Influence of bombesin on threshold for feeding and reward in the rat.
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Bombesin's purported role in satiety mechanisms prompted this investigation of its effects on thresholds for stimulation-induced feeding and self-stimulation in the rat. Single electrodes were implanted in the lateral hypothalamus and the ability of each electrode to support self-stimulation and stimulation-induced feeding was evaluated at four current levels between 80 and 320 microA. The frequency thresholds associated with each current value were assessed following four intraperitoneal doses of bombesin, 2, 4, 8, and 16 micrograms/kg, as well as a saline dose. Bombesin increased the thresholds for stimulation-induced feeding at doses known to reduce food intake without influencing self-stimulation thresholds. From these findings we conclude that (1) the effects of peripheral bombesin on stimulation-induced feeding are analogous to its effects on normal feeding and (2) the data provide additional evidence for a pharmacological dissociation between stimulation-induced feeding and reward. (+info)
Behavioral evidence of depolarization block of dopamine neurons after chronic treatment with haloperidol and clozapine.
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Electrophysiological studies have shown that chronic treatment with haloperidol causes depolarization block (DB) of dopamine cells in anesthetized and paralyzed rats. It has been proposed that the emergence of DB underlies the therapeutic and side effects of this drug. However, the relevance of DB to the clinical actions of haloperidol has been questioned on the grounds that chronic drug-induced DB has not yet been demonstrated in freely moving animals. In this study, responding for rewarding electrical brain stimulation was used to assess the occurrence of DB in rats chronically treated with haloperidol or clozapine. The time course of the effects of acute haloperidol (7.8-500 microg/kg) and clozapine (5-40 mg/kg) and of withdrawal from chronic drug treatment on reward and performance measures were also characterized. Haloperidol and clozapine dose-dependently attenuated reward and performance, haloperidol producing a predominant suppression of performance, and clozapine preferentially attenuating reward. Chronic (21 d) treatment with haloperidol (500 microg/kg) caused responding to cease in the six rats tested, and repeated injection with apomorphine restored the behavior in all of them; such an effect of apomorphine was observed in only two of six rats treated acutely with the same dose of haloperidol. Chronic treatment with clozapine (20 mg/kg) increased reward thresholds, an effect that was reversed by apomorphine in chronically, but not acutely, treated rats. The times at which chronic haloperidol-treated rats resumed responding was positively correlated with indices of behavioral supersensitivity after withdrawal, suggesting that the effect of apomorphine was not caused by direct stimulation of upregulated postsynaptic receptors. These findings constitute the first behavioral evidence of DB in unanesthetized, freely moving animals treated chronically with antipsychotics. They also demonstrate that the neural substrates mediating reward and performance are functionally independent and differentially sensitive to haloperidol and clozapine. (+info)
Dual serotonin (5-HT) projections to the nucleus accumbens core and shell: relation of the 5-HT transporter to amphetamine-induced neurotoxicity.
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Dopamine release in the nucleus accumbens (NAc) has been implicated as mediating the rewarding effects of stimulant drugs; however, recent studies suggest that 5-HT release may also contribute. In an effort to assess the role of 5-HT in drug-mediated reward, this study analyzed the serotonergic innervation of NAc using immunocytochemistry for 5-HT and the 5-HT transporter (SERT). We report that in control rats the NAc receives two distinct types of 5-HT axons that differ in regional distribution, morphology, and SERT expression. Most regions of the NAc are innervated by thin 5-HT axons that express SERT, but in the caudal NAc shell nearly all 5-HT axons lack SERT and have large spherical varicosities. Two weeks after methamphetamine or p-chloroamphetamine (PCA) treatment, most 5-HT axons in dorsal striatum and NAc have degenerated; however, the varicose axons in the shell appear intact. These drug-resistant 5-HT axons that lack SERT densely innervate the caudal one-third of the accumbens shell, the same location where dopamine axons are spared after methamphetamine. Moreover, 4 hr after PCA, the varicose axons in the caudal shell retain prominent stores of 5-HT, whereas 5-HT axons in the rest of the NAc are depleted of neurotransmitter. The results demonstrate that two functionally different 5-HT projections innervate separate regions of the NAc and that selective vulnerability to amphetamines may result from differential expression of SERT. We postulate that action potentials conducted from the raphe nuclei can release 5-HT throughout the NAc, whereas transporter-mediated release induced by stimulant drugs is more restricted and unlikely to occur in the caudal NAc shell. (+info)
Distinct sites of opiate reward and aversion within the midbrain identified using a herpes simplex virus vector expressing GluR1.
