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This study examined the effects of varying the predictability of nonrewarding events on behavior and neural activation using a rapid mixed-trial functional magnetic resonance imagery (fMRI) design. Twelve adult subjects were scanned with echo planar imaging during performance of a visual detection task where the probability of events (target and nontarget) varied. This task included expected and unexpected nonrewarding events (expected target, unexpected nontarget, and omission of target) in a design that closely parallels studies of dopamine function and reward processing in the alert monkey. We predicted that activation in dopamine-rich areas of the forebrain would behave like the animal literature shows that dopamine neurons in the midbrain behave. Specifically, we predicted increased activity in these regions when an unexpected event occurred and decreased activity when an expected event was omitted. Two main regions, the anterior cingulate and dorsal striatum, showed this pattern. The response in these regions was distinguished by enhanced anterior cingulate activity following the occurrence of an unexpected event and greater suppression of caudate activity following the omission of an expected event. These results suggest that neural activity within specific dopamine-rich brain regions can be modulated by violations in the expectation of nonrewarding events and that the direction of the modulation depends on the nature of the violations.

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The effect of dopaminergic drugs on the timing of conditioned keypecking in ring doves was studied in two experiments. Subjects were given pairings of a keylight with food and the temporal distribution of keypecks was obtained during unreinforced probe trials. Experiment 1 demonstrated that injections of pimozide before each session immediately decreased response rates but shifted timing distributions gradually to the right over several days of treatment. Experiment 2 showed similar results using a longer interstimulus interval (ISI). No shifts were observed when the drug was injected after training sessions, or when a delay, identical to each subject's average latency to eat during the drug condition, was inserted between keylight offset and food presentation. Consequently, the shifts in timing were mediated neither by mere accumulation of the drug nor a delay from keylight offset to food presentation resulting from the drug's ability to slow motor processes. The results suggest that pimozide modulates response rate through its effect on motor processes or incentive value, and response timing through a conditioned response (CR) to injection-related cues established via their repeated pairings with the drug.

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RATIONALE: Dopamine agonists elevate locomotion, sniffing, grooming, and a number of other behaviors. However, the D2 family (D2/D3/D4) agonist quinpirole, across a wide dose range, produces a period of locomotor inhibition that precedes the drug's locomotor excitatory effects. OBJECTIVES: The present study asked whether the suppressive actions of quinpirole also extend to other aspects of spontaneous behavior, such as sniffing, rearing and grooming, or whether this suppression of locomotion occurs while the frequency of other behaviors is increased or unaffected. METHODS: Locomotion, sniffing, rearing and grooming were observed over a 150-min test session in rats treated with 0, 0.1, 0.5, 1.0, or 10.0 mg/kg quinpirole. RESULTS: At 0.1 mg/kg, quinpirole suppressed locomotion. Higher doses (0.5-10.0 mg/kg) produced locomotor suppression followed by locomotor excitation. During the period of locomotor suppression, quinpirole also reduced the frequency of rearing and grooming. However, animals under high doses (1 and 10 mg/kg) of quinpirole showed elevated sniffing during the period of locomotor, rear and groom suppression. CONCLUSIONS: These results demonstrate that the well-documented locomotor suppression that precedes quinpirole's excitatory locomotor actions occurs in the midst of active sniffing. These results suggest that the suppressive effects of quinpirole on locomotion do not reflect a state of general behavioral suppression.

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Parkinsonian behavioral deficits are reduced in the presence of strong eliciting stimuli and are most pronounced when the response requires internal generation. In the present study, rats' head entries into a food compartment were measured in the presence and absence of an eliciting stimulus. The D2 receptor blocker raclopride suppressed the emission of spontaneous head entries but did not slow head entries emitted in response to a food cue. Rats subjected to a pharmacological disruption in dopamine (DA) transmission show response impairments that are reduced, and in this case eliminated, in the presence of strong eliciting stimuli. The present results support the view that neuroleptic-induced reductions in DA transmission do not produce an absolute limit on the speed with which an individual response can be generated but that they reduce the likelihood of response generation in the absence of strong eliciting stimuli.

