Faculty Bibliography

RATIONALE: Previous studies indicate that the D(3) dopamine (DA) receptor is preferentially expressed in limbic forebrain DA terminal areas and may mediate functional effects opposite those of the D(1) and D(2) receptor types. However, the locations of the D(3) receptors that regulate behavior, and the range of behavioral functions regulated, are not clear. OBJECTIVE: The objective of this study was to evaluate behavioral and cellular effects of the preferential D(3) dopamine receptor antagonist, U99194A. METHODS: In experiment 1, the rewarding effect of U99194A (5.0, 10.0 and 20.0 mg/kg, SC) was measured in terms of its ability to lower the threshold for lateral hypothalamic self-stimulation (LHSS) in ad libitum fed rats. To amplify a possibly weak reward signal, testing was also conducted in food-restricted rats. The ability of U99194A to alter the threshold-lowering effect of d-amphetamine was also assessed. In experiment 2, effects of U99194A on horizontal and vertical motor activity were compared in ad libitum fed and food-restricted rats. In experiment 3, effects of a behaviorally active dose of U99194A (5.0 mg/kg) on brain c-fos expression were measured and compared to those produced by d-amphetamine (0.5 mg/kg, IP). In experiment 4, the motor and cellular activating effects of U99194A were challenged with the D(1) dopamine receptor antagonist, SCH-23390 (0.1 mg/kg). RESULTS: U99194A displayed no rewarding efficacy in the LHSS paradigm. U99194A did, however, augment the rewarding effect of d-amphetamine. U99194A also produced a motor activating effect, reversible by SCH-23390, which was greater in food-restricted than ad libitum fed rats. The pattern and intensity of fos-like immunoreactivity (FLI) induced by U99194A was similar to that produced by d-amphetamine and was blocked, in caudate-putamen and nucleus accumbens, by SCH-23390. CONCLUSIONS: These results indicate that U99194A has psychostimulant-like effects on motor activity and striatal c-fos expression that are dependent upon the D(1) DA receptor. However, doses of U99194A that are adequate to stimulate motor activity and c-fos expression in striatal and limbic structures do not possess direct rewarding effects in the LHSS paradigm. Overall, these results seem consistent with the hypothesis that D(3) antagonism enhances D(1)/D(2) mediated signaling with behavioral effects dependent on both the density of D(3) receptors and the prevailing level of DA transmission in particular brain regions

Chronic food restriction and maintenance of low body weight have long been known to increase the self-administration and motor-activating effects of abused drugs. Using a lateral hypothalamic self-stimulation (LHSS) rate-frequency method, it is shown that chronic food restriction augments the rewarding (i.e., threshold lowering) effect of diverse drugs of abuse. Further, the effect is attributed to increased sensitivity of a neural substrate, rather than a change in drug bioavailability or pharmacokinetics, because it is preserved when drugs are injected directly into the lateral cerebral ventricle (intracerebroventricularly). The food restriction regimen that augments drug reward also increases the induction of c-fos, by intracerebroventricular amphetamine, in limbic forebrain dopamine (DA) terminal areas. The possibility of increased DA receptor function is suggested by findings that rewarding and motor-activating effects of direct DA receptor agonists are augmented by food restriction, and the augmented behavioral effects of amphetamine are reversed by an otherwise subthreshold dose of D-1 antagonist. Initial studies of DA receptor-mediated signal transduction, that are focused on the D-2 receptor, suggest increased functional coupling between receptor and G-protein (i.e., quinpirole-stimulated [35S]GTPgammaS binding) in dorsal striatum. Unlike behavioral sensitization induced by intermittent stress or psychostimulant treatment, which persist indefinitely following induction, the augmenting effect of food restriction abates within 1 week of restored ad libitum feeding and weight gain. The possible involvement of endocrine hormones and/or 'feeding-related' neuropeptides, whose levels change dynamically with depletion and repletion of adipose stores, is therefore under investigation. Initial tests have been limited to acute treatments aimed at attenuating the effects of hypoinsulinemia, hypoleptinemia and elevated corticosterone levels in food-restricted rats. None of these treatments has attenuated the behavioral effect of food restriction. While a melanocortin receptor agonist has been found to enhance drug reward, melanocortin receptors do not seem to mediate the augmenting effect of food restriction. Continuing investigations of endocrine adiposity signals, 'feeding-related' neuropeptides and dopaminergic signal transduction may further elucidate the way in which drugs of abuse exploit mechanisms that mediate survival-related behavior, and help explain the high comorbidity of drug abuse and eating disorders

