when the unobstructed arm contained no food pellets, and the only way to obtain food was to climb the barrier, rats with accumbens DA depletions showed only a modest effect on choice of the obstructed arm, which recovered by the second week of testing. DA-depleted rats that were tested with food in the unobstructed arm showed significantly fewer barrier crossings than DA-depleted rats that were tested with no food in the unobstructed arm. Thus, these findings were not consistent with the notion that accumbens DA depletion rendered the animals unable to climb the SALAMONE, COUSINS AND SI~YDER" barrier, or set an absolute ceiling on the number of barrier crossings the animals could perform. Instead, these results indicated that accumbens DA depletions affected the relative allocation of barrier climbing responses if alterna- tive food sources were available. Although rats with accumbens DA depletions crossed the barrier if this was the only source of food, these rats did have significant latency deficits (43). Interestingly, latency to leave the start box was significantly longer in this group, despite the fact this particular measure would not be affected directly by the time it takes to climb the barrier. Thus, DA depleted rats that eventually crossed the barrier took longer to inititate their responses. It is possible that this increased latency to leave the start box reflects a deficit in the planning stage of a complex movement such as barrier climbing, although the DA-depleted rats do eventually leave the start chamber and climb the barrier. 6. CONCLUSIONS The behavioral functions of nucleus accumbens DA remain complex and enigmatic. Certainly, it is unwise sim- ply to describe the functions of accumbeps DA with the unqualified use of such terms as "motor", "motivation", "reinforcement" or "reward". These terms are extremely blunt instruments, and they are inadequate for the task of precisely defining the functions of this structure. As noted above, there is considerable evidence that would cause one to question the notion that accumbens DA directly mediates the primary "rewarding" effects of food stimuli. Thus, it may be most useful to try and resist the current "zeitgeist", which would have one simply state that DA in nucleus accumbens directly mediates "reward". The processes of reir~forcement, motor control and moti- vation are not irreducible in nature; each term refers to several different components. Moreover, there is consider- able overlap between these processes (131,189). The gen- eration of,responses is affected by reinforcement, but it is also an aspect of motor control and sensorimotor function. The ability to form associations between stimuli and responses is an aspect of reinforcement, an aspect of learn- ing and an aspect of sensorimotor integration. The beha- vioral activation induced by motivational stimuli is an aspect of motivation, an aspect of reinforcement and an aspect of motor control and sensorimotor responsiveness. The work of Zeigler (264-266) has shown that lesions of sensory trigeminal circuits disrupt both sensorimotor and motivational aspects of feeding. One of the difficulties in identifying the behavioral functions of accumbens DA is that its functions lie in the areas of overlap between motivational and motor processes. Thus, one way of "describing the functions of accumbens DA would be to state that it is involved in higher order motor and sensor- imotor processes that are important for activational aspects of motivation, response allocation, and responsiveness to conditioned stimuli. Unfortunately, this may not roll off the tongue quite as fluently as the word "reward". Never- theless, the statement given above may be more useful and informative than any single word yet invented in the English language or technical lexicon. Essentially, it is being argued that the absolute distinction between "motor" and "reward" functions of DA, an idea which is so critical for the General Anhedonia Model, has I I I I I°

BEHAVIORAL FUNCTIONS OF NUCLEUS ACCUMBENS DOPAMINE 353 in 10 tO has reached the end of its useful life and should be discarded. ~For the overlap between motor and motivational years, pro- cesses has been emphasized by behavioral researchers (57,261). Cofer and Appley (33) suggested that conditioned ~stimuli activated an "anticipation-invigoration mechan- ism" that induced motor activities and increased the vigor of instrumental responding. These important behavioral functions, which for so long were described in the absence ~of any understanding of brain mechanisms, seem highly suitable as descriptions of the behavioral functions of accumbens DA. It has been suggested that DA systems are important for overall energy regulation (45,186,222). ~lIn contrast to the use of the term "anhedonia", the term "anergia" has been used to describe the effects of DA antagonism and accumbens DA depletion (192). [[Various phrases have been used to describe these functions of accumbens DA, including "behavioral activation", "behavioral reactivity", "motivational arousal", and. "psychomotor stimulation" (111,167,187-191,207,208, 1 248-250). In order to capture the integrative nature of these functions of DA, researchers have employed terms such as "sensorimotor" and "limbic-motor" (18,160,161, 188,189,220,256-258). I| A r/ecessary part of this rejection of the motor/reward !1 dichotomy must also be a revision of our understanding of the motor functions of nucleus accumbens. Considerable i, evidence indicates that locomotor activity is reduced by II accumbens DA depletions (44,125-127,246). Yet it should be emphasized that nucleus accumbens DA neurons are several synapses removed from the actual production of ~motor acts; indeed, they are ill suited for the task of directly controlling motor output, and there is little evidence that they are phasically active in specific relation to particular motor acts (191). It has been shown that accumbens lesions did not alter the .motor pattern of locomotion (236) and that accumbens DA depletions did not affect food intake or food handling (197). Interference with accumbens DA does not produce paralysis, and does not lead to the severe motor deficits produced by lateral stdatal DA depletions. The behavioral functions of accumbens differ from those of neostriatum, and these differences probably reflect the functional heterogeneity of striatal subregions as well as the hierarchical organization of frontal lobe and basal ganglia motor circuits (189,196). Nevertheless, accumbens DA depletions produce motor slowing, and appear to make the animal less behaviorally reactive to stimuli, so that higher levels of stimulation are necessary for instigating vigorous instrumental behaviors (43). This would indicate that nucleus accumbens DA is involved in modulating behavioral responsiveness to motivational stimuli, which represents ~in aspect of sensorimotor function. Accumbens DA appears to be involved in the regulation of motor activities but not the specific execution of motor acts. Release of DA in accumbens may prepare organisms for movement, but other structures more directly participate in the execution of motor acts ( 189,191). Depletions of accum- bens DA alter the temporal characteristics of movement, the probability of spontaneous movement being generated, and the ability of stimuli to elicit movement. Accumbens DA depletions do not irreversibly impair the ability to lever press or climb barriers to obtain food, but instead set constraints upon which instrumental response is selected. The general effect of accumbens DA depletions is to alter the relative allocation of responses with different kinetic requirements, such that behavior is biased in the direction of lower effort alternatives. Thus, accumbens DA participates in the process of enabling animals to overcome the obstacles that separate them from significant stimuli such as food. In economic terms, nucleus accumbens DA is important for the relative inelasticity of demand for food reinforcers. Nucleus accumbens DA may participate in the motor planning functions of prefrontal and premotor cortices (43), and may also be involved in modulating some of the conditioned and unconditioned excitatory properties of stimuli (93). 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