Paul J. Wellman

PVN infusion of GLP-1-(7—36) amide suppresses feeding but does not induce aversion or alter locomotion in rats

Intracerebroventricular infusion of glucagon-like peptide-1-(7-36) amide (GLP-1) reduces feeding in rats, an effect that could be localized to the hypothalamic paraventricular nucleus (PVN). Intracerebroventricular GLP-1, however, may also induce conditioned taste aversion (CTA), thereby putting into question the specificity of the action of GLP-1 on feeding. The present experiments evaluated the action of PVN GLP-1 (0, 100, or 200 ng) on induction of CTA, on locomotion, and finally, on feeding and drinking in rats. PVN infusion of GLP-1 (100 or 200 ng) did not support the induction of CTA and did not reliably alter locomotion, but did suppress feeding and drinking. The present study suggests that GLP-1 infusions into the PVN reduce food and water intake without producing illness or disrupting locomotor behavior. These data, in conjunction with reports of increased feeding following antagonism of central GLP-1 receptors, support the notion that endogenous GLP-1, perhaps within the PVN, functions to suppress feeding in the rat.

Norepinephrine and the Control of Food Intake

The focus of the present review is to reconsider the role of endogenous norepinephrine (NE) in brain, specifically within the hypothalamic paraventricular nucleus (PVN), with regard to its potential role in eliciting eating or satiety. The PVN is innervated by NE fibers and is a site at which infusion of exogenous NE elicits eating at low doses. Two subtypes of alpha-adrenergic receptors within the PVN exert antagonistic actions on eating in the rat: activation of PVN alpha(2)-adrenoceptors increases eating, whereas activation of PVN alpha(1)-adrenoceptors suppresses eating. Pharmacologic manipulations that elevate NE can increase or decrease food intake, depending on the site and type of NE manipulation. Certain antiobesity drugs may act to reduce eating via release of NE and subsequent activation of alpha(1)-adrenoceptors. The PVN exhibits a reliable rhythm in the secretion of endogenous NE over the dark-and-light cycle, and this rhythm may interact with changes in numbers of PVN alpha(1)- and alpha(2)-adrenoceptors to modulate eating during the dark-and-light cycle. Push-and-pull and microdialysis studies indicate that NE secretion is strongly associated with eating, particularly at the start of the dark phase. The present review considers potential interactions of NE with substances such as leptin and neuropeptide Y that alter eating.

Caffeine exposure sensitizes rats to the reinforcing effects of cocaine

The present study examined the effect of pre-exposure to a moderate dose of caffeine (20 mg kg-1) on the acquisition of self-administration of cocaine (0.125 mg kg-1/infusion or 0.25 mg kg-1/infusion) in the rat. Rats pre-exposed to caffeine acquired self-administration more rapidly. Furthermore, sensitization to cocaines reinforcing effects was accompanied by an increase in the neurochemical response of the mesolimbic dopamine system to an acute injection of cocaine (10 mg kg-1, i.p.) as measured by in vivo microdialysis. Thus, the data suggest that exposure to caffeine can increase the reinforcing effects of cocaine, possibly via an enhanced response to the mesolimbic dopamine system.

Augmentation of cocaine hyperactivity in rats by systemic ghrelin

The feeding-relevant pathway by which food deprivation (FD) augments cocaine action is unknown. Systemic administration of the 28 amino acid acylated peptide ghrelin (1-10 nmol) increases food intake in rats and circulating levels of rat ghrelin are up-regulated by FD. The present experiment examined the impact of ghrelin or vehicle pretreatment on the locomotion and stereotypy induced by systemic cocaine hydrochloride. Male Sprague-Dawley rats were pretreated at -60 min with 0 or 5 nmol rat ghrelin (IP) and then injected (IP) at time 0 with 0, 2.5, 5.0, or 10.0 mg/kg cocaine. Locomotor activity was monitored over a 45-min post-cocaine period. Rats received the same ghrelin dose, but a different cocaine dose (in random order) on each of the four drug trials, with each drug trial separated by at least 2 days. Administration of 5 nmol ghrelin-0 mg/kg cocaine slightly increased locomotion relative to that of 0 nmol ghrelin-0 mg/kg cocaine. Cocaine increased locomotion as a function of dose in the 0 nmol ghrelin group, but the effect of cocaine was even greater when preceded by 5 nmol ghrelin. These results indicate that acute injection of ghrelin, at a feeding-relevant dose, augments the acute effects of cocaine on locomotion in rats.

