Cocaine self-administration and reinstatement in female rats selectively bred for high and low voluntary running.

BACKGROUND: Previous research has found that rats behaviorally screened for high (vs. low) wheel running were more vulnerable to cocaine abuse. To assess the extent to which a genetic component is involved in this drug-abuse vulnerability, rats selectively bred for high or low voluntary running (HVR or LVR, respectively) were examined for differences in cocaine seeking in the present study. METHODS: Female rats were trained to lever press for food and then were assessed for differences in acquisition of cocaine (0.4mg/kg; i.v.) self-administration across 10 sessions. Once acquired, rats self-administered cocaine for a 14-day maintenance phase, followed by a 14-day extinction phase when cocaine was no longer available. Subsequently, reinstatement of cocaine seeking was examined with priming injections of cocaine (5, 10 & 15mg/kg), caffeine (30mg/kg), yohimbine (2.5mg/kg) and cocaine-paired cues. RESULTS: A greater percentage of LVR rats met the acquisition criteria for cocaine self-administration and in fewer sessions than HVR rats. No differences in responding for cocaine were observed between phenotypes during maintenance. However, during extinction LVR rats initially responded at higher rates and persisted in cocaine seeking for a greater number of sessions. No phenotype differences were observed following drug and cue-primed reinstatement of cocaine seeking. CONCLUSIONS: In general, LVR rats were more sensitive to the reinforcing effects of cocaine than HVR rats during periods of transition into and out of cocaine self-administration. Thus, LVR rats sometimes showed a greater vulnerability cocaine seeking than HVR rats.

Effects of a metabotropic glutamate receptor 5 positive allosteric modulator, CDPPB, on spatial learning task performance in rodents.

Metabotropic glutamate receptor 5 (mGlu5) has been implicated in a variety of learning and memory processes and is important for avoidance learning. The present studies used an mGlu5 receptor positive allosteric modulator, 3-cyano-N-(1,3 diphenyl-1H-hyrazol-5-yl)benzamide (CDPPB), to characterize the importance of mGlu5 receptors in aversively- and appetitively-motivated spatial learning tasks (tasks in which the instrumental contingency involves discriminative cues that differ in spatial location). C57Bl/6 male mice were initially trained in the Barnes maze in the absence of drug. Subsequently, CDPPB (30mg/kg, i.p.), administered 20min prior to each of 3 daily reversal learning training sessions in the Barnes maze, significantly enhanced performance compared to vehicle-treated controls and had a significant effect on search strategy. Mice treated with CDPPB also displayed significantly less perseverative behavior than control-treated animals. In a second experiment, male Sprague-Dawley rats were trained in an appetitively-motivated, delayed alternation version of a T-maze. 30mg/kg CDPPB (s.c.), delivered 20min prior to each of 5 daily training sessions, enhanced the delay rats were able to withstand between the sample and choice portions of each T-maze trial. The present results emphasize the role of mGlu5 receptors in spatial learning tasks and support previous studies which report mGlu5 positive allosteric modulators can enhance learning in some tasks and may have potential as nootropic drugs.

Restricted daily consumption of a highly palatable food (chocolate Ensure(R)) alters striatal enkephalin gene expression.

Brain opioid peptide systems are known to play an important role in motivation, emotion, attachment behaviour, the response to stress and pain, and the control of food intake. Opioid peptides within the ventral striatum are thought to play a key role in the latter function, regulating the affective response to highly palatable, energy-dense foods such as those containing fat and sugar. It has been shown previously that stimulation of mu opiate receptors within the ventral striatum increases intake of palatable food. In the present study, we examined enkephalin peptide gene expression within the striatum in rats that had been given restricted daily access to an energy-dense, palatable liquid food, chocolate Ensure(R). Rats maintained on an ad libitum diet of rat chow and water were given 3-h access to Ensure(R) daily for two weeks. One day following the end of this period, preproenkephalin gene expression was measured with quantitative in situ hybridization. Compared with control animals, rats that had been exposed to Ensure(R) had significantly reduced enkephalin gene expression in several striatal regions including the ventral striatum (nucleus accumbens), a finding that was confirmed in a different group with Northern blot analysis. Rats fed this regimen of Ensure(R) did not differ in weight from controls. In contrast to chronic Ensure(R), acute ingestion of Ensure(R) did not appear to affect enkephalin peptide gene expression. These results suggest that repeated consumption of a highly rewarding, energy-dense food induces neuroadaptations in cognitive-motivational circuits.

