Comparison of the effects of flickering and steady light on dopamine release and horizontal cell coupling in the mudpuppy retina.

1. The effects of flickering adapting illumination (repetitive flashes) on horizontal cell responses to illumination of the center and surround portions of the receptive field were compared with those of steady adapting illumination in dark-adapted mudpuppy retinas. 2. Exposure to flickering adapting light caused an increase in amplitude of responses to small spots in the receptive-field center and a decrease in the response to a concentric annulus. This is interpreted as due to an increase in coupling resistance between horizontal cells. 3. The uncoupling effect of flickering adapting light was no greater than that of the same quantity of steady adapting light at the same intensity, even when the rate of flickering was varied by a factor of 10. 4. The uncoupling effect of flickering light was blocked by the dopamine antagonists fluphenazine and SCH23390, indicating that it is mediated by dopamine release. 5. The uncoupling effect of flickering light was also blocked in the presence of 2-amino-4-phosphonobutyrate (APB), which prevents light responses of on-center but not off-center bipolar cells, suggesting that flickering light increases dopamine release via the on-pathway. 6. The gamma-aminobutyric acid (GABA) antagonist bicuculline had an uncoupling effect similar to that of adapting illumination. This effect was blocked by dopamine antagonists, indicating that there is tonic GABA-mediated inhibition of dopamine release in mudpuppy retina similar to that previously reported by others in fish and turtle retinas. 7. The uncoupling effect of bicuculline was not reversed by APB. However, APB alone caused an increase in coupling that was rapidly reversed by bicuculline.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of luminance and flicker on ocular dominance shift in kitten visual cortex

Summary We raised monocularly deprived kittens in visual environments with low level illumination that was either steady or flickering. With steady scotopic luminance ocular dominance shifted as it does in normal photopic lighting. In flickering light with an average frequency of 2 Hz there was virtually no ocular dominance shift, while in flickering light averaging 0.1 Hz there was a significant shift. Recordings from the 2 Hz flicker-reared were similar to the dark-reared recordings. The flickering illumination was produced in one case by a high contrast-low brightness TV near the cage, and in another case, by a low voltage incandescent bulb driven by a pseudo-random sequence generator. This circuit delivered either a maximum ON time of 1.7 s or a maximum of 40 s, for the 2 Hz and 0.1 Hz respectively. Both the TV and flickering bulb produced average illumination comparable to the dim (0.01 cd/ m²) steady scotopic illumination. We conclude that dim flickering light is not a sufficient stimulus for promoting ocular dominance shift in kittens in the critical period unless the flicker rate approaches 0.1 Hz. Furthermore results from the TV rearing suggest that flicker may be capable of preventing an ocular dominance shift expected from a concurrent steady low light level background.This work was supported by ONR Contract N00014-81-K-0136. Flaxedil was supplied by Lederle Laboratories. We thank K. Cullen, M. Sutter, J. Kape and M. Motuz for technical assistance. L.N. Cooper and J.P. Rauschecker provided helpful comments.     

Failure of dark adaptation to upregulate D-1 dopamine receptors in retina of senescent rats

The effect of aging on the binding parameters of 3H-SCH 23390, the most selective ligand of D-1 DA receptors, was studied in membrane preparations from the rat retina. DA-stimulated adenylate cyclase activity was also measured in order to better characterize the changes in retinal D-1 DA receptors induced by aging. The binding studies revealed that the density of 3H-SCH 23390 was increased (34 and 73%) in the retina of 14- and 26-month-old rats, when compared to young adult animals, respectively. In contrast, aging failed to alter the sensitivity of the adenylate cyclase to the action of DA. In fact, DA (10(-6) M to 10(-4) M) elicited a similar enhancement in cyclic AMP formation in retinal homogenates of both adult and senescent rats. Since dark adaptation increases the density of D-1 DA receptors in the retina of adult rats we studied the effect of light deprivation on 3H-SCH 23390 binding and DA-sensitive adenylate cyclase activity in the retina of senescent rats. As previously shown (25) light deprivation increased 3H-SCH 23390 binding and enhanced DA-sensitive adenylate cyclase activity in the retina of young adult rats. On the contrary, dark adaptation failed to increase 3H-SCH 23390 binding and to enhance DA-sensitive adenylate cyclase activity in the retina of senescent rats. Taken together these results indicate that D-1 DA receptors in the retina of aged rats have biochemical and functional properties different from those found in the retina of adult animals; these changes may result in an altered response to the physiological stimuli elicited by environmental lighting.     

