Faculty Bibliography

Numerous forms of evidence support a functional association between drug-seeking and ingestive behavior. We recently demonstrated that lateral ventricular injections of the melanocortin receptor agonist, MTII, potentiate the rewarding effect of amphetamine in rats (Cabeza de Vaca, et al., Psychopharm, 2002, 161:77-85). The objective of the present study was to explore the effect of MTII on the rewarding effect of cocaine (3.0 mg/kg, i.p.). Rewarding effects were measured in terms of the lowering of threshold for lateral hypothalamic self-stimulation (LHSS) using a psychophysical rate-frequency method. Results: MTII at 0.5 mg and 1.0 mg doses decreased overnight food intake by 61% and 80%, respectively. These same doses had no effect on LHSS thresholds when administered alone but potentiated the threshold-lowering effect of cocaine by approximately 53% and 67%, respectively. Initial experiments in a microinjection mapping study cast doubt on nucleus accumbens (NAC) as the site of MTII action on cocaine reward. The present results parallel the findings previously reported for another psychostimulant, d-amphetamine

RATIONALE: Previous studies indicate that chronic food restriction augments the rewarding and motor-activating effects of diverse drugs of abuse. The drugs that have so far proved susceptible to the augmenting effect of food restriction all increase synaptic concentrations of dopamine (DA). It is not known whether behavioral effects of selective, direct DA receptor agonists are also subject to the augmenting effect of food restriction. OBJECTIVES: The first objective of this study was to investigate whether the rewarding and locomotor-activating effects of the D1 agonist, A77636, and the D2 agonist, quinpirole are augmented by chronic food restriction. The second purpose was to investigate whether the augmented rewarding and locomotor-activating effects of d-amphetamine in food-restricted rats are reversed by the D1 antagonist, SCH23390. METHODS: Rewarding effects of drugs were measured in terms of their ability to lower the threshold for lateral hypothalamic self-stimulation (LHSS) using a rate-frequency method. Locomotor-activating effects were measured in terms of the number of midline crossings exhibited by rats in a shuttle apparatus. RESULTS: A77636 (1.0 and 2.5 mg/kg, i.p.) produced a greater threshold-lowering effect in food-restricted than ad libitum fed rats but produced variable effects on locomotor activity with no difference between groups. Quinpirole (0.2 and 0.5 mg/kg, i.p.) produced a marginally greater threshold-lowering effect in food-restricted rats and a dramatic locomotor response that was exclusive to food-restricted rats. The D1 antagonist, SCH23390, at a dose of 0.01 mg/kg (i.p.), had no effect on the lowering of LHSS threshold by amphetamine (0.5 mg/kg, i.p.) in ad libitum fed rats but blocked the augmentation otherwise observed in food-restricted rats. SCH23390, at a dose of 0.025 mg/kg, had no effect on locomotor activity induced by amphetamine (0.5 mg/kg) in ad libitum fed rats but blocked the augmentation otherwise observed in food-restricted rats. CONCLUSIONS: These results indicate that the augmentation of reward by food restriction extends to drugs that bypass the DA terminal and act postsynaptically. When taken together with prior immunohistochemical and behavioral findings, these results suggest that food restriction may increase the 'enabling' effect of the D1 receptor on DA-mediated behaviors