Nucleus accumbens mu-opioids regulate intake of a high-fat diet via activation of a distributed brain network.

Endogenous opioid peptides within the nucleus accumbens, a forebrain site critical for the regulation of reward-related behavior, are believed to play an important role in the control of appetite. In particular, this system is thought to mediate the hedonic aspects of food intake, governing the positive emotional response to highly palatable food such as fat and sugar. Previous work has shown that intra-accumbens administration of the mu-opioid agonist D-Ala2,Nme-Phe4,Glyol5-enkephalin (DAMGO) markedly increases food intake and preferentially enhances the intake of palatable foods such as fat, sucrose, and salt. Using information from recently performed c-fos mapping experiments, we sought to explore the involvement of structures efferent to the nucleus accumbens in this feeding response. Free-feeding rats with dual sets of bilateral cannulas aimed at the nucleus accumbens and one of several output structures were infused with DAMGO (0, 0.25 microg/0.5 microl) in the accumbens, and fat intake was measured over a 2 hr period. Concurrent temporary inactivation with the GABA(A) agonist muscimol (5-20 ng/0.25 microl) of the dorsomedial hypothalamic nucleus, lateral hypothalamus, ventral tegmental area, or the intermediate region of the nucleus of the solitary tract blocked the robust increase in fat intake induced by intra-accumbens DAMGO at doses of muscimol that did not affect general motor activity. Muscimol alone also inhibited and augmented baseline fat intake in the lateral and dorsomedial hypothalamic nuclei, respectively. These results suggest that intake of energy-dense palatable food is controlled by activity in a neural network linking ventral striatal opioids with diencephalic and brainstem structures.

Blockade of alpha1 adrenoreceptors in the dorsal raphe nucleus prevents enhanced conditioned fear and impaired escape performance following uncontrollable stressor exposure in rats.

Previous research has shown that the effect of exposure to uncontrollable stressors on conditioned fear responding and escape behavior in rats is dependent on serotonergic neural activity in the dorsal raphe nucleus (DRN). The role that norepinephrine released in the DRN plays in producing the behavioral consequences of exposure to inescapable tail shock in rats was investigated in the present study. The selective alpha1 adrenoreceptor antagonist benoxathian was injected into the DRN before exposure to inescapable tail shock or before behavioral testing conducted 24 h later. Benoxathian prevented the impairment of escape responding produced by inescapable shock, but did not reverse this effect when given before testing. The enhancement of conditioned fear produced by prior inescapable shock was attenuated by benoxathian administered before inescapable shock or before behavioral testing. These results support the view that noradrenergic input to the DRN is necessary to produce the behavioral effects of inescapable tail shock.

Opioid modulation of taste hedonics within the ventral striatum.

There is a long-standing interest in the role of endogenous opioid peptides in feeding behavior and, in particular, in the modulation of food reward and palatability. Since drugs such as heroin, morphine, alcohol, and cannabinoids, interact with this system, there may be important common neural substrates between food and drug reward with regard to the brain's opioid systems. In this paper, we review the proposed functional role of opioid neurotransmission and mu opiate receptors within the nucleus accumbens and surrounding ventral striatum. Opioid compounds, particularly those selective for the mu receptor, induce a potent increase in food intake, sucrose, salt, saccharin, and ethanol intake. We have explored this phenomenon with regard to macronutrient selection, regional specificity, role of output structures, Fos mapping, analysis of motivational state, and enkephalin gene expression. We hypothesize that opioid-mediated mechanisms within ventral striatal medium spiny neurons mediate the affective or hedonic response to food ('liking' or food 'pleasure'). A further refinement of this hypothesis is that activation of ventral striatal opioids specifically encodes positive affect induced by tasty and/or calorically dense foods (such as sugar and fat), and promotes behaviors associated with this enhanced palatability. It is proposed that this brain mechanism was beneficial in evolutionary development for ensuring the consumption of relatively scarce, high-energy food sources. However, in modern times, with unlimited supplies of high-calorie food, it has contributed to the present epidemic of obesity.

Timecourse and corticosterone sensitivity of the brain, pituitary, and serum interleukin-1beta protein response to acute stress.