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While it has previously been assumed that mesolimbic dopamine neurons carry a reward signal, recent data from single-unit, microdialysis and voltammetry studies suggest that these neurons respond to a large category of salient and arousing events, including appetitive, aversive, high intensity, and novel stimuli. Elevations in dopamine release within mesolimbic, mesocortical and nigrostriatal target sites coincide with arousal, and the increase in dopamine activity within target sites modulates a number of behavioral functions. However, because dopamine neurons respond to a category of salient events that extend beyond that of reward stimuli, dopamine levels are not likely to code for the reward value of encountered events. The paper (i) examines evidence showing that dopamine neurons respond to salient and arousing change in environmental conditions, regardless of the motivational valence of that change, and (ii) asks how this might shape our thinking about the role of dopamine systems in goal-directed behavior.

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Recent evidence suggests an important relationship between dopamine (DA) modulation of feeding and locomotor activity. To investigate this relationship, the free-feeding and locomotor behavior of rats under the influence of D(1)/D(2) antagonist cis-flupenthixol was examined. DA antagonists are known to produce within-session declines in reinforced behavior, with behavioral suppression occurring only after a number of normal responses have been emitted. In the present study, cis-flupenthixol (0.30 mg/kg ) produced a within-session decrement in both free-feeding behavior and in locomotor/exploratory activity of animals in an environment that had never been paired with food. In addition to producing similar patterns of disruption in feeding and locomotion, the drug also produced a similar magnitude of suppression in the two behaviors. The results show that disruption of DA activity suppresses locomotor/exploratory activity in a manner that closely mirrors neuroleptic suppression of feeding. Although neuroleptic-induced suppression of locomotion and feeding are traditionally presumed to reflect an attenuation of DA motor and reward functions, respectively, the present results suggest that DA plays a similar role in the modulation of these two behaviors.

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Many drugs need to be taken multiple times to achieve a therapeutic effect. Researchers have identified several mechanisms to account for the slow onset of drug action, including drug accumulation and structural changes induced by drugs. This article provides an example of a new mechanism to account for this change in drug action. Stimuli that accompany drug administration may come to evoke conditioned responses (CRs), and these CRs may be the basis for changes in drug efficacy. Specifically, this research shows that a dopamine antagonist, pimozide, changes response rates through the direct action of the drug but changes time perception through the CRs elicited by drug administration.

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In light of evidence implicating dopamine in the pathophysiology of attention deficit disorder and schizophrenia, diseases involving attentional or sensory processing abnormalities, it was of interest to determine whether and how dopamine neurons in the ventral tegmental area respond to sensory stimuli. The single-unit responses of ventral tegmental dopamine neurons were recorded in freely-moving cats during the presentation of brief, non-conditioned auditory and visual stimuli. Both auditory and visual stimuli produced neuronal excitation, involving a greater than 5-fold increase in the probability of burst firing followed by a period of burst inhibition. The burst nature of the single-unit response suggests that sensory-induced dopamine release at target sites was disproportionally large relative to the discharge frequency. While characteristics of the dopaminergic sensory response were similar for auditory and visual stimuli, the response latency was longer for visual stimuli. The results demonstrate that dopamine neurons in the ventral tegmental area, the site of origin for mesolimbocortical dopamine neurons, are reliably activated by non-conditioned auditory and visual stimuli.

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The present study examined whether thirsty rats pretreated with the dopamine receptor blocker, pimozide, would show patterns of unconditioned drinking behavior similar to those produced by reductions in water deprivation. An examination of the drinking behavior of 23-, 16-, 12-, 4-, and 0-h water-deprived animals showed that reductions in thirst produced increased latencies to initiate drinking, changes in the within-session pattern of licking, and reductions in the total number of licks emitted. In contrast, administration of pimozide to 23-h deprived rats produced no effect on either initiation latencies or lick patterns, and only marginally reduced the total number of licks emitted during the session. Finally, pimozide produced no effect on either individual lick durations or interlick intervals. These results suggest that the primary motivational (i.e., "thirst") mechanisms and motoric processes underlying drinking behavior are relatively invulnerable to pimozide challenge.