RATIONALE: Chronic food restriction augments the self-administration and locomotor stimulating effects of opiates, psychostimulants and NMDA antagonists. The extent to which these effects can be attributed to changes in drug pharmacokinetics and bioavailability versus sensitivity of the neuronal circuits that mediate the affected behavioral functions, has not been established. Recent studies point to central adaptive changes insofar as rewarding, locomotor and c-fos-inducing effects of amphetamine and MK-801, injected directly into the lateral ventricle, are greater in food-restricted than ad libitum fed rats. The increased expression of c-fos in nucleus accumbens (NAC) shell, in particular, suggests that food restriction may augment drug reward by modulating dopamine (DA) synaptic function in this area. OBJECTIVES: The first purpose of this study was to investigate whether the rewarding effects of cocaine and the delta1 opioid agonist DPDPE, both of which increase DA synaptic transmission, are augmented by food restriction. The second purpose was to determine whether the delta2 opioid agonist, deltorphin-II, which has been reported to exert DA-independent rewarding effects, is subject to the potentiating effect of food restriction. METHODS: Rewarding effects of drugs were measured in terms of their ability to lower the threshold for lateral hypothalamic self-stimulation (LHSS) using a rate-frequency method. RESULTS: In separate experiments, cocaine (50, 100 and 150 microg, ICV) and DPDPE (10 and 25 microg, ICV) produced greater threshold-lowering effects in food-restricted than ad libitum fed rats. Deltorphin-II (5.0, 10 and 25 microg, ICV) had no effect on reward thresholds, regardless of feeding regimen. CONCLUSIONS: While the reported DA-independence of deltorphin-II rewarding effects seemed to offer a means of testing the hypothesis that DA transmission is the critical modulated variable in food-restricted subjects, rewarding effects of this compound could not be demonstrated in the LHSS paradigm. The present results do, however, confirm and extend prior findings indicating that the enhanced self-administration of abused drugs by food-restricted subjects is due to enhanced sensitivity of a final common pathway for drug reward

7 days beyond cessation of insulin treatment) elevation of threshold in ad libitum fed rats and, more transiently, reversed the threshold-lowering effect of food restriction. Acute insulin treatment (3 mU, 15 min prior) also elevated threshold in food-restricted rats. These results are consistent with the hypothesis that insulin modulates sensitivity of a brain reward system and that hypoinsulinemia may be the common factor in food restriction and diabetes that accounts for the enhancement of perifornical LHSS

Chronic food restriction (FR) augments the locomotor and rewarding effects of abused drugs (Cabeza de Vaca and Carr, J. Neurosci. 18:7502,1998). FR also augments the induction of c-fos by amphetamine in nucleus accumbens, central nucleus of the amygdala (CEA) and bed nucleus of the stria terminalis (BNST) (Carr and Kutchukhidze, Brain Res. 861:88, 2000). Because all drugs tested to date, whose rewarding effects are augmented by FR, directly or indirectly stimulate dopamine (DA) release, the c-fos findings suggest that FR may augment behavioral responses by enhancing DA releasability in one or more DA terminal regions. The purpose of this study was to test whether direct DA receptor agonists are exempt from the effect of FR. In Exp. 1, the D-2 agonist quinpirole (0.2 and 0.5 mg/kg, i.p.) produced a dramatic locomotor response in FR rats and no response in ad libitum fed controls. The D-1 agonist A77636 (1.0 and 2.5 mg/kg, i.p.) did not differentially affect the two groups. In Exp. 2, the rewarding effect of A77636 (1.0 and 2.5 mg/kg, i.p.), assessed in a self-stimulation rate-frequency paradigm, was greater in FR rats than controls. The rewarding effect of quinpirole (0.2 and 0.5 mg/kg, i.p.) displayed only a trend in that direction. In Exp. 3, quinpirole (0.5 mg/kg, i.p.) induced fos-like immunoreactivity (FLI) in globus pallidus, BNST, and CEA; the response in CEA was augmented by FR. The behavioral results indicate that augmentation of rewarding/stimulant drug effects by FR may be mediated, at least in part, by postsynaptic DA mechanisms. The immunohistochemical results suggest that augmented transsynaptic effects of quinpirole on cellular activity in CEA may be involved in the locomotor response to this drug in FR rats

