Rogue AI: Cautionary Cases in Neuroradiology and What We Can Learn From Them.

Introduction In recent years, artificial intelligence (AI) in medical imaging has undergone unprecedented innovation and advancement, sparking a revolutionary transformation in healthcare. The field of radiology is particularly implicated, as clinical radiologists are expected to interpret an ever-increasing number of complex cases in record time. Machine learning software purchased by our institution is expected to help our radiologists come to a more prompt diagnosis by delivering point-of-care quantitative analysis of suspicious findings and streamlining clinical workflow. This paper explores AI's impact on neuroradiology, an area accounting for a substantial portion of recent radiology studies. We present a case series evaluating an AI software's performance in detecting neurovascular findings, highlighting five cases where AI interpretations differed from radiologists' assessments. Our study underscores common pitfalls of AI in the context of CT head angiograms, aiming to guide future AI algorithms.  Methods We conducted a retrospective case series study at Stony Brook University Hospital, a large medical center in Stony Brook, New York, spanning from October 1, 2021 to December 31, 2021, analyzing 140 randomly sampled CT angiograms using AI software. This software assessed various neurovascular parameters, and AI findings were compared with neuroradiologists' interpretations. Five cases with divergent interpretations were selected for detailed analysis. Results Five representative cases in which AI findings were discordant with radiologists' interpretations are presented with diagnoses including diffuse anoxic ischemic injury, cortical laminar necrosis, colloid cyst, right superficial temporal artery-to-middle cerebral artery (STA-MCA) bypass, and subacute bilateral subdural hematomas. Discussion The errors identified in our case series expose AI's limitations in radiology. Our case series reveals that AI's incorrect interpretations can stem from complexities in pathology, challenges in distinguishing densities, inability to identify artifacts, identifying post-surgical changes in normal anatomy, sensitivity limitations, and insufficient pattern recognition. AI's potential for improvement lies in refining its algorithms to effectively recognize and differentiate pathologies. Incorporating more diverse training datasets, multimodal data, deep-reinforcement learning, clinical context, and real-time learning capabilities are some ways to improve AI's performance in the field of radiology. Conclusion Overall, it is apparent that AI applications in radiology have much room for improvement before becoming more widely integrated into clinical workflows. While AI demonstrates remarkable potential to aid in diagnosis and streamline workflows, our case series highlights common pitfalls that underscore the need for continuous improvement. By refining algorithms, incorporating diverse datasets, embracing multimodal information, and leveraging innovative machine learning strategies, AI's diagnostic accuracy can be significantly improved.

2-Arachidonoylglycerol as a possible treatment for anorexia nervosa in animal model in mice.

We have investigated the effects of 0.001mg/kg 2-arachidonoylglycerol (2-AG) administered in combination with compounds present in the body alongside 2-AG like 2-palmitoylglycerol and 2-linoleylglycerol (also termed "entourage"), on cognitive function,food intake, and neurotransmitter levels in the hippocampus and hypothalamus of mice under diet restriction. Young female Sabra mice were treated with vehicle, 2-AG, 2-AG+entourage, 2-AG+entourage+5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)- 4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (SR141716A, a CB1 antagonist) and SR141716A. The mice were fed for 2.5h a day for 14days. Cognitive function was evaluated by the eight arm maze test, and neurotransmitter (norepinephrine, dopamine, L-DOPA and serotonin) levels were measured in the hippocampus and hypothalamus by high-performance liquid chromatography-electrochemical detection. Food intake was increased by 2-AG and, to an even greater extent, by 2-AG+entourage. SR141716A reversed the effect of 2-AG+entourage. The administration of 2-AG+entourage improved cognitive function compared to the vehicle mice, and this improvement was blocked by SR141716A. 2-AG+entourage-treated mice showed an increase in norepinephrine (NE), dopamine and L-DOPA levels in the hippocampus. SR141716A normalized NE and L-DOPA levels. There were no significant changes in hypothalamic neurotransmitter levels. The use of very low doses of the endocannabinoid 2-AG+entourage can improve cognitive function by elevating norepinephrine and L-DOPA levels in the hippocampus, without cannabinomimetic side effects. These findings may have implications for cognitive enhancement in anorexia nervosa.