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Hungary rats were exposed to a conditioned stimulus (CS) event (either light onset or offset) before food delivery. After several weeks of contingent CS+/food pairings, animals were pretreated with either 0, 0.5, 0.75, or 1.0 mg/kg pimozide and exposed to the CS+ alone. Both vehicle- and neuroleptic-treated rats showed large elevations in locomotor activity immediately after CS+ presentation, in relation to pre-CS+ activity levels. This elevation in activity was apparently due to the conditioned motivational properties of the stimulus because animals that had previously received unpaired presentations of the CS and food failed to show similar responsiveness to the CS. Although pimozide did not affect responsiveness to the CS+, the neuroleptic did produce an overall suppression of locomotor activity during both pre- and post-CS+ periods. The results suggest that neuroleptic treatment produces a suppression of general activity but leaves the motivational properties of food-paired stimuli intact.

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Thirsty animals were trained to traverse a straight runway once each day for a reward consisting of 100 licks from a water-filled drinking tube. Once running speeds had stabilized, single daily extinction trials were initiated during which no water reinforcement was provided in the goal box. Extinction trials continued until running had slowed to levels approximately half of that observed during reinforced trials. A single treatment trial was then conducted in which some animals found water in the goal box and others continued to find an empty water bottle. Those subjects that were reinforced on treatment day subsequently demonstrated a reinstatement of their operant running response on the very next trial (i.e., 24 hr later). However, pretreatment with 1.0 mg/kg (but not 0.5 mg/kg) of the dopamine antagonist drug, pimozide, attenuated this response-reinstating effect of water-reinforcement. This action of pimozide was not likely a consequence of some residual sedative or motor incapacitation since a) the test day was conducted 24 hr after the treatment day by which time the pharmacological actions of the drug had greatly subsided; b) a Motor Control group administered pimozide after the reinforced trial exhibited normal response-reinstatement 24 hr later on Test Day; and c) on treatment day, pimozide did not reliably attenuate running times, latency to initiate drinking, nor the rate of licking behavior. Together, these data suggest that dopamine receptor antagonism can produce an attenuation in the reinforcing efficacy of water.

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To test the hypothesis that dopamine antagonist drugs attenuate the reinforcing properties of food, rats previously trained to traverse a straight runway for food reward subsequently underwent extinction sessions. After running speeds had substantially decreased, rats received a single food-rewarded trial either in the presence or absence of haloperidol (0, 0.15 or 0.30 mg/kg IP). Twenty-four hours later, animals were tested for reinstatement of the running response during a drug-free test trial. Animals that were nondrugged during the food-rewarded trial showed increases in running speed on the test trial relative to extinction baseline speeds. In contrast, animals under the influence of haloperidol during the food-rewarded trial failed to show test day increases in running speed. Additional control groups ruled out the possibility that the haloperidol results were due to either motor or state-dependent learning effects. The findings support the view that dopamine systems play a role in the neural substrates underlying food reinforcement. In addition, the study demonstrates a simple and effective methodology for separating neuroleptic effects on motor and reinforcement processes.

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Circadian rhythms and levels of wheelrunning were studied in thyroidectomized, parathyroidectomized, thyro-parathyroidectomized, and sham-operated male rats. Animals were entrained to a 12:12 light:dark schedule, then exposed to constant dim red illumination, and then given a diet containing lithium. Under constant conditions, free-running circadian activity rhythms were shorter, and levels of activity were greater, in thyroidectomized and thyroparathyroidectomized animals. Lithium reversed these effects, lengthening free-running circadian periods in all groups, with a greater reduction of activity observed in animals with thyroids removed. Parathyroidectomy had no clear effects. Since lithium slowed circadian rhythms and reduced activity even in the absence of intact thyroid or parathyroid glands, these effects may have been due to the action of lithium at some other site. The same may be true of other thyroid suppressors reported to affect circadian rhythms. These findings may be relevant to the biological substrates of major affective disorders in humans, which have been associated with abnormalities of thyroid function, abnormally short circadian rhythms, abnormal activity levels, and responsiveness to lithium therapy.

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