Chronic food restriction increases the systemic self-administration and locomotor-stimulating effect of abused drugs. However, it is not clear whether these behavioral changes reflect enhanced rewarding potency or a CNS-based modulatory process. The purpose of this study was to determine whether food restriction specifically increases the rewarding potency of drugs, as indexed by their threshold-lowering effect on lateral hypothalamic self-stimulation, and whether any such effect can be attributed to an enhanced central response rather than changes in drug disposition. When drugs were administered systemically, food restriction potentiated the threshold-lowering effect of amphetamine (0.125, 0.25, and 0.5 mg/kg, i.p.), phencyclidine (1.0, 2.0, and 3.0 mg/kg, i.p.), and dizocilpine (MK-801) (0.0125, 0.05, and 0.1 mg/kg, i.p.) but not nicotine (0.15, 0.3, 0.45 mg/kg, s.c.). When amphetamine (25.0, 50.0, and 100.0 microgram) and MK-801 (5.0, 10.0, and 20.0 microgram) were administered via the intracerebroventricular route, food restriction again potentiated the threshold-lowering effects and increased the locomotor-stimulating effects of both drugs. These results indicate that food restriction increases the sensitivity of neural substrates for rewarding and stimulant effects of drugs. In light of work that attributes rewarding effects of MK-801 to blockade of NMDA receptors on medium spiny neurons in nucleus accumbens, the elements affected by food restriction may lie downstream from the mesoaccumbens dopamine neurons whose terminals are the site of amphetamine-rewarding action. Possible metabolic-endocrine triggers of this effect are discussed, as is the likelihood that mechanisms mediating the modulatory effect of food restriction differ from those mediating sensitization by intermittent drug exposure

Food deprivation and restriction increase the rewarding potency of food, drugs of abuse, and electrical brain stimulation. Based on evidence that the rewarding effects of these stimuli are mediated by the same neuronal circuitry, lateral hypothalamic self-stimulation (LHSS) was used to investigate the involvement of various metabolic signals in the sensitization of reward. In Experiment 1, glucoprivation with 2-deoxy-d-glucose (150 mg/kg, intraperitoneally (i.p.)) and lipoprivation with nicotinic acid (150 mg/kg, subcutaneously (s.c.)), individually and in combination, failed to affect the LHSS threshold in ad lib.-fed rats. These results suggest that signals associated with acute shortage of metabolic substrate do not sensitize reward. Because numerous responses to more prolonged negative energy balance are mediated by neuropeptide Y (NPY), the effect of exogenous neuropeptide Y upon LHSS was investigated in Experiment 2. Intraventricular infusion of orexigenic neuropeptide Y doses (2.0, 5.0, and 12.5 g), in ad lib.-fed rats, had no effect on LHSS threshold. In Experiment 3, other concomitants of prolonged negative energy balance--high circulating levels of free fatty acids (FFA) and beta-hydroxybutyrate (HDB)-were investigated. Nicotinic acid (250 mg/kg, s.c.), which suppressed serum HDB and FFA levels, had no effect on LHSS in food-restricted or ad lib.-fed rats. Mercaptoacetate (68.4 mg/kg, i.p.), which suppressed serum HDB levels and exacerbated the elevation of FFA levels, also had no effect. Thus, the brain reward system, if modulated by these substances, is not affected by transient, though marked, changes in their levels. To investigate the effect of a sustained increase in levels of FFA and HDB, a 'ketogenic' diet was employed. Although this diet produced a fourfold increase in serum HDB levels, it had no effect on LHSS thresholds. Moreover, the failure of mercaptoacetate (68.4 mg/kg, i.p.) to decrease LHSS thresholds in these rats supports the conclusion that acute shortage of metabolic substrate does not sensitize reward. Other possible mechanisms of reward sensitization, including sustained decreases in circulating insulin and leptin and increases in corticosterone, are discussed

In four experiments investigating human timing, subjects produced estimates of sample durations by bracketing their endpoints. On each trial, subjects reproduced a sample duration by pressing a button before the estimated sample duration elapsed (start time) and releasing it after the estimated duration elapsed (stop time). From these responses, middle time (start + stop/2) and spread time (stop - start) were calculated, representing the point of subjective equality and the difference limen, respectively. In all experiments, subjects produced middle times that varied directly with sample duration. In Experiment 2, middle times lengthened when feedback was withheld. Consistent with Weber timing, spread times, as well as the standard deviation of middle times, varied directly with middle time (Experiments 1, 3, and 4). On the basis of an internal clock model of timing (Gibbon & Church, 1990), the data permitted inferences regarding memory processes and response threshold. Correlations between start and stop times and between start and spread times agreed with earlier findings in animals suggesting that the variance of temporal estimates across trials is based in part upon the selection of a single temporal memory sample from a reference memory store and upon one or two threshold samples for initiating and terminating each estimate within a trial.