Augmented cocaine conditioned place preference in rats pretreated with systemic ghrelin.

The physiological mechanism through which food restriction (FR) enhances the biobehavioral actions of psychostimulants is unknown but may involve the gut peptide ghrelin. Plasma levels of ghrelin are increased by FR and reduced by eating. Moreover, systemically administered ghrelin crosses into the brain and is known to augment the locomotor-stimulating effects of cocaine [COC: Wellman et al., 2005]. This study sought to determine whether pretreatment with ghrelin (5 nmol) would enhance the rewarding properties of COC (0.0, 0.312, 0.625, or 1.25 mg/kg i.p.) as measured by conditioned place preference (CPP). Adult male Sprague-Dawley rats were given free access to both sides of a CPP chamber to determine initial side preference. The rats were then confined for 30 min to either their preferred side or non-preferred side on 8 consecutive days. When rats were confined to the least preferred side, each was injected with 0.5 ml (i.p.) of either ghrelin (5 nmol) or saline 1 h before the conditioning trial and then injected (i.p.) with one of the COC doses immediately prior to the conditioning trial. On alternate days, rats were injected with vehicle one hour before and again immediately before the conditioning trial. Place preference scores were computed as the differences in time (min) spent on the least preferred side of the chamber for the pre-test and the postconditioning test, covaried by the initial degree of preference (% time spent on the black side during the pre-test). These analyses indicated a significant interaction between ghrelin pretreatment and COC dose on changes in preference scores. Significantly higher place preference scores were noted for rats treated with either 0.312 or 0.625 mg/kg COC doses, but only when these COC doses were preceded by administration of 5 nmol ghrelin. In contrast, saline pretreated rats exhibited significant CPP at the 1.25 mg/kg COC dose, but the ghrelin pretreated group did not. These results provide partial support for the contention that ghrelin pretreatment can augment the rewarding effects of sub-threshold doses of COC in a CPP procedure. Moreover, these findings are consistent with the view that ghrelin may play a role in the capacity of FR to augment psychostimulant action.

Brown adipose tissue thermogenesis induced by low level electrical stimulation of hypothalamus in rats

Brown adipose tissue (BAT) is an energy dissipating form of adipose tissue implicated in non-shivering thermogenesis as well as diet-induced thermogenesis. In the present study, in vivo interscapular BAT (IBAT) temperature was recorded prior to and following low level electrical stimulation (a 30 sec train of 60 Hz, 100 microA 0.5 msec isolated pulses) of various hypothalamic regions in rats. Significant increases in IBAT temperature were observed after stimulation of the anterior, medial preoptic, paraventricular and dorsomedial hypothalamus but not after stimulation of either ventromedial or caudal hypothalamus. For positive sites, IBAT temperature typically increased at 3-4 minutes following stimulation, peaked at 7-8 minutes after stimulation and declined at 20 minutes after stimulation. Although alterations in diet-induced thermogenesis have been reported after ventromedial hypothalamic lesions, the increases in BAT temperature noted in the present study suggest that inhibitory fibers that course through the paraventricular hypothalamus may form part of the central nervous system control of brown adipose tissue thermogenesis induced by overfeeding.

Impairment of acquisition of cocaine self-administration in rats maintained on a high-fat diet

Variations in dietary constituents such as carbohydrate are known to alter psychostimulant function in brain. Relatively few studies have examined the reinforcing effects of psychostimulants in subjects maintained on high-fat diets. The present experiment compared the rate of acquisition of an operant response for intravenous (i.v.) cocaine infusions (0.2 mg/kg) in rats fed either a chow-pellet diet or a 35.9% (by weight) high-fat diet for 45 days prior to cocaine self-administration testing. Rats maintained on a high-fat diet for 45 days exhibited diminished acquisition of cocaine self-administration, and this effect was not a function of dietary-induced obesity. The results suggest that prolonged exposure to a high-fat diet diminishes the efficacy of cocaine reinforcement.