Activation of peripheral immune cells leads to increases of interleukin-1beta (IL-1beta) mRNA, immunoreactivity, and protein levels in brain and pituitary. Furthermore, IL-1beta in brain plays a role in mediating many of the behavioral, physiological, and endocrine adjustments induced by immune activation. A similarity between the consequences of immune activation and exposure to stressors has often been noted, but the potential relationship between stress and brain IL-1beta has received very little attention. A prior report indicated that exposure to inescapable tailshocks (IS) raised levels of brain IL-1beta protein 2 h after IS, but only in adrenalectomized (and basal corticosterone replaced) subjects. The studies reported here explore this issue in more detail. A more careful examination revealed that IL-1beta protein levels in hypothalamus were elevated by IS in intact subjects, although adrenalectomy, ADX (with basal corticosterone replacement) exaggerated this effect. IL-1beta protein increases were already present immediately after the stress session, both in the hypothalamus and in other brain regions in adrenalectomized subjects, and no longer present 24 h later. Furthermore, IS elevated levels of IL-1beta protein in the pituitary, and did so in both intact and adrenalectomized subjects. IS also produced increased blood levels of IL-1beta, but only in adrenalectomized subjects. Finally, the administration of corticosterone in an amount that led to blood levels in adrenalectomized subjects that match those produced by IS, inhibited the IS-induced rise in IL-1beta in hypothalamus and pituitary, but not in other brain regions or blood.

Activation of serotonin-immunoreactive cells in the dorsal raphe nucleus in rats exposed to an uncontrollable stressor.

The dorsal raphe nucleus (DRN) and its serotonergic terminal regions have been suggested to be part of the neural substrate by which exposure to uncontrollable stressors produces poor escape responding and enhanced conditioned fear expression. Such stressor exposure is thought to selectively activate DRN serotonergic neurons in such a way as to render them transiently sensitized to further input. As a result of this sensitized state, behavioral testing procedures are thought to cause excess serotonergic activity in brain regions that control these behaviors. The present studies were conducted to investigate activity in the DRN following exposure to escapable and yoked, inescapable tailshock. Neural activity was characterized using immunohistochemistry to detect the immediate early gene product Fos in serotonin-immunoreactive cells in the DRN. Inescapable tailshock led to greater serotonergic neural activity than did escapable tailshock, supporting the hypothesis that uncontrollable stressors preferentially activate serotonergic neurons in the DRN.

Uncontrollable stress potentiates morphine's rewarding properties.

Strategies used to explore the role of stressors in drug addiction include measuring stressor's effects on drug's rewarding properties. The current investigation explored the effect of an acute stressor on morphine conditioned place preference. Twenty-four hours following either inescapable tail shock or home-cage control treatment, all subjects were conditioned with morphine (0, 1, 2, and 3 mg/kg s.c.) over 2 days, and later tested for conditioned place preference. Inescapably shocked subjects demonstrated a potentiated place preference compared to controls. The inescapable shock-induced potentiated place preference developed even when conditioning was delayed until 6 and 7 days following the stressor, while no longer occurring after a 14- and 15-day interval. The potentiation was not a result of reduced locomotion in the inescapably shocked subjects, as activity in inescapably shocked and home-cage control subjects was the same following "mock" saline conditioning. Furthermore, the anxiogenic methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) (0.3 mg/kg i.p.), which produces effects similar to those produced by inescapable shock, also potentiated morphine place preference. In addition, the potentiation in inescapably shocked subjects was dependent upon the stressor's uncontrollability, as identical escapable shock did not potentiate place preference above control subjects. Finally, the inescapable shock-induced potentiated place preference was drug specific, as amphetamine place preference was not affected.

Benign keratotic squamous epithelial neoplasm of the palate: a unique lesion.

BACKGROUND: This case report describes a unique palatal tumor with features of a dermal neoplasm. Microscopically, the lesion appeared similar to a trichoepithelioma and trichoadenoma. METHODS: Light microscopic and immunohistochemical studies were performed to arrive at the final diagnosis. RESULTS: The lesion arose from the surface epithelium and had features of a dermal tumor. CONCLUSIONS: The case report describes a unique benign palatal neoplasm.

Gender and racial variations in cephalometric analysis.

Cephalometric analysis has earned a vital role in the evaluation of obstructive sleep apnea. However, the normal measurements cited in the literature are not sex or race specific. Skeletal differences in sexes and races have been established. This study was initiated to examine whether race and sex variations in soft tissue and skeletal measurements exist in cephalometric analysis. A total of 89 volunteers of different race and sex participated in this study. The data support the hypothesis that there are statistically significant differences in (1) sella-nasion-subspinale angle (SNA) between black men, and both Caucasian and Hispanic men, (2) sella-nasion-supramentale angle (SNB) between black men and Caucasian men, (3) posterior airway space between Caucasian men and women, and (4) mandibular plane to hyoid distance between Caucasian men and women. These data suggest that only SNA and SNB need racial specificity. Furthermore, Caucasian women need a separate set of normal values from men, specifically posterior airway space and mandibular plane to hyoid bone.

Inescapable shock-induced potentiation of morphine analgesia.

Exposure to various stressors potentiates nociceptive and nonnociceptive responses to morphine. These phenomena have received little study despite their seeming generality and importance for understanding analgesia and opiate action. The present experiments characterize inescapable shock (IS)-induced potentiation of morphine analgesia. Rats were exposed to IS, equal escapable shocks (ESs), or restraint (control). Potentiation of analgesia (tail-flick [TF] test and hotplate test) was observed only in rats given IS 24 or 48 hr earlier, in agreement with previously reported learned-helplessness effects. Finally, no change in tail temperature or motor function was found that could be inaccurately interpreted as analgesia. The relevance of these findings to stressor-induced enhancement of morphine analgesia and potential substrates of IS effects are discussed.

Actinic cheilitis: a premalignant condition.

Actinic cheilitis is a premalignant, irreversible disease that frequently affects the vermilion border of the lower lip. Since there is no correlation between clinical appearance and histologic aggressiveness, a biopsy is mandated. A vermilionectomy procedure is described, as well as the most frequently encountered complications.

Primary varicella-zoster-induced rhabdomyolysis.

Acute rhabdomyolysis after uncomplicated, primary varicella-zoster infection is a rare condition that is sparsely reported in the literature. We report a case of acute rhabdomyolysis due to varicella-zoster infection and review the literature regarding the etiology, diagnosis, and management of this potentially life-threatening condition. Rapid recognition, along with appropriate treatment, should result in an excellent recovery without adverse sequelae.

Comparison of cephalometric analysis with ethnicity in obstructive sleep apnea syndrome.

Many studies have documented significant craniomandibular abnormalities in obstructive sleep apnea syndrome (OSAS) patients. Recent literature clearly describes the cephalometric abnormalities commonly associated with OSAS. Studies have not evaluated specific cephalometric abnormalities that may contribute to OSAS by various ethnic groups. Data were collected on 48 patients (20 Caucasian, 15 Black and 13 Hispanic) with completed cephalometric analysis and polysomnography. Cephalometric landmarks, angles and measurements [angle measured from sella to nasion to subspinale point (SNA), angle measured from sella to nasion to supramentale point (SNB), difference between SNA and SNB (ANB), perpendicular distance from gonion to gnathion to hyoid (MP-H), distance from posterior nasal spine to tip of soft palate (PNS-P) and posterior airway space (PAS)] commonly used in the evaluation of OSAS patients were recorded. Measurements were normalized by dividing the observed value by the mean value for the ethnic group. Statistically significant differences in normalized SNA and SNB appeared in the Black and Hispanic groups when compared to the Caucasian group. For both SNA and SNB, Blacks averaged approximately 3.5% above their ethnic mean, whereas Hispanics averaged 1.8-2.8% below their ethnic mean. There was a statistically significant correlation between respiratory distress index (RDI) and MP-H. These baseline cephalometric differences in the ethnic groups studied suggest that surgical intervention might be approached differently in various ethnic groups. Further studies that evaluate the surgical success achieved by various procedures among different ethnic groups may help define surgical protocol in various ethnic groups for OSAS.

Expression of interpersonal aggression by angered and nonangered persons with the type A and type B behavior patterns.

Thirty-seven subjects with the Type A or the Type B behavior pattern were first either angered or not angered in a problem-solving task by a confederate who posed as another subject. In a subsequent bogus learning experiment, the Type A and Type B subjects had the opportunity to punish or reward the confederate. The effectiveness of the anger manipulation was attested to by the fact that angered subjects had reliably higher pulse rates, systolic blood pressure, and diastolic blood pressure. In the learning experiment, Type A subjects who had not been angered gave the confederate reliably higher levels of punishment than did Type B subjects, but there was not a difference in the levels of punishment given by Type A and Type B subjects who had been angered. There was not a difference between Type A and Type B subjects in the levels of reward they gave the confederate. The results provided behavioral evidence for aggression in persons with the Type A behavior pattern. The fact that the difference in aggression was limited to nonangered subjects was interpreted in terms of differences in attributions of responsibility.