Circadian rhythms of pineal melatonin release in the pigeon measured by in vivo microdialysis.

Circadian rhythms of pineal melatonin release were measured in freely moving pigeons (Columba livia) by in vivo microdialysis. The birds were placed in light-dark cycles with 12 h of light and 12 h of darkness (LD 12:12) or continuous dim light (LLdim) after LD 12:12. Although the level of melatonin was various, daily changes of melatonin with higher levels during the dark and lower levels during the light were observed in all of the birds examined. The daily changes of melatonin persisted in LLdim, indicating circadian nature of pineal melatonin release. Moreover pineal melatonin release was inhibited by acute exposure of light during the dark. These results indicate that microdialysis is useful for studying circadian pineal melatonin rhythms of birds.     

Circadian rhythm of histamine release from the hypothalamus of freely moving rats.

Using an in vivo microdialysis technique coupled with HPLC-fluorometry, the release of neuronal histamine from the anterior hypothalamic area was monitored continuously in conscious, freely moving rats under a 12:12 h light:dark cycle. Spontaneous locomotor activity of the rats was measured simultaneously using a locomotor activity counter. Histamine release gradually increased in the second half of the light period (1400-2000) and the average histamine release during the dark period (2000-0800, 0.20 +/- 0.02 pmol/30 min) was significantly higher than that during the light period (0.12 +/- 0.01 pmol/30 min). This clear circadian change in the release suggests that the central histaminergic system is related to the circadian rhythm of rats.     

The effect of systemically applied cholinergic drugs on the striatal release of dopamine and its metabolites, as determined by automated brain dialysis in conscious rats

The effects of cholinergic drugs on the in vivo release of dopamine (DA) and its metabolites were studied in the striatum of freely moving rats. The endogenous compounds were sampled by microdialysis and analysed by on-line HPLC. High doses of oxotremorine (5 mumol/kg), physostigmine (3.6 mumol/kg), nicotine (3 mumol/kg) and atropine (10 mumol/kg) were injected i.p. Oxotremorine, physostigmine and atropine failed to modify the release of DA, while nicotine induced a slight (30%) but significant increase in the release of the transmitter. In contrast, oxotremorine and physostigmine did produce a significant rise of the dialysate contents of the DA metabolites. Thus, these data demonstrate clearly that changes in DA metabolism do not necessarily reflect changes in the release of DA. The most interesting findings of the present study is the fact that muscarinic receptor stimulation or blockade does not modify the release of DA from the rat striatum, while nicotine receptor stimulation may exert some stimulatory effect on the release of DA. This conclusion does not support the concept that the mode of action of anticholinergic drugs used in the treatment of parkinsonism, can be ascribed to a modulation of striatal dopaminergic activity.     

The effect of chronic clozapine on basal dopamine release and apomorphine-induced DA release in the striatum and nucleus accumbens as measured by in vivo brain microdialysis.

Previous studies have produced conflicting results concerning the effect of chronic oral vs. parenteral (i.p.) clozapine administration on dopamine (DA) release and metabolism in the striatum and nucleus accumbens (n. accumbens) of freely moving rats using in vivo microdialysis. In this study, parenteral chronic clozapine (20 mg/kg/day for 21 days, i.p.) had no effect on basal DA release and metabolism in either region. Chronic treatment with parenteral clozapine also did not reverse the decrease in DA release and metabolism in striatum and n. accumbens produced by apomorphine (100 micrograms/kg, s.c.). These results differ significantly from a previous report following i.p. clozapine and confirm the results previously reported with oral clozapine.     

Changes in striatal dopamine release and metabolism during and after subchronic haloperidol administration in rats.

The release and metabolism of dopamine (DA) in the striatum of rats during and after subchronic haloperidol (HAL) administration (3 weeks) was assessed using in vivo microdialysis. Basal extracellular levels of DA, DA metabolites (homovanillic acid and 3,4-dihydroxyphenylacetic acid) and the serotonin metabolite (5-hydroxyindoleacetic acid) were not significantly different from control values at 3 weeks of HAL administration and 3 days after drug withdrawal. The specific DA D2 receptor antagonist, raclopride (0.5 mg/kg, i.p.), significantly increased DA release and metabolism in control animals, but decreased DA release in the HAL-treated groups at 3 weeks of drug treatment. This effect was not significant following drug withdrawal. These results contrast with our previous finding that chronic HAL treatment (32 weeks) increases basal DA metabolism and further support the possibility that changes in DA function differ following short term vs. long term neuroleptic exposure.     

