The novel cannabinoid CB1 antagonist AM6545 suppresses food intake and food-reinforced behavior.

Drugs that interfere with cannabinoid CB1 transmission suppress food-motivated behaviors, and may be useful clinically as appetite suppressants. However, there may also be undesirable side effects (e.g., nausea, malaise, anxiety, and depression) that are produced by the current generation of CB1 inverse agonists such as rimonabant and taranabant. For that reason, it is important to continue research on novel cannabinoid antagonists. The present studies examined the effects of the novel compound AM6545, which is a neutral antagonist of CB1 receptors that is thought to have relatively poor penetrability into the central nervous system. Intraperitoneal administration of AM6545 significantly reduced food-reinforced operant responding at doses of 4.0, 8.0 and 16.0 mg/kg. AM6545 also produced a strong suppression of the intake of high-carbohydrate and high-fat diets in the same dose range, but only produced a mild suppression of lab chow intake at the highest dose (16.0 mg/kg). Although AM6545 did not affect food handling, it did reduce time spent feeding and feeding rate. Taken together, these results suggest that AM6545 is a compound that warrants further study as a potential appetite suppressant drug.

Differential effects of selective adenosine antagonists on the effort-related impairments induced by dopamine D1 and D2 antagonism.

Mesolimbic dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation and effort-related processes. Rats with impaired DA transmission reallocate their instrumental behavior away from food-reinforced tasks with high response requirements, and instead select less effortful food-seeking behaviors. Previous work showed that adenosine A(2A) antagonists can reverse the effects of DA D(2) antagonists on effort-related choice. However, less is known about the effects of adenosine A(1) antagonists. Despite anatomical data showing that A(1) and D(1) receptors are co-localized on the same striatal neurons, it is uncertain if A(1) antagonists can reverse the effects DA D(1) antagonists. The present work systematically compared the ability of adenosine A(1) and A(2A) receptor antagonists to reverse the effects of DA D(1) and D(2) antagonists on a concurrent lever pressing/feeding choice task. With this procedure, rats can choose between responding on a fixed ratio 5 lever-pressing schedule for a highly preferred food (i.e. high carbohydrate pellets) vs. approaching and consuming a less preferred rodent chow. The D(1) antagonist ecopipam (0.2 mg/kg i.p.) and the D(2) antagonist eticlopride (0.08 mg/kg i.p.) altered choice behavior, reducing lever pressing and increasing lab chow intake. Co-administration of the adenosine A(1) receptor antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.375, 0.75, and 1.5 mg/kg i.p.), and 8-cyclopentyltheophylline (CPT; 3.0, 6.0, 12.0 mg/kg i.p.) failed to reverse the effects of either the D(1) or D(2) antagonist. In contrast, the adenosine A(2A) antagonist KW-6002 (0.125, 0.25 and 0.5 mg/kg i.p.) was able to produce a robust reversal of the effects of eticlopride, as well as a mild partial reversal of the effects of ecopipam. Adenosine A(2A) and DA D(2) receptors interact to regulate effort-related choice behavior, which may have implications for the treatment of psychiatric symptoms such as psychomotor slowing, fatigue or anergia that can be observed in depression and other disorders.

Nucleus accumbens and effort-related functions: behavioral and neural markers of the interactions between adenosine A2A and dopamine D2 receptors.

Nucleus accumbens dopamine (DA) is a critical component of the brain circuitry regulating work output in reinforcement-seeking behavior and effort-related choice behavior. Moreover, there is evidence of an interaction between DA D(2) and adenosine A(2A) receptor function. Systemic administration of adenosine A(2A) antagonists reverses the effects of D(2) antagonists on tasks that assess effort related choice. The present experiments were conducted to determine if nucleus accumbens is a brain locus at which adenosine A(2A) and DA D(2) antagonists interact to regulate effort-related choice behavior. A concurrent fixed ratio 5 (FR5)/chow feeding procedure was used; with this procedure, rats can choose between completing an FR5 lever-pressing requirement for a preferred food (i.e., high carbohydrate operant pellets) or approaching and consuming a freely available food (i.e., standard rodent chow). Rats trained with this procedure spend most of their time pressing the lever for the preferred food, and eat very little of the concurrently available chow. Intracranial injections of the selective DA D(2) receptor antagonist eticlopride (1.0, 2.0, 4.0 microg) into nucleus accumbens core, but not a dorsal control site, suppressed FR5 lever-pressing and increased consumption of freely available chow. Either systemic or intra-accumbens injections of the adenosine A(2A) receptor antagonist MSX-3 reversed these effects of eticlopride on effort-related choice. Intra-accumbens injections of eticlopride also increased local expression of c-Fos immunoreactivity, and this effect was attenuated by co-administration of MSX-3. Adenosine and DA systems interact to regulate instrumental behavior and effort-related processes, and nucleus accumbens is an important locus for this interaction. These findings may have implications for the treatment of psychiatric symptoms such as psychomotor slowing, anergia and fatigue.

Potential anxiogenic effects of cannabinoid CB1 receptor antagonists/inverse agonists in rats: comparisons between AM4113, AM251, and the benzodiazepine inverse agonist FG-7142.

Cannabinoid CB1 inverse agonists suppress food-motivated behaviors, but may also induce psychiatric effects such as depression and anxiety. To evaluate behaviors potentially related to anxiety, the present experiments assessed the CB1 inverse agonist AM251 (2.0-8.0mg/kg), the CB1 antagonist AM4113 (3.0-12.0mg/kg), and the benzodiazepine inverse agonist FG-7142 (10.0-20.0mg/kg), using the open field test and the elevated plus maze. Although all three drugs affected open field behavior, these effects were largely due to actions on locomotion. In the elevated plus maze, FG-7142 and AM251 both produced anxiogenic effects. FG-7142 and AM251 also significantly increased c-Fos activity in the amygdala and nucleus accumbens shell. In contrast, AM4113 failed to affect performance in the plus maze, and did not induce c-Fos immunoreactivity. The weak effects of AM4113 are consistent with biochemical data showing that AM4113 induces little or no intrinsic cellular activity. This research may lead to the development of novel appetite suppressants with reduced anxiogenic effects.

MR imaging in the evaluation of the chest after uncomplicated median sternotomy.

Although complications of median sternotomy are infrequent, they are associated with high morbidity and mortality. Current imaging modalities have proved to be of limited value in the evaluation of these abnormalities. The search for more efficacious means of assessment is continual. The appearance of the thorax was evaluated in 10 patients who were undergoing median sternotomy for coronary artery bypass graft surgery. Three serial magnetic resonance (MR) imaging examinations were performed on each patient. These examinations included a baseline preoperative study and two postoperative studies. Each patient included in the study had an uncomplicated postoperative clinical course. Usual postoperative findings included pleural effusions, pulmonary parenchymal abnormalities, mediastinal edema, and pericardial effusions. On the basis of this limited study, the authors believe that MR imaging is a feasible means of evaluating the chest after surgery. An appreciation of the normal postoperative appearance is essential before complications can be reliably identified and characterized.

Developmental lymphatic disorders of the thorax.

Developmental disorders that involve the lymphatic channels of the thorax, although rare, are important and must be distinguished from the more common causes of chest masses or diffuse lung disease. There are four major types of developmental lymphatic disorders that affect the thorax: lymphangiectasis, characterized by congenital anomalous dilatation of pulmonary lymph vessels; localized lymphangioma, a rare and benign, usually cystic, lesion characterized by masslike proliferation of lymph vessels; diffuse lymphangioma, a proliferation of vascular, mainly lymphatic, spaces in which visceral and skeletal involvement are common; and lymphangioleiomyoma, which involves a haphazard proliferation of smooth muscle in the lungs and dilatation of lymphatic spaces. These characteristic findings can be seen with radiographic studies as well as with histologic evaluation. The discovery of one of these lymphatic disorders may prompt an investigation for associated congenital anomalies, including Noonan syndrome, asplenia, Gorham syndrome, and tuberous sclerosis.

Calcified hilar and mediastinal lymph nodes in an AIDS patient with Pneumocystis carinii infection.

An unusual radiologic manifestation of Pneumocystis carinii infection (enlarged, calcified hilar and mediastinal lymph nodes) in a patient with acquired immunodeficiency syndrome is described. This atypical manifestation caused significant diagnostic confusion. Recognition that P carinii infection can cause calcification of hilar and mediastinal lymph nodes may prevent this confusion and facilitate diagnosis and treatment.

Pulmonary arterial hypertension: a contemporary review.

Pulmonary arterial hypertension has many causes, only some of which are well understood. The radiographic findings in pulmonary arterial hypertension are very similar regardless of the cause. Some radiographic features such as cardiac chamber enlargement, occur secondary to elevation of pulmonary pressures. In addition, sequential radiographs may demonstrate dramatic changes as the hypertension develops. This article presents examples of the various forms of pulmonary arterial hypertension, with pathologic correlation. Included are chronic pulmonary thromboembolism, plexogenic pulmonary arteriopathy, pulmonary venooclusive disease and persistent fetal circulation. Examples of lesions causing secondary pulmonary arterial hypertension: parenchymal lung disease, pulmonary venous hypertension, and congenital heart disease, are also illustrated.