RATIONALE: Numerous forms of evidence support a functional association between drug-seeking and ingestive behavior. One example is the augmentation of rewarding and cellular-activating effects of abused drugs by chronic food restriction. Within the past several years, a variety of orexigenic and anorexigenic neuropeptides that mediate adaptive responses to changes in energy balance and body weight have been identified. The involvement of these neuropeptidergic signaling systems in the modulation of drug reward has received little experimental attention. alpha-Melanocyte-stimulating hormone (alpha-MSH) and agouti-related protein, which act as agonist and antagonist, respectively, at melanocortin receptors (MCRs), are of particular interest because of their neuroanatomical distribution and opponent actions at a common receptor type. OBJECTIVES: The objective of this study was to determine whether lateral ventricular (i.c.v.) injections of the MCR agonist MTII and MCR antagonist SHU9119 at doses that decrease and increase food intake, respectively, modify the rewarding effect of amphetamine. METHODS: The rewarding effect of amphetamine was measured in terms of its ability to lower the threshold for lateral hypothalamic self-stimulation (LHSS) using a rate-frequency method. The modulatory effects of MTII and SHU9119 were evaluated by preceding i.c.v. amphetamine injection with i.c.v. injection of one of these MCR ligands or vehicle. Tests were conducted in both ad-libitum-fed and food-restricted subjects. RESULTS: SHU9119, the agouti-related protein-like antagonist, markedly increased overnight food intake of ad-libitum-fm-fed rats following i.c.v. injection of 1.0 microg and 0.5 microg. However, these injections had no effect on thresholds for LHSS tested 25 min or 60 min post-injection, nor did they alter the threshold-lowering effect of amphetamine (50 microg) tested 25 min, 100 min, or 24 h post-injection. MTII, the alpha-MSH-like agonist, suppressed overnight food intake of ad-libitum-fed rats following i.c.v. injection of 1.0 microg. MTII had no effect on thresholds for LHSS tested 60 min post-injection. However, this MCR agonist potentiated the threshold-lowering effect of amphetamine tested 100 min but not 24 h post-injection. This effect was evident in both ad-libitum-fed and food-restricted rats. CONCLUSIONS: These results indicate that agonist activity at MCRs potentiates amphetamine reward and that the anorexigenic neuropeptide alpha-MSH may exert this effect physiologically

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

Chronic food restriction augments the rewarding, motor-and cellular-activating effects of direct and indirect dopamine (DA) agonists injected directly into the brain ventricular system. Neuroadaptations within the brain DA system that may be involved in these effects have yet to be demonstrated. In the present study, rats had ad libitum access to food or were restricted to a single 10 g meal per day until body weight decreased by 20% (approximately 2 weeks). Rats were then maintained for an additional week with body weight of the food-restricted group clamped at this value. Caudate-putamen (CPU) and nucleus accumbens (NAC) were micropunched from frozen coronal brain sections. Stimulation of (35S)GTPgammaS binding in membranes, by the D2/3 DA agonist, quinpirole, was measured using quinpirole concentrations ranging from 30nM to 100muM. The maximal stimulation observed in CPU membranes of ad libitum fed rats was 33.9% over the basal level. In CPU membranes of food-restricted rats, the concentration-response curve was shifted to the left and maximal stimulation increased to 43.9% over the basal level (p<.05). Although quinpirole also produced a concentration-related stimulation of (35S)GTPgammaS binding in NAC membranes, there was no difference between groups. These results suggest that an amplification of D2-mediated signal transduction in CPU may be involved in the augmented behavioral effects of quinpirole and various indirect DA agonists in chronically food-restricted rats

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

Electrophysiological studies suggest that drug therapy of anxiety/depression involves regionally-specific changes in 5-HT1A receptor sensitivity. Furthermore, the purported net effect of clinically-relevant repeated drug treatment is enhancement of hippocampal 5-HT neurotransmission. Depending on the drug, decreased sensitivity of inhibitory somatodendritic autoreceptors, increased sensitivity of postsynaptic hippocampal receptors, or both, occurs after 2-3 weeks of treatment. This hypothesis was tested using autoradiographic analysis of agonist-stimulated (35S)GTPgammaS binding. Groups of rats were treated with saline, fluoxetine, 10; imipramine, 10; clorgyline, 1; or ipsapirone, 2X20 mg/kg for 21 days and sacrificed on day 22. Quadruplicate serial sections were incubated under standard conditions as described previously (JPET 292:684, 2000) in the presence or absence of 3 muM N,N-dipropyl-5-carboxamidotryptamine. Three brain regions were examined: dorsal raphe (DR; somatodendritic), and dorsal hippocampus (DH) and lateral septum (LS) (postsynaptic). Only imipramine (+17%) and (unexpectedly) fluoxetine (+54%) significantly increased agonist-stimulated binding in DH. All drugs except imipramine decreased binding in DR (-20 to -40%). While the results support the concept of net enhancement of hippocampal 5-HT neurotransmission, the pattern of changes in receptor sensitivity differed somewhat from the results of electrophysiological studies. The most consistent and striking effect, however, was a decrease in (35S)GTPgammaS binding in the LS by all four drug treatments (-14 to -23%), a finding previously reported also after chronic buspirone treatment

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

The noncompetitive NMDA antagonist, MK-801, produces stimulant and rewarding effects that are mediated by a combination of dopamine-dependent and -independent mechanisms. It was recently demonstrated that, similar to amphetamine, the rewarding and locomotor effects of intraventricular (i.c.v.) MK-801 are potentiated by chronic food restriction. Because food restriction also increases c-Fos expression induced by i.c.v. amphetamine in several subcortical dopamine (DA) terminal areas, Fos-like immunoreactivity (FLI) induced by i.c.v. MK-801 was evaluated in an effort to identify responses that are common to amphetamine and MK-801 and similarly augmented by food restriction. Unlike amphetamine, MK-801 did not increase FLI in caudate-putamen, bed nucleus of the stria terminalis, or ventral pallidum. Similar to amphetamine, MK-801 increased FLI in cingulate cortex, central nucleus of the amygdala and nucleus accumbens (NAC) core, but in none of these areas was the response augmented by food restriction. In medial prefrontal cortex, retrosplenial cortex, and NAC shell, however, MK-801 induced FLI that was augmented by food restriction. An effect that is common to amphetamine and MK-801 is the augmentation of FLI by food restriction in NAC shell. It is therefore suggested that increased releasability of DA, or upregulation of the D-1 receptor linked signal transduction pathway, in NAC shell may mediate the enhanced behavioral sensitivity of food-restricted subjects to drugs of abuse

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