Isolation rearing of rats alters release of 5-hydroxytryptamine and dopamine in the frontal cortex: an in vivo electrochemical study

Summary The effects of rearing hooded Lister rats either in groups of seven or singly on 5-hydroxytryptamine (5-HT) and dopamine (DA) release in the frontal cortex were investigated using in vivo voltammetry together with Nafion coated carbon fibre micro-electrodes. The selective detection of basal extracellular levels of 5-HT with this technique (Peak B) was confirmed with parallel experiments using intracranial microdialysis to measure 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels in vivo. The DA voltammetric signal (Peak A) was observed in vivo only following pharmacological or electrical stimulation of DA release. Enhanced efflux of cortical DA and 5-HT in response to local application of KCl and that of 5-HT following parentelar fenfluramine were selectively detected by the association: differential pulse voltammetry (DPV) — Nafion coated microbiosensors, supporting the capability of this electrochemical method to selectively monitor release of these amine neurotransmitters in vivo and in situ. The locomotor behaviour data indicated that isolation rearing resulted in augmented locomotor activity in a novel environment. In addition, the in vivo voltammetric results showed that following KC1 or fenfluramine treatment cortical 5-HT release is prolonged while that of DA is increased in rats reared in isolation when compared with socially reared rats. This imbalance between extracellular levels of DA and 5-HT recorded in the frontal cortex of rats exposed to isolated housing conditions may contribute to the behavioural differences reported between isolation and group reared rats.Abbreviations 5-HT 5-hydroxytryptamine - DA dopamine - 5-HIAA 5-hydroxyindoleacetic acid - DPV differential pulse voltammetry - CFE carbon fibre micro-electrode - DOPAC dihydroxy phenilacetic acid - FC frontal cortex - MAO-I monoamine oxidase inhibitor     

Increase of hippocampal acetylcholine release at the onset of dark phase is suppressed in a mutant mice model of evening-type individuals

We have previously reported that clock mutant mice on Jcl:ICR background show about 2-h delayed circadian profiles in body temperature, spontaneous activity and sleep-wake rhythm, and that they appear to be useful as a model of evening-type of individual. Hippocampal acetylcholine (ACh) release which is positively correlated with attention, learning and memory shows a circadian variation. In this study, changes in hippocampal ACh release in transitional phase from light (rest) to dark (active) period in clock mutant mice were monitored using an in vivo microdialysis method. Compared with wild mice, the increase in hippocampal ACh in the first 2 h of the active period in the mutant mice was suppressed in parallel with peak frequency in electroencephalogram theta rhythm. The molecular basis of the circadian system appears to have a strong effect on hippocampal cholinergic function, and is probably associating with individual temporal differences in voluntary behavior, cognition, learning and/or memory performance.     

Striatal dopamine metabolism increases during long-term haloperidol administration in rats but shows tolerance in response to acute challenge with raclopride.

The release and metabolism of dopamine (DA) in the striatum of rats during long-term haloperidol administration (32 weeks) was assessed using in vivo microdialysis. Basal levels of homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) were significantly elevated over control values, while basal DA release was not significantly increased. The specific DA D2 receptor antagonist, raclopride (0.5 mg/kg, i.p.), increased DA release and metabolism in control animals, but this effect was profoundly blocked in the haloperidol treated group. These results suggest that chronic haloperidol treatment may induce compensatory increases in basal DA activity even though response to an acute D2 antagonist shows significant tolerance.     

Eating and drinking cause increased dopamine release in the nucleus accumbens and ventral tegmental area in the rat: measurement by in vivo microdialysis.

Dopamine (DA) release was simultaneously monitored in the nucleus accumbens (NAC) and ventral tegmental area (VTA) of conscious rats using in vivo microdialysis. During dialysis perfusion, rats were allowed access to food or water for 20 min following a 36 h food and water deprivation period. DA release increased significantly in the NAC and VTA in response to eating and drinking. The increases in both regions continued until 20-60 min after the end of the feeding or drinking session. These results show that the mesolimbic DA pathway is activated in response to ingestive behavior, and that DA release occurs in the cell body (A10) region as well as in the mesolimbic DA nerve terminals.     

Effects of acute and chronic nicotine on somatodendritic dopamine release of the rat ventral tegmental area: in vivