Faculty Bibliography

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

An emerging body of evidence indicates that the adrenal hormone corticosterone modulates behavioral effects of abused drugs. Recently, it was reported that the self-administration and locomotor stimulatory effect of cocaine are blocked by adrenalectomy (ADX). In order to evaluate the effect of ADX on the brain reward system in general, and cocaine reward in particular, the effect of ADX on lateral hypothalamic self-stimulation (LHSS) and its facilitation by cocaine were investigated. Using curve-shift methodology, effects of cocaine (1.0, 3.0 and 10.0 mg/kg, i.p.) on the rewarding efficacy of brain stimulation were determined in ADX rats, with and without corticosterone supplementation, and compared with sham-operated controls. Results indicate that ADX does not affect LHSS or the facilitatory effect of cocaine. The divergence between these results and the results of cocaine self-administration studies is discussed in terms of the neuroanatomical and psychological processing of reward

It was previously reported that chronic food restriction and streptozotocin-induced diabetes lead to brain region-specific changes in levels of Prodyn-derived peptides. These changes parallel behavioral adaptations that are reversed by opioid antagonists. In the present study, effects of food restriction and diabetes on Prodyn gene expression were measured in rat brain regions using a quantitative solution hybridization mRNA assay. Picogram amounts of Prodyn mRNA were determined in extracts of five brain regions. The highest density of Prodyn mRNA was observed in extracts of nucleus accumbens (4.68 pg/microg total RNA), bed nucleus of the stria terminalis (4.18 pg/microg), and in caudate nucleus (3.51 pg/microg). Lower levels were observed in the lateral hypothalamus (1.87 pg/microg) and central nucleus of the amygdala (1.22 pg/microg). Food restriction and diabetes both markedly increased the levels of Prodyn mRNA in the central amygdala (163% and 93%, respectively). Levels in the lateral hypothalamus were also increased (35% and 29%, respectively), though only the food-restriction effect was statistically significant. Neither treatment altered prodynorphin mRNA levels in the caudate nucleus, nucleus accumbens or bed nucleus of the stria terminalis. These results suggest that dynorphin neurons in central amygdala and lateral hypothalamus may be involved in behavioral or physiological adaptations to sustained metabolic need

Previous studies in female rats have shown that estrogen increases preproenkephalin (PPE) mRNA levels in the ventrolateral part of the ventromedial nucleus of the hypothalamus (VMHVL), an area implicated in the modulation of sexual behavior. In order to assess the physiological role of hypothalamic opioid expression in lordosis reflex 16-mer oligodeoxynucleotide (ODN) directed towards the PPE mRNA were acutely microinjected above the VMH of estradiol-primed ovariectomized rats. Estradiol-induced lordosis behavior was observed in response to a stud male 2 days thereafter. Antisense (without or with 4 mismatches) ODN injections near the VMHVL resulted in a significant reduction in lordosis quotient compared to control (reverse sense) ODN treatment or to antisense ODN injections targeted anterior or posterior to the VMHVL. In contrast, locomotor activity of these animals in the open-field test was not affected by ODN treatments. Enkephalin immunoreactive levels were determined by radioimmunoassay in the preoptic area, a major terminal field of the VMHVL. Estradiol-induced enkephalin levels were greatly reduced in antisense-treated groups. Using the in situ hybridization technique, PPE mRNA levels in the VMHVL were also determined. A 1.5-2-fold increase in PPE mRNA levels was observed in estradiol-treated rats compared to ovariectomized rats as previously described. This increase in PPE mRNA levels was not affected by ODN treatment, suggesting that the reduction of enkephalin expression was mainly due to physical blockade of PPE mRNA translation and not to its degradation. Taken together, these data further support the behavioral role of PPE expressing VMHVL neurons. They also highlight the in vivo potency of acute administration of antisense phosphorothioate ODNs in blocking neuronal target gene expression

It was previously observed that the corticosteroid synthesis inhibitor, aminoglutethimide (AG), markedly facilitates lateral hypothalamide (AG), markedly facilitates lateral hypothalamic self-stimulation (LHSS) in food-restricted rats. This effect is not present 30 min after injection when plasma corticosterone levels are suppressed, but rather at 2 h when corticosterone has recovered from suppression. In experiment 1, it was confirmed that AG (50.0 mg/kg, s.c.) lowers the threshold for LHSS in food-restricted rats but not in control rats that have ad libitum access to food. This effect occurred independently of whether food restriction, by itself, lowered threshold. Experiment 2 examined whether the facilitation of LHSS coincides with biosynthetic rebound of corticosteroid precursors. While a pregnenolone surge was demonstrated by radioimmunoassay, dose-response testing with exogenous pregnenolone and progesterone (0.1, 1.0 and 10.0 mg/kg, s.c.) failed to confirm the prediction that one of these precursors facilitates reward. Therefore, a general test of the involvement of adrenocortical biosynthetic events was conducted in experiment 3 where rats were adrenalectomized (ADX) or sham-operated prior to food restriction. Surprisingly, ADX did not diminish the effect of AG. This finding raises the possibility of a CNS, rather than adrenal, site of action. AG is known to penetrate the blood-brain barrier and exert weak anticonvulsant effects. The facilitation of reward may result from central inhibitory effects of the drug and share a common basis with the enhanced reinforcing potency of other CNS depressants in food-restricted rats