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PubMed1994

Trophic factors during normal brain aging and after functional damage.

There is an increasing body of information concerning the physiological role of several target-derived neurotrophic proteins that are structurally and functionally related to the classical neurotrophic molecule NGF and which resemble a genetic family called neurotrophins. However apart from NGF, there is little knowledge about the pathophysiological role of these neurotrophins concerning aging or dementia. To our present knowledge, decreased NGF production does not seem to play a causal role in age-related cognitive impairment which is usually associated with neurodegenerative processes in the cholinergic basal forebrain system. However, there are several experimentally found indications that NGF might be of importance in the stimulation of compensatory changes and repair mechanisms. Moreover, recent findings suggest that disturbances in cerebral glucose metabolism may play an important role in cognitive disabilities during normal aging and also in dementia disorders such as Alzheimer's disease. Intracerebroventricular (ICV) injection of streptozotocin (STZ) has been reported to decrease cerebral glucose utilization and energy metabolism and to impair passive avoidance learning in adult rats. One week after ICV STZ treatment, NGF content was significantly decreased in the septal region, where NGF-responsive cell bodies are known to be located and where NGF exerts its neurotrophic action after retrograde transport from NGF-producing targets. In contrast, NGF levels were increased within 3 weeks after ICV STZ treatment by about the same magnitude as has been observed for aged learning-impaired rats in the target regions for the basal forebrain cholinergic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1983

The orbitofrontal cortex: neuronal activity in the behaving monkey.

Single unit recording of neurons in the orbitofrontal cortex of the alert rhesus monkey was used to investigate responses to sensory stimulation. 32.4% of the neurons had visual responses that had typical latencies of 100-200 ms, and 9.4% responded to gustatory inputs. Most neurons were selective, in that they responded consistently to some stimuli such as foods or aversive objects, but not to others. In a number of cases the neurons responded selectively to particular foods or aversive stimuli. However, this high selectivity could not be explained by simple sensory features of the stimulus, since the responses of some neurons could be readily reversed if the meaning of the stimulus (i.e. whether it was food or aversive) was changed, even though its physical appearance remained identical. Further, some bimodal neurons received convergent visual and gustatory inputs, with matching selectivity for the same stimulus in both modalities, again suggesting that an explanation in terms of simple sensory features is inadequate. Neurons were also studied during the performance of tasks known to be disrupted by orbitofrontal lesions, including a go/no go visual discrimination task and its reversal. 8.6% of neurons had differential responses to the two discriminative stimuli in the task, one of which indicated that reward was available and the other saline. Reversing the meaning of the two stimuli showed that whereas some differential units were closely linked to the sensory features of the stimuli, and some to their behavioural significance, others were conditional, in that they would only respond if a particular stimulus was present, and if it was the one being currently rewarded. Other neurons had activity related to the outcome of the animal's response, with some indicating that reinforcement had been received and others, that an error had been made and that a reversal was required. Thus, neurons in the orbitofrontal cortex possess highly coded information about which stimuli are present, as well as information about the consequences of the animal's own responses. It is suggested that together they may constitute a neuronal mechanism for determining whether particular visual stimuli continue to be associated with reinforcement, as well as providing for the modification of the animal's behavioural responses to such stimuli when those responses are no longer appropriate.

Animals↗
PubMed1980

Effect on memory processes of anti-vasopressin serum microinjected into the dorsal raphe nucleus: the role of catecholaminergic neurotransmission.

Anti-arginine8-vasopressin serum was microinjected into the mesencephalic dorsal raphe nucleus immediately after the learning trial, in a one-trial learning passive avoidance reaction. The treatment attenuated passive avoidance behavior 24 h after treatment, suggesting a role of the endogenous vasopressin of this area in memory processes. On the other hand, the antiserum did not influence passive avoidance behavior if 6-hydroxydopamine was microinjected into the raphe region. The data suggest that the antiserum may have primarily interacted with catecholaminergic terminals, which enter the dorsal raphe nucleus.

Animals↗
PubMed1996

Glial fibrillary acidic protein and RNA expression in adult rat hippocampus following low-level lead exposure during development.

The astroglial cytoskeletal element, glial fibrillary acidic protein (GFAP), is a generally accepted sensitive indicator for neurotoxic effects in the mature brain. We used GFAP as a marker for structural changes in rat hippocampus related to chronic low level lead exposure during different developmental periods. Four groups of rats were investigated: a control group, a perinatal group, which was exposed during brain development (E0-P16), a permanent group, exposed during and after brain development (E0-P100), and a postweaning group, exposed after brain development (P16-P100). Sections were processed for light microscopy (hematoxylin-eosin, Nissl, periodic acid Schiff (PAS) and GFAP-specific immunohistology), for electron microscopy, and for in-situ hybridization (GFAP). Sections were prepared from animals tested for active avoidance learning (AAL) and long-term potentiation (LTP). Chronic lead exposure did not affect glial and neuronal functions, as assessed by LTP and AAL, when lead exposure started after brain development (postweaning group). In this group, astrocytes displayed increased GFAP and GFAP gene transcript levels. However, lead exposure affected neuronal and glial function when the intoxication fell into the developmental period of the brain (perinatal and permanent groups). In these groups, LTP and AAL were impaired, and astrocytes failed to react to the toxic exposure with an adequate increase of GFAP and GFAP gene transcripts. Although GFAP is an accepted marker for neurotoxicity, our data suggest the marker function of GFAP to be restricted to postnatal toxic insult.

Animals↗
PubMed1993

Sequence-specific effects of neurokinin substance P on memory, reinforcement, and brain dopamine activity.

There is ample evidence that the neurokinin substance P (SP) can have neurotrophic as well as memory-promoting effects. This paper outlines a recent series of experiments dealing with the effects of SP and its N- and C-terminal fragments on memory, reinforcement, and brain monoamine metabolism. It was shown that SP, when applied peripherally (IP), promotes memory (inhibitory avoidance learning) and is reinforcing (place preference task) at the same dose of 37 nmol/kg. Most important, however, is the finding that these effects seemed to be encoded by different SP sequences, since the N-terminal SP1-7 (185 nmol/kg) enhanced memory, whereas C-terminal hepta- and hexapeptide sequences of SP proved to be reinforcing in a dose equimolar to SP. These differential behavioral effects were paralleled by selective and site-specific changes in dopamine (DA) activity, as both SP and its C-, but not N-terminus, increased extracellular DA in the nucleus accumbens (NAc), but not in the neostriatum. The neurochemical changes lasted at least 2 h after injection. These results show that the reinforcing action of peripheral administered SP may be mediated by its C-terminal sequence, and that this effect could be related to DA activity in the NAc. Direct application of SP (0.74 pmol) into the region of the nucleus basalis magnocellularis (NBM) was also memory-promoting and reinforcing, and again, these effects were differentially produced by the N-terminus and C-terminus, supporting the proposed structure-activity relationship for SP's effects on memory and reinfrocement. These results may provide a hypothetical link between the memory-modulating and reinforcing effects of SP and the impairment in associative functioning accompanying certain neurodegenerative processes.

Amino Acid Sequence↗
PubMedDate not supplied

Reversal of long-delay conditioned taste aversion learning in rats by sex hormone manipulation.

Conditioned taste aversion (CTA) learning is an adaptive, robust, well-established learning and memory paradigm. Strong taste aversions develop to the conditioned stimulus (CS = saccharin) despite long delays between exposure to the CS and unconditioned stimulus (US = LiCl). Rats display a sexually dimorphic pattern of long-delay CTA learning (Foy et al., 1996). The present study examines whether this sex difference is a result of activational or organizational hormone action, because here we implanted gonadectomized rats with their normal hormone replacements, or with opposing hormones prior to testing in a 4-hr delayed CTA learning task. We found that gonadally intact male rats displayed a more robust CTA response than intact female rats. Gonadectomy essentially eliminated this sex difference; gonadectomized males and gonadectomized females displayed similar CTA responses. In gonadectomized rats, when their normal sex hormones were replaced with implanted hormone pellets, the sex difference in CTA learning was reinstated. In contrast, when gonadectomized rats were implanted with opposing hormones, the sex difference was reversed. Gonadectomized female rats implanted with 5alpha-DHT pellets (metabolite of testosterone) displayed a stronger CTA response compared to gonadectomized males implanted with 17beta-estradiol pellets. Regardless of the original developmental hormonal environment, our study suggests that an activational manipulation of circulating hormones serves to significantly influence long-delay CTA learning in rats.

Androgens↗
PubMedDate not supplied

Are anticipatory first and second interval skin conductance responses indicators of predicted aversiveness?

The experiment reviewed here was an attempt to examine whether or not magnitudes of first and second interval skin conductance responses (FIR, SIR) to different conditioned stimuli (CS), each predicting another unconditioned stimulus (US), mirror the aversiveness of the predicted USs. Twenty human subjects received a differential Pavlovian conditioning training with five CSs, each one paired eight times with a specific US. Magnitudes of FIR and SIR elicited by CSs increased with increasing aversiveness of the USs predicted. It is concluded therefore that the SIR is not a mere indicator of a cognitive expectancy process but is also affected by emotional aspects.

Adult↗
PubMed2000

Prostaglandin E1 improves hepatic encephalopathy produced by ischaemia-reperfusion liver injury in rats.

OBJECTIVE: To investigate the action of prostaglandin E1 on hepatic encephalopathy. DESIGN: Prospective, randomised, controlled animal study. SETTING: University animal laboratory. SUBJECTS: Male Wistar rats. INTERVENTIONS: After passive avoidance learning, acute liver failure was induced by occlusion of the left portal vein and the hepatic artery for 90 min. Then memory retention was evaluated 48 h later. The effects of prostaglandin E1 on memory retention were examined in animals treated with the agent systemically (intravenous injections with prostaglandin E1 twice before and after surgery, 20 microg/kg each time) and animals treated with the agent topically (intracerebroventricular injection with prostaglandin E1, 0.1 microg/h for 48 h beginning at liver ischaemia). MEASUREMENTS AND RESULTS: Marked damage was found on plasma analysis in animals subjected to liver ischaemia, and the memory retention was also impaired. Intravenous administration of prostaglandin E1 improved both the liver injury and memory retention. However, intracerebroventricular administration of prostaglandin E1 alleviated neither. CONCLUSION: These findings show that prostaglandin E1 contributes to the amelioration of hepatic encephalopathy by improving liver function.

Alprostadil↗
PubMed2005

Bupropion attenuates nicotine abstinence syndrome in the rat.

RATIONALE: Bupropion reduces discomfort and craving associated with smoking cessation. This study determined whether a rat model of nicotine dependence could detect such nicotine abstinence-alleviating effects. OBJECTIVES: Experiments determined whether the abstinence-alleviating effects of bupropion were detectable by (1) behavioral abstinence signs precipitated by the nicotinic antagonist mecamylamine, (2) place aversion conditioned to mecamylamine-precipitated nicotine abstinence, and (3) spontaneous behavioral abstinence signs after abrupt nicotine withdrawal. METHODS: In experiments 1 and 2, nicotine-dependent rats were coinfused for 7 days with 3.15 mg/kg/day nicotine and 20 mg/kg/day bupropion or with nicotine alone. They were then challenged with 1 mg/kg mecamylamine and observed for behavioral abstinence signs (experiment 1) or place aversion conditioned to precipitated abstinence (experiment 2). In experiment 3, rats were nicotine-infused for 7 days as above. A day after termination of nicotine infusion, rats were observed for spontaneous nicotine abstinence signs before and after injection with saline or bupropion. RESULTS: In experiment 1, rats coinfused with nicotine and bupropion had significantly fewer mecamylamine-precipitated abstinence signs than rats infused with nicotine alone but similar numbers to rats infused with saline alone. In experiment 2, bupropion pretreatment significantly reduced the aversiveness of mecamylamine-precipitated nicotine abstinence. In experiment 3, a single bupropion injection dose-dependently alleviated spontaneous nicotine abstinence syndrome. CONCLUSIONS: These results suggest that these rat models of nicotine dependence and abstinence syndrome may be useful in detecting nicotine abstinence-alleviating effects of potential medications for smoking cessation. The effects of acute bupropion administration raise interesting questions regarding bupropion's mechanism of action.

Animals↗
PubMed2006

Effects of the FAAH inhibitor, URB597, and anandamide on lithium-induced taste reactivity responses: a measure of nausea in the rat.

RATIONALE: The endogenous cannabinoid system plays a vital role in the control of nausea and emesis. Because of the rapid breakdown and hydrolysis of endocannabinoids, such as anandamide, the therapeutic effects may be enhanced by prolonging their duration of action. OBJECTIVE: The present experiment evaluated the potential of various doses of URB597, a fatty acid amide hydrolase (FAAH) inhibitor, alone and in combination with systemic administration of anandamide to modulate the establishment of lithium-induced conditioned taste reactivity responses in rats. MATERIALS AND METHODS: In experiment 1, on the conditioning day, rats first received an injection of 0.3 mg/kg URB597, 0.15 mg/kg URB597, or vehicle and then received a second injection of anandamide (5 mg/kg) or vehicle, before a 3-min exposure of 0.1% saccharin by intraoral infusion. Immediately after the saccharin exposure, the rats were injected with lithium chloride. On each of three test days, rats received a 3-min intraoral infusion of saccharin solution, and the taste reactivity responses were videotaped and monitored. In experiment 2, the effects of pretreatment with the CB(1) antagonist, AM-251, on URB597 and anandamide-induced suppressed aversion was evaluated. RESULTS: Administration of URB597 alone and in combination with anandamide reduced active rejection reactions elicited by a LiCl-paired saccharin solution; both effects were reversed by pretreatment with AM-251, suggesting that they were CB(1) receptor mediated. CONCLUSIONS: The results suggest that prolonging the action of anandamide by pretreatment with the FAAH inhibitor, URB597, suppresses lithium-induced nausea in the rat.

Amidohydrolases↗
PubMed2001

Effects of contextual or olfactory cues previously paired with morphine withdrawal on behavior and pain sensitivity in the rat.

RATIONALE: Pavlovian conditioning processes have been accorded an important role in maintaining persistent opiate administration. At least one locus for this contribution is during opiate withdrawal. These experiments studied the contribution of Pavlovian conditioning processes to morphine withdrawal. OBJECTIVES: To determine whether exposure to a distinctive context or odor paired with morphine withdrawal would provoke a withdrawal syndrome, defensive behaviors (e.g., freezing) and pain modulatory (e.g., hypoalgesia) responses similar to those produced by exposure to stimuli signaling other sources of aversive stimulation (e.g., footshock), or whether both withdrawal and fear-like responses would be provoked. METHODS: Rats were used in four experiments to study the effects on defensive behavior and pain sensitivity of naloxone-precipitated morphine withdrawal or exposure to a distinctive context or odor previously paired with such withdrawal. RESULTS: Injection of 2.5 mg/kg naloxone in morphine-dependent rats precipitated a withdrawal syndrome characterized by whole body shaking, diarrhea, ptosis, and postural abnormalities (experiment 1). Exposure to either a distinctive context (experiment 2) or odor (experiments 3) previously paired with morphine withdrawal provoked the species-typical defense response of freezing but not signs of withdrawal. Exposure to an odor previously paired with morphine withdrawal also provoked hypoalgesia in the formalin test, which was mediated by activity at opioid receptors (experiment 4). CONCLUSIONS: These results show that opiate withdrawal supports the conditioning of defensive and hypoalgesic responses consistent with the arousal of a fear motivational system. The emergence of fear in these experiments, and the relationship between the freezing observed here and the learned avoidance and suppression observed in other withdrawal conditioning preparations, is discussed with reference to dual representation accounts of Pavlovian conditioning.

Analgesics, Opioid↗
PubMed2003

Physiological responses during cycling with noncircular "Harmonic" and circular chainrings.

The aim of the present study was to compare physiological data obtained during cycling using a noncircular "Harmonic" chainring versus a standard circular chainring over a range of speeds and slopes in endurance-trained cyclists. Thirteen male subnational cyclists (16-45 years) performed two maximal graded exercises on their own bicycle: one with a circular chainring, the other with a Harmonic chainring with the same gearwheel (52 teeth). The two chainrings were randomly assigned to avoid learning effects. The tests were carried out on a simulator. Speeds and/or slopes were increased every 2 min 30 s until exhaustion of the subject. Ventilation, oxygen uptake, carbon dioxide output, respiratory exchange ratio, and heart rate were continuously measured during the tests. Blood lactate concentration was measured during the last 30 s of each level. No significant difference was observed in any of the submaximal parameters measured during the tests ( P>0.05). Similarly, maximal values were not statistically different ( P>0.05). In conclusion, although the design of the Harmonic chainring was based on optimization analysis, comparison of the physiological response in this study did not translate into an advantage of the Harmonic over circular chainring during submaximal and maximal pedaling in trained cyclists.

Adult↗
PubMed2005

Tetrodotoxin-dependent glycine release in the rat nucleus accumbens during correction of feeding behavior.

Studies on male Sprague-Dawley rats using vital intracerebral microdialysis and high-performance liquid chromatography addressed changes in glycine levels in the intercellular space of the nucleus accumbens during forced correction of feeding behavior. The results showed that presentation to food-consuming rats of a tone previously combined with pain stimulation induced increases in extracellular glycine levels in the nucleus accumbens, which was completely prevented by administration of the sodium channel blocker tetrodotoxin (1 microm) into this structure. Isolated presentation of the tone previously combined with pain stimulation and combined presentation of food and a tone not associated with pain stimulation were not accompanied by glycine release. These data provide evidence for the involvement of glycine mechanisms of the nucleus accumbens in processes associated with forced correction of feeding behavior.

Animals↗
PubMed1993

Familial resemblances in disgust sensitivity and animal phobias.

This paper reports the results of two studies, both of which suggest there are close intrafamilial resemblances between parental disgust sensitivity and various measures of offspring animal phobia. In Study 1, a multiple regression analysis identified parental disgust sensitivity as a primary predictor of offspring animal fear in general (as measured by the animal phobia sub-scale of the Fear Survey Schedule), and offspring spider fear in particular. Study 2 indicated that parental disgust sensitivity was only related to offsprings' fear of animals known to be associated with the disgust reaction. These intrafamilial resemblances are discussed in relation to genetic and cultural transmission of the disgust reaction.

Adolescent↗