Brain neurotransmitters in an animal model with postpartum depressive-like behavior.

Post-Partum Depression (PPD) occurs in 15% of pregnancies and its patho-physiology is not known. We studied female BALB/c ("depressive") and C57BL/6 (control) mice as a model for PPD and assessed their behavior and correlates with brain neurotransmitters (NTs) - norepinephrine, dopamine, serotonin and intermediates, during the pre-pregnancy (PREP), pregnancy (PREG) and post-partum (PP) periods. Depressive-like behavior was evaluated by the Open Field (OFT), Tail Suspension (TST) and Forced Swim (FST) tests. Neurotransmitters (NTs) were determined in the striatum (care-giving), hippocampus (cognitive function) and hypothalamus (maternal care & eating behavior). In the BALB/c mice, while their performance in all behavioral tests was significantly reduced during pregnancy and P-P indicative of the development of depressive-like responses, no changes were observed in the C57BL/6 mice. Changes in NTs in BALB/C were as follows: PREP, all NTs in the three brain areas were decreased, although an increase in dopamine release was observed in the hippocampus. PREG: No changes were observed in the NTs except for a decrease in 5-HT in the striatum. P-P: striatum, low 5-HT, NE and dopamine; Hippocampus: low 5-HT, NE and high Dopamine; hypothalamus: all NTs increased, especially NE. Following pregnancy and delivery, the BALB/c mice developed depressive-like behavior associated with a significant decrease in 5-HT, dopamine and NE in the striatum and 5-HT and NE in the hippocampus. Dopamine increased in the latter together with a significant increase in all NTs in the hypothalamus. These findings suggest that the development of PPD may be associated with NT changes. Normalization of these alterations may have a role in the treatment of PPD.

Probiotics in addition to antibiotics for the treatment of acute tonsillitis: a randomized, placebo-controlled study.

Probiotics are live microorganisms which, when administered in adequate amounts, confer a health benefit on the host. The probiotic Streptococcus salivarius has been shown to be effective in reducing the frequency of recurrent pharyngeal infections in children and adult populations. However, probiotics have not yet been evaluated in the treatment of acute pharyngotonsillitis in adults. We aimed to examine whether the addition of S. salivarius probiotics to the routine therapy of acute pharyngotonsillitis in adult patients may shorten disease duration and reduce symptom severity. This study was a prospective, randomized, placebo-controlled, double-blinded study comparing treatment with probiotics to placebo in addition to antibiotics in patients who were hospitalized with severe pharyngotonsillitis. Laboratory results, pain levels, body temperature, and daily volume of fluids consumed were recorded for both groups. Sixty participants were recruited, 30 for each group. No statistically significant differences between the two groups were observed regarding any of the major clinical and laboratory parameters examined. Supplement probiotic treatment with S. salivarius in patients with acute pharyngotonsillitis treated with penicillin is ineffective in relation to the parameters examined in this study and we cannot, therefore, recommend the use of S. salivarius during active pharyngotonsillar infection treated with penicillin.

Delayed leptin administration after stroke induces neurogenesis and angiogenesis.

Leptin is a potent AMP kinase (AMPK) inhibitor that induces neuroprotection, neurogenesis, and angiogenesis when administered immediately after stroke. To dissociate these effects, we explored the effects of delayed administration of leptin, at 10 days after stroke onset, on neurogenesis and angiogenesis after stroke. Sabra mice underwent photothrombotic stroke and were treated with vehicle or leptin given either as a single dose or in triple dosing, 10 days later. Newborn cells were labeled with bromodeoxyuridine. Functional outcome was studied with the neurological severity score for 90 days poststroke, and the brains were then evaluated via immunohistochemistry. Final infarct volumes did not differ between the groups. Exogenous leptin led to significant increments in the number of proliferating BrdU(+) cells in the subventricular zone and in the cortex abutting the lesion (2.5-fold and 1.4-fold, respectively). There were significant increments in the number of newborn neurons and glia (4- and 3.4-fold, respectively) in leptin-treated animals. Leptin also significantly increased the number of blood vessels in the perilesioned cortex. However, animals treated with leptin failed to demonstrate significantly better functional states. In conclusion, leptin induces neurogenesis and angiogenesis even when given late after stroke but does not lead to better functional outcome in this delayed-treatment paradigm. These results suggest that the main beneficial effects of leptin after stroke are associated with its early neuroprotective role rather than with its proneurogenic or proangiogenic effects.