Meal patterns in male rats during and after intermittent nicotine administration

Previously we observed in male rats that intermittent administration of nicotine (NIC) during the dark phase reduces food intake (FI) by initially decreasing only dark phase meal size. This was followed several days later by an increase in dark phase meal frequency such that FI returned to normal, while body weight remained suppressed. Termination of NIC treatment resulted in a modest dark phase hyperphagia. Since some human females use NIC as a weight control drug, the present study investigated changes in FI and body weight regulation in adult female rats treated for five estrous cycles with saline or a 1.40 mg/kg/day (free base) dose of NIC, which was given in four equal i.p. doses during the dark phase. The rats were followed for 15 days after cessation of NIC. Initially both dark and light phase FI were reduced and this was caused by an immediate decrease in dark and light phase meal size; the attenuation of meal size continued after cessation of NIC. On day 7 of NIC, the rats compensated by significantly increasing the number of dark, but not light, phase meals they took. This resulted in a normal 24-h FI, which was caused by a dark phase increase in FI coupled with a continued decrease in light phase FI. Importantly, these changes in meal patterns persisted for some time after termination of NIC. Upon NIC cessation, the NIC group showed no hyperphagia even though their body weight was significantly decreased. These results document that administration of NIC during the dark phase resulted in a reorganization of the microstructure of FI in females rats that resembles, but does not exactly duplicate, that observed in male rats. Like males, long lasting alterations in the microstructure of FI (e.g., meal size and meal number), were noted in female rats for up to 2 weeks after cessation of NIC. These results differ from studies in which NIC was given continuously 24-h per day and indicate that dark phase NIC administration in rats may represent an appropriate model to study the impact of NIC on meal patterns.

Interactions between caffeine and cocaine in tests of self-administration

Interactions between the effects of cocaine and caffeine have been demonstrated in tests of motor activity and drug discrimination. Since both drugs are widely consumed by humans, the present study was undertaken to determine whether a similar interaction between the reinforcing effects of these drugs could be demonstrated. Experienced cocaine self-administering rats were treated with caffeine either as an i.p. injection (20.0 mg/kg) prior to each self-administration test or as a co-administered drug within the infusion syringe (0.25 mg/kg/infusion). Both of these routes of administration of caffeine increased the intake of low doses of cocaine. Since caffeine is not reliably self-administered by laboratory animals, these data suggest that caffeine potentiated the reinforcing effects of cocaine.

Cocaine-induced hypophagia and hyperlocomotion in rats are attenuated by prazosin

The present studies examined the effects of antagonizing alpha(1)-adrenoceptors via systemic administration of prazosin on the behavioral actions of cocaine in rats, including induction of locomotion and suppression of eating. In Experiment 1, locomotor activity was monitored in automated chambers for 80 min in adult male rats pretreated with the alpha(1)-adrenoceptor antagonist prazosin (0, 0.5, or 2 mg/kg, i.p.) and then treated (i.p.) with either 0, 10, 20, or 40 mg/kg cocaine hydrochloride. Cocaine dose-dependently increased total distance traveled and the number of stereotypy counts, and significantly decreased rest time. Each dose of prazosin produced a significant attenuation of the locomotor effects of a limited range of cocaine doses (i.e. 10 and/or 20 mg/kg cocaine, but not 40 mg/kg cocaine). Prazosin alone did not alter any measure of locomotion. In Experiment 2, eating and drinking were monitored for 60 min in male rats pretreated with prazosin (0, 1, and 2 mg/kg, i.p.) and then treated with 0, 10, 20, or 40 mg/kg (i.p.) cocaine. Rats pretreated with vehicle exhibited a dose-dependent suppression of eating, but not drinking, to cocaine. The impact of prazosin on cocaine-induced hypophagia paralleled that noted for locomotion in that administration of prazosin significantly attenuated the hypophagic action of 20 mg/kg cocaine, but not that of 40 mg/kg cocaine. These findings confirm earlier studies noting a partial role for alpha(1)-adrenoceptors in the locomotor stimulant actions of cocaine and extend those findings to the feeding-inhibitory actions of cocaine.