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Repeated administration of morphine increases expression of GluR1 (an AMPA glutamate receptor subunit) in the ventral tegmental area (VTA) of the midbrain, an important neural substrate for the rewarding actions of morphine. Microinjections of a herpes simplex virus (HSV) vector that causes local overexpression of GluR1 (HSV-GluR1) into the VTA can enhance the ability of morphine to establish conditioned place preferences, suggesting that altered GluR1 expression in this region is directly associated with changes in the rewarding efficacy of morphine. We now report that in rats given HSV-GluR1 directly into the VTA, morphine is most rewarding when maximal transgene expression is in the rostral VTA, whereas morphine is aversive when maximal transgene expression is in the caudal VTA. Dual-labeling immunohistochemistry shows that this difference cannot be explained by a different fraction of dopaminergic neurons infected in the rostral versus caudal VTA. No such anatomical specificity is seen in rats given VTA microinjections of HSV-LacZ, a vector expressing a control protein (-galactosidase). These results suggest that distinct substrates within the VTA itself differentially contribute to the rewarding and aversive properties of opiates. (+info)
Reward and somatic changes during precipitated nicotine withdrawal in rats: centrally and peripherally mediated effects.
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The negative affective aspects of nicotine withdrawal have been hypothesized to contribute to tobacco dependence. In the present studies in rats, brain stimulation reward thresholds, conditioned place aversions, and somatic signs of withdrawal were used to investigate the role of central and peripheral nicotinic acetylcholine and opioid receptors in nicotine withdrawal. Rats prepared with s.c. osmotic mini-pumps delivering 9.0 mg/kg/day nicotine hydrogen tartrate or saline were administered various doses of the nicotinic antagonists mecamylamine (s.c.), chlorisondamine (s. c. or i.c.v.), dihydro-beta-erythroidine (s.c.), or the opiate antagonist naloxone (s.c.). Nicotine-treated rats receiving mecamylamine or i.c.v. chlorisondamine exhibited elevated thresholds and more somatic signs than saline-treated rats. Nicotine-treated rats receiving s.c. chlorisondamine, at doses that do not readily cross the blood-brain barrier, exhibited more somatic signs than saline-treated rats with no threshold elevations. Naloxone administration produced threshold elevations and somatic signs only at high doses that induced similar magnitude effects in both nicotine- and saline-treated subjects. Mecamylamine or dihydro-beta-erythroidine administration induced conditioned place aversions in nicotine-treated rats but required higher doses than those needed to precipitate threshold elevations. In contrast, naloxone administration induced conditioned place aversions at lower doses than those required to precipitate threshold elevations and somatic signs. These data provide evidence for a dissociation between centrally mediated elevations in reward thresholds and somatic signs that are both centrally and peripherally mediated. Furthermore, threshold elevations and somatic signs of withdrawal appear to be mediated by cholinergic neurotransmission, whereas conditioned place aversions appear to be primarily mediated by the opioid system. (+info)
Backward inhibitory learning in honeybees: a behavioral analysis of reinforcement processing.
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One class of theoretical accounts of associative learning suggests that reinforcers are processed according to learning rules that minimize the predictive error between the expected strength of future reinforcement and its actual strength. The omission of reinforcement in a situation where it is expected leads to inhibitory learning of stimuli indicative for such a violation of the prediction. There are, however, results indicating that inhibitory learning can also be induced by other mechanisms. Here, we present data from olfactory reward conditioning in honeybees that show that (1) one- and multiple-trial backward conditioning results in conditioned inhibition (CI); (2) the inhibition is maximal for a 15-sec interval between US and CS; (3) there is a nonmonotonic dependency on the degree of CI from the US-CS interval during backward pairing; and (4) the prior association of context stimuli with reinforcement is not necessary for the development of CI. These results cannot be explained by models that only minimize a prediction error. Rather, they are consistent with models of associative learning that, in addition, assume that learning depends on the temporal overlap of a CS with two processes, a fast excitatory and a slow inhibitory one, both evoked by a reinforcer. The fmdings from this behavioral analysis of reinforcement processing are compared with the known properties of an individual, identified neuron involved in reinforcement processing in the bee brain, to further understand the mechanisms underlying predictive reward learning. (+info)
Response differences in monkey TE and perirhinal cortex: stimulus association related to reward schedules.
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Anatomic and behavioral evidence shows that TE and perirhinal cortices are two directly connected but distinct inferior temporal areas. Despite this distinctness, physiological properties of neurons in these two areas generally have been similar with neurons in both areas showing selectivity for complex visual patterns and showing response modulations related to behavioral context in the sequential delayed match-to-sample (DMS) trials, attention, and stimulus familiarity. Here we identify physiological differences in the neuronal activity of these two areas. We recorded single neurons from area TE and perirhinal cortex while the monkeys performed a simple behavioral task using randomly interleaved visually cued reward schedules of one, two, or three DMS trials. The monkeys used the cue's relation to the reward schedule (indicated by the brightness) to adjust their behavioral performance. They performed most quickly and most accurately in trials in which reward was immediately forthcoming and progressively less well as more intermediate trials remained. Thus the monkeys appeared more motivated as they progressed through the trial schedule. Neurons in both TE and perirhinal cortex responded to both the visual cues related to the reward schedules and the stimulus patterns used in the DMS trials. As expected, neurons in both areas showed response selectivity to the DMS patterns, and significant, but small, modulations related to the behavioral context in the DMS trial. However, TE and perirhinal neurons showed strikingly different response properties. The latency distribution of perirhinal responses was centered 66 ms later than the distribution of TE responses, a larger difference than the 10-15 ms usually found in sequentially connected visual cortical areas. In TE, cue-related responses were related to the cue's brightness. In perirhinal cortex, cue-related responses were related to the trial schedules independently of the cue's brightness. For example, some perirhinal neurons responded in the first trial of any reward schedule including the one trial schedule, whereas other neurons failed to respond in the first trial but respond in the last trial of any schedule. The majority of perirhinal neurons had more complicated relations to the schedule. The cue-related activity of TE neurons is interpreted most parsimoniously as a response to the stimulus brightness, whereas the cue-related activity of perirhinal neurons is interpreted most parsimoniously as carrying associative information about the animal's progress through the reward schedule. Perirhinal cortex may be part of a system gauging the relation between work schedules and rewards. (+info)
Delay activity of orbital and lateral prefrontal neurons of the monkey varying with different rewards.
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We examined neuronal activity in the orbitofrontal cortex (OFC) in relation to reward expectancy and compared findings with those of the lateral prefrontal cortex (LPFC) in the monkey. Activity of OFC neurons was examined in a delayed reaction time task where every four trials constituted one block within which three kinds of rewards and no reward were delivered in a fixed order. More than half of OFC delay neurons were related to the expectancy of delivery or nodelivery of a reward as the response outcome, while some neurons showed nature-of-reward-specific anticipatory activity changes. These delay-related activities reflected the preference of the animal for each kind of reward and were modulated by the motivational state of the animal. LPFC neurons are reported to show nature-ofreward-specific anticipatory activity changes in a delayed response task when several different kinds of rewards are used. Such rewarddependent activity is observed in LPFC delay neurons both with and without spatially differential delay (working memory-related) activity. Although reward expectancy-related activity is commonly observed in both OFC and LPFC, it is suggested that the OFC is more concerned with motivational aspects, while the LPFC is related to both the cognitive and motivational aspects of the expectancy of response outcome. (+info)