Leptin induces neuroprotection neurogenesis and angiogenesis after stroke.

Leptin is a potent AMP kinase (AMPK) inhibitor that is central to cell survival. Hence, we explored the effects of leptin on neurogenesis and angiogenesis after stroke. Neural stem cells (NSC) were grown as neurospheres in culture and treated with vehicle or leptin and neurosphere size and terminal differentiation were then determined. We then explored the effects of leptin on endogenous repair mechanisms in vivo. Sabra mice underwent photothrombotic stroke, were given vehicle or leptin and newborn cells were labeled with Bromo-deoxy-Uridine. Functional outcome was studied with the neurological severity score for 90 days post stroke and the brains were then evaluated with immunohistochemistry. In a subset of animals the brains were also evaluated for changes in the expression of leptin receptor and AMPK. In vitro, leptin led to a 2-fold increase in neurosphere size but did not change the differentiation of newborn cells. Following stroke, exogenous leptin led to a 4-fold increase in the number of NSC in the cortex abutting the lesion. There was a 1.5-fold increase in the number of newborn neurons and glia in leptin treated animals. Leptin also significantly increased the number of blood vessels in the peri-lesioned cortex. Leptin treated mice had increased expression of leptin receptor and increased phosphorylated AMPK concentration. Animals treated with leptin also had significantly better functional states. In conclusion, leptin induces neurogenesis and angiogenesis after stroke and leads to increased leptin receptor and pAMPK concentrations. This may explain at least in part the better functional outcome observed in leptin treated animals after stroke.

Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice.

BACKGROUND AND PURPOSE: Hepatic encephalopathy is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We investigated the effects of cannabidiol, a non-psychoactive constituent of Cannabis sativa with anti-inflammatory properties that activates the 5-hydroxytryptamine receptor 5-HT(1A) , on brain and liver functions in a model of hepatic encephalopathy associated with fulminant hepatic failure induced in mice by thioacetamide. EXPERIMENTAL APPROACH: Female Sabra mice were injected with either saline or thioacetamide and were treated with either vehicle or cannabidiol. Neurological and motor functions were evaluated 2 and 3 days, respectively, after induction of hepatic failure, after which brains and livers were removed for histopathological analysis and blood was drawn for analysis of plasma liver enzymes. In a separate group of animals, cognitive function was tested after 8 days and brain 5-HT levels were measured 12 days after induction of hepatic failure. KEY RESULTS: Neurological and cognitive functions were severely impaired in thioacetamide-treated mice and were restored by cannabidiol. Similarly, decreased motor activity in thioacetamide-treated mice was partially restored by cannabidiol. Increased plasma levels of ammonia, bilirubin and liver enzymes, as well as enhanced 5-HT levels in thioacetamide-treated mice were normalized following cannabidiol administration. Likewise, astrogliosis in the brains of thioacetamide-treated mice was moderated after cannabidiol treatment. CONCLUSIONS AND IMPLICATIONS: Cannabidiol restores liver function, normalizes 5-HT levels and improves brain pathology in accordance with normalization of brain function. Therefore, the effects of cannabidiol may result from a combination of its actions in the liver and brain.

Cannabidiol ameliorates cognitive and motor impairments in bile-duct ligated mice via 5-HT1A receptor activation.

BACKGROUND AND PURPOSE: We aimed to demonstrate the involvement of 5-HT(1A) receptors in the therapeutic effect of cannabidiol, a non-psychoactive constituent of Cannabis sativa, in a model of hepatic encephalopathy induced by bile-duct ligation (BDL) in mice. EXPERIMENTAL APPROACH: Cannabidiol (5 mg x kg(-1); i.p.) was administered over 4 weeks to BDL mice. Cognition and locomotion were evaluated using the eight-arm maze and the open field tests respectively. Hippocampi were analysed by RT-PCR for expression of the genes for tumour necrosis factor-alpha receptor 1, brain-derived neurotrophic factor (BDNF) and 5-HT(1A) receptor. N-(2-(4-(2-methoxy-phenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide (WAY-100635), a 5-HT(1A) receptor antagonist (0.5 mg x kg(-1)), was co-administered with cannabidiol. Liver function was evaluated by measuring plasma liver enzymes and bilirubin. KEY RESULTS: Cannabidiol improved cognition and locomotion, which were impaired by BDL, and restored hippocampal expression of the tumour necrosis factor-alpha receptor 1 and the BDNF genes, which increased and decreased, respectively, following BDL. It did not affect reduced 5-HT(1A) expression in BDL mice. All the effects of cannabidiol, except for that on BDNF expression, were blocked by WAY-100635, indicating 5-HT(1A) receptor involvement in cannabidiol's effects. Cannabidiol did not affect the impaired liver function in BDL. CONCLUSIONS AND IMPLICATIONS: The behavioural outcomes of BDL result from both 5-HT(1A) receptor down-regulation and neuroinflammation. Cannabidiol reverses these effects through a combination of anti-inflammatory activity and activation of this receptor, leading to improvement of the neurological deficits without affecting 5-HT(1A) receptor expression or liver function. BDNF up-regulation by cannabidiol does not seem to account for the cognitive improvement.

Capsaicin affects brain function in a model of hepatic encephalopathy associated with fulminant hepatic failure in mice.

BACKGROUND AND PURPOSE: Hepatic encephalopathy is a neuropsychiatric syndrome caused by liver failure. In view of the effects of cannabinoids in a thioacetamide-induced model of hepatic encephalopathy and liver disease and the beneficial effect of capsaicin (a TRPV1 agonist) in liver disease, we assumed that capsaicin may also affect hepatic encephalopathy. EXPERIMENTAL APPROACH: Fulminant hepatic failure was induced in mice by thioacetamide and 24 h later, the animals were injected with one of the following compound(s): 2-arachidonoylglycerol (CB(1), CB(2) and TRPV1 receptor agonist); HU308 (CB(2) receptor agonist), SR141716A (CB(1) receptor antagonist); SR141716A+2-arachidonoylglycerol; SR144528 (CB(2) receptor antagonist); capsaicin; and capsazepine (TRPV1 receptor agonist and antagonist respectively). Their neurological effects were evaluated on the basis of activity in the open field, cognitive function in an eight-arm maze and a neurological severity score. The mice were killed 3 or 14 days after thioacetamide administration. 2-arachidonoylglycerol and 5-hydroxytryptamine (5-HT) levels were determined by gas chromatography-mass spectrometry and high-performance liquid chromatography with electrochemical detection, respectively. RESULTS: Capsaicin had a neuroprotective effect in this animal model as shown by the neurological score, activity and cognitive function. The effect of capsaicin was blocked by capsazepine. Thioacetamide induced astrogliosis in the hippocampus and the cerebellum and raised brain 5-hydroxytryptamine levels, which were decreased by capsaicin, SR141716A and HU-308. Thioacetamide lowered brain 2-arachidonoylglycerol levels, an effect reversed by capsaicin. CONCLUSIONS: Capsaicin improved both liver and brain dysfunction caused by thioacetamide, suggesting that both the endocannabinoid and the vanilloid systems play important roles in hepatic encephalopathy. Modulation of these systems may have therapeutic value.

Intra-arterial thrombolysis and stent placement for traumatic carotid dissection with subsequent stroke: a combined, simultaneous endovascular approach.

Traumatic carotid dissection is a well-known cause of ischemic stroke and although the treatment of the dissection itself has received some attention in recent years, the treatment of the concomitant stroke has been less investigated. We present a 43-year-old patient with blunt traumatic internal carotid artery dissection associated with subocclusive stenosis and major cerebral thromboembolic complication. Combined, simultaneous intra-arterial fibrinolysis and carotid stenting through a bilateral approach was successfully performed allowing the complete clinical recovery of the patient. Contralateral carotid artery approach allowed the beginning of intra-arterial thrombolysis without delay, while stent-assisted angioplasty of the injured carotid was simultaneously performed. This approach was proved to be safe and effective and may deserve further evaluation.

Endocannabinoids, feeding and suckling--from our perspective.

In this overview we have summarized some aspects of our published work related to the effects of the endocannabinoid system on appetite and suckling. As noted also by several other groups we have found that anandamide, a major endocannabinoid, enhances appetite in mice. On partial or full food deprivation over 24 h the levels of 2-arachidonoyl glycerol (2-AG), a second major cannabinoid, are initially elevated in mouse brain; however, partial food deprivation over a longer period causes reduction of 2-AG levels. Blocking the endocannabinoid system with a CB1 antagonist on the 1st day after birth leads to inhibition of suckling; later administration also affects suckling, but does not fully block it.

Tyrosine improves appetite, cognition, and exercise tolerance in activity anorexia.

PURPOSE: We have modified for mice the activity wheel model of Routtenberg to study the effects of tyrosine on exercise tolerance, behavior, and brain neurochemistry. METHODS: Mice were fed for 2 h.d(-1) over a 2-wk period. During the second week, each group was injected daily with either saline or tyrosine (100 mg.kg(-1).d(-1)) and exercised on a running wheel. Controls were in cages with inactivated wheels and received the same treatment and feeding protocols as the experimental groups. Food consumption and cognitive function (eight-arm maze) were evaluated for 1 wk. Brains were then assayed for adrenergic and serotonergic metabolites. RESULTS: Activity together with a restricted diet caused extreme weight loss (27%) (P < 0.001) together with decreased food consumption (22%) (P < 0.001). Tyrosine restored food consumption to that of the controls (P < 0.001) with no effect on weight, since there was a 22% increase in activity (P < 0.001). Saline injections caused an 18% decrease in activity (P < 0.001). Both activity and tyrosine improved maze performance (P < 0.05). In the hypothalamus, activity caused a significant increase in 5-hydroxytryptamine (5-HT) (P < 0.001), 5-hydroxyindoleacetic acid (5-HIAA) (P < 0.01), and dopamine (P < 0.05); tyrosine prevented the increase in 5-HT (P < 0.05) and increased 5-HIAA in the controls (P < 0.01). With regard to hippocampal 5-HT, there was a significant increase in 5-HIAA following activity (P < 0.05), whereas tyrosine caused significant increase in 5-HIAA in the controls (P < 0.01). Activity significantly decreased the level of hippocampal 3,4-dihydroxyphenylacetic acid (DOPAC), whereas tyrosine decreased its level only in the controls (both at P < 0.0001). The level of tyrosine hydroxylase increased with activity (P < 0.05), and tyrosine decreased it significantly (P < 0.05). CONCLUSION: Activity anorexia is associated with increased hypothalamic 5-HT concentrations. Tyrosine administration reverses this, and significantly improves food consumption, cognitive behavior, and activity performance. Such nutritional modulations may have implications for the treatment of eating disorders and, in normal circumstances, tyrosine may improve exercise tolerance and delay fatigue.

Separation-induced body weight loss, impairment in alternation behavior, and autonomic tone: effects of tyrosine.

We have investigated the effects of tyrosine on alternation behavior and hippocampal adrenergic and cholinergic tone in a model of self-induced weight loss caused by separation stress. Separation decreased body weight in mice (P < .001) and spontaneous alternations in the T-maze (P < .001). This impairment was associated with depletion of both norepinephrine (NE, P < .001) and dopamine (P < .01) while increasing MHPG (P < .05) and the ratio of MHPG/NE (P < .05). Increasing tyrosine availability restored performance to control levels (P < .001) and repleted dopamine (P < .05) and presumably also NE (indicated by increases in both MHPG, P < .001, and MHPG/NE, P < .05). Stress increased adrenergic alpha(2)-receptor density (P < .001) without changing its K(d) and the B(max) and K(d) of beta-receptors, suggesting that it decreased NE transmission through action on alpha(2)-receptors. The balance between beta- and alpha(2)-receptors appeared to be related to alternation behavior as shown by the decrease (P < .01) and increase (P < .05) in their ratios induced by stress and tyrosine, respectively. With regard to cholinergic tone, separation stress increased M1 receptor density (P < .05) and its mRNA signal (P < .001). Tyrosine further increased M1 receptor density of stressed mice (P < .05). Tyrosine might be a potential therapy for cognitive and mood problems associated with the maintenance of a reduced body weight in the treatment of obesity and in the extreme case of anorexia nervosa.

Diet restriction in mice causes a decrease in hippocampal choline uptake and muscarinic receptors that is restored by administration of tyrosine: interaction between cholinergic and adrenergic receptors influencing cognitive function.

We have studied the effects of diet restriction (DR) to 60% and 40% of daily requirements, and tyrosine administration on cognitive function in mice, to define the nutritional-neurochemical interactions on autonomic tone involved in behavior and energy regulation. Cognitive function in the Morris Water maze was significantly impaired after 40% DR compared to both control and 60% DR. It was restored after tyrosine in association with increased M1 cholinergic and beta-adrenergic receptor function, and decreased alpha-adrenergic function. DR to 40% significantly decreased choline uptake (p <.05) and M1 receptor number (Bmax) (p <.05), without changes in affinity (Kd), choline acetyl transferase (ChAT) or acetyl cholinesterase (AChE) activity. Tyrosine administration significantly increased choline uptake (Bmax) (p <.05) and M1 density in the 40% DR (p <.01) without changes in affinity. ChAT activity was decreased after tyrosine--significantly after 40% DR (p <.05) while AChE was not affected. Both M1 mRNA and protein were not influenced by DR or tyrosine administration. Tyrosine hydroxylase mRNA was decreased significantly by 40% DR (p <.01). The effect of DR and tyrosine appeared to be both pre- and post-synaptic, indicating modulation of cholinergic activity by adrenergic tone. Nutritional effect on behavior and autonomic tone may have implications for the treatment of mood changes associated with weight loss and semi-starvation.

Low dose anandamide affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice.

This investigation reports the possible role of the endocannabinoid anandamide on modulating the behavioral and neurochemical consequences of semi-starvation. We studied the effect of very low dose anandamide (0.001 mg/kg) administration on food intake, cognitive function and catecholaminergic and serotonergic pathways in two murine brain areas concerned with appetite (hypothalamus) and learning (hippocampus), and the peripheral corticosterone response to the stress of 40% diet restriction. Anandamide-treated mice consumed 44% more food (P<0.05) during 1 week of 2.5-h feeding each day. In the hypothalamus, there were significantly increased concentrations of norepinephrine (P<0.01), dopamine (P<0.05) and 5-hydroxytryptamine (5-HT) (P<0.001). In the hippocampus, anandamide increased significantly norepinephrine and dopamine, but decreased 5-HT (all at P<0.001). Diet restriction was accompanied in both areas by a significant decrease in all neurotransmitter concentrations that were partially restored by anandamide for dopamine and 5-HT, but not for norepinephrine. In animals on diet restriction, anandamide significantly improved impaired maze performance. Norepinephrine turnover and plasma corticosterone levels were also raised significantly by anandamide. The fact that low dose anandamide improved food intake, cognitive function and reversed some of the neurotransmitter changes caused by diet restriction, might have implications for the treatment of cachexia associated with acquired immunodeficiency syndrome (AIDS) and cancer, for mood changes sometimes associated with dieting, and in the extreme case, of patients with anorexia.

Diet Restriction Increases Enkephalin- and Dynorphin-like Immunoreactivity in Rat Brain and Attenuates Long-term Retention of Passive Avoidance.

The present study examines effects of diet restriction (DR) on behavior and on the opioid peptides enkephalin (Enk) and dynorphin (Dyn). Female rats were assigned to ad libitum food intake (AL), DR 60% (DR60) or 40% (DR40) of AL. After 4 weeks, DR reduced fearful behavior in the elevated plus maze. DR rats displayed good retention of passive avoidance at 24 h, but DR40 rats had reduced retention, at 5 and 11 days post training. Changes in Enk- and Dyn-like immunoreactivity (LI) in the hippocampal mossy fibers (MF), hypothalamus, septum, central nucleus of amygdala (CeAm) and thalamus depended on the severity of DR. In DR60, Enk-LI and Dyn-LI were not changed except for reduction in CeAm. In DR40, Dyn-LI increased significantly above AL levels in MF, CeAm and hypothalamus, whereas Enk-LI increased significantly above AL levels in the CA3 subregion of the MF system and in thalamus. Serum glucose was tightly correlated with Enk-LI reaching highest values in the MF (r= -0.82). Increased opioid-LI in CeAm and MF was associated with reduced fearfulness in the elevated plus maze. Thus, hippocampal and amygdala opioid subsystems are uniquely sensitive to DR and may be relevant to psychophysiological problems in human starvation including anorexia.

Separation as a new animal model for self-induced weight loss.

Animal models for weight loss are generally either stress mediated or following diet restriction (DR) schedules. We investigated weight loss in mice subjected to activity stress (ACT), DR schedules of 40, 60 and 100% of daily requirements, and propose a new model for animal weight loss based upon separation. Mice were separated (SEP) from each other by perspex partitioning for 23 h per day, with free access to food for one hour. No significant differences in weight loss were found between the ACT, SEP and 40% groups. However, mean food intake in the 40% group was half that of the ACT group (p < 0.001) and significantly less (p < 0.01) than the SEP group, which consumed amounts equivalent to 65% of daily requirement. Separation of mice increases metabolic demands and may be used as a new, easily performed, animal model for weight loss.

Behavioral and neurochemical alterations caused by diet restriction--the effect of tyrosine administration in mice.

We have investigated the effect of tyrosine administration on the cognitive and neurochemical alterations caused by diet restriction (DR) in mice, as a possible model for some of the behavioral symptoms of patients with anorexia nervosa. Young female mice were fed to 100, 60, and 40% of the calculated daily nutritional requirements for a period of up to 18 days. Cognitive function was evaluated using a modified eight-arm maze with water as a reward. Animals fed to 60% of controls showed significantly improved maze performance while this was impaired in animals on DR to 40%. However, in these animals, injections of tyrosine (100 mg/kg/day) restored performance. Improved maze performance in the 60% DR and 40% DR + tyrosine animals was related to increased beta:alpha tone in the hippocampus- an area, together with the septum, responsible for spatial learning. This was associated with changes in alpha- and beta-receptor density (Bmax), without affecting affinity (Kd); and increased norepinephrine (NE) in the 40% DR + tyrosine group, and methoxyhydroxyphenylglycol (MHPG) in both groups. In the hypothalamus, the brain area responsible for energy metabolism, there was a progressive increase in alpha:beta tone with increasing DR associated with changes in Bmax. Tyrosine treatment reversed these alterations. Tyrosine improves some of the neurobiological disturbances of DR without causing an increase in body weight. Such a strategy might have important implications for the possible treatment of patients with anorexia nervosa.

Alterations in septohippocampal cholinergic innervations and related behaviors after early exposure to heroin and phencyclidine.

Mice were exposed to diacetylmorphine (heroin) or phencyclidine (PCP) prenatally or neonatally. At a later age, they were tested for hippocampus-related behavioral deficits and concomitant alterations in the septohippocampal cholinergic innervations. Actually, this is an application of the previously established phenobarbital neuroteratogenicity model to heroin and PCP. Prenatal exposure was accomplished transplacentally by injecting the mother 10 mg/kg heroin or PCP on gestation days 9-18. Neonatal administrations were applied directly by injections of 10 mg/kg of either drug to the pups between neonatal days 2-21. At the age of 50 days, mice exposed to heroin and PCP prenatally exhibited a 107% and 159% increase in their muscarinic cholinergic receptors Bmax, respectively. Neonatal exposure to heroin or PCP caused an 83% and 76% increase in the receptors respectively. On the behavioral level, both prenatal and neonatal exposure to heroin or PCP reduced performance in the hippocampus related eight-arm maze and Morris mazes. Depending on the drug, the test and the period of drug administration, the reduction ranged between 10% and 75%. The results suggest that heroin and PCP induce alterations in the septohippocampal cholinergic innervations and in related behavioral performance. Further studies are necessary in order to connect the biochemical and behavioral events in causal relationships.