Radiographic appearances of the St. Jude Medical Valve.

The St. Jude Medical Valve (SJMV), one of the more popular prosthetic cardiac valves in use today, has been described as poorly visualized on plain radiographs, being visible only at fluoroscopy. The chest radiographs of 76 patients (85 valves) in whom the SJMV had been implanted were reviewed in order to assess the visibility and appearances of the SJMV. We found that the SJMV was visible postoperatively in 70 of the 76 patients (92%) on either frontal or lateral chest radiographs or both. Knowing the various normal appearances of the SJMV described here and the anatomic locations of the heart valves, radiologists should be able to visualize and identify this prosthetic valve on chest radiographs in the majority of patients.

Composite graft replacement of the ascending aorta and aortic valve. Late follow-up with intra-arterial digital subtraction angiography.

Between 1979 and 1986, 30 patients underwent replacement of the aortic valve and ascending aorta by a composite graft, with aortic wrapping of the graft. Thirteen patients had annuloaortic ectasia; six had DeBakey type I dissection (five acute, one chronic); three had DeBakey type II dissection (one acute, two chronic); three had left ventricular-aortic discontinuity caused by prosthetic valve endocarditis; three had sinus of Valsalva aneurysms after previous aortic valve procedures; and two had atherosclerotic aneurysms. Three patients died (10%). The mean duration of follow-up was 54 months. Fifteen patients consented to be restudied by intra-arterial digital subtraction angiography; studies were performed 6 to 58 months (mean 25 months) after composite graft replacement. Two patients had pseudoaneurysms at the right coronary anastomosis, which were repaired successfully. One patient showed persistent dissection beyond the distal aortic anastomosis; no reoperation has been done. One patient had pulmonary edema. Emergency study and reoperation showed disruption of the proximal aortic anastomosis and right coronary anastomosis. Anastomotic dehiscence after composite graft replacement is potentially lethal. Follow-up by means of intra-arterial digital subtraction angiography is simple and highly accurate. We suggest that dehiscences may occur early in the postoperative period and that restudy may be appropriate within a few months after operation.

The continuum of pulmonary developmental anomalies.

The classic features of six common pulmonary developmental anomalies have been presented. In addition, several overlap cases, each demonstrating features of more than one anomaly, have been illustrated. Such cases serve to emphasize that pulmonary developmental anomalies exist as a continuum, often frustrating our attempts at discrete classification. Future advances in pulmonary embryology may further elucidate the pathogenesis of these entities.

Chest tube tracks.

Chest tube tracks may simulate normal structures or pathology. This article will help the radiologist to understand their formation and to recognize them as iatrogenic shadows.

Complete extra-anatomic bypass of the aortic root: treatment of recurrent mediastinal infection.

A 45-year-old woman underwent complete extra-anatomic bypass of the aortic root for recurrent mediastinal infection. Operative repair consisted of removal of an aortic valve prosthesis and an ascending aortic graft. The aortic root and transverse aortic arch were closed primarily and a valved conduit was placed from the left ventricular apex to the descending aorta. Coronary flow was reestablished with saphenous vein grafts taken from the innominate and subclavian arteries to the coronary artery orifices. Infection did not recur, but the patient died 9 months following operation apparently of right coronary artery graft occlusion.

Mild hypothermia: its effect on cardiac output and regional perfusion in the neonatal piglet.

Cardiac output and regional perfusion was measured in neonatal piglets using radionuclide labeled microspheres. Measurements made at normal core body temperature (38-39.5 degrees C) were compared to those obtained after a 4-5 degrees C reduction in temperature. There is a significant reduction in cardiac output and in the myocardial, renal, pancreatic, and adrenal blood flow. The separated layers of the gastrointestinal tract wall are subject to varying decreases in blood flow. The mucosa of the distal small intestine demonstrated the most significant decreases in blood flow during mild hypothermia.

Vascular dysgenesis associated with skeletal dysplasia of the lower limb.

Three patients who had shortening or absence of the fibula were evaluated angiographically. An abnormal arterial pattern was found in all of the dysplastic limbs. This abnormality was characterized by persistence of an embryonic vascular pattern, absence of one of the normal arteries, and failure of formation of the plantar arch. In each patient there was a large posterior artery in the leg, termed the tibialis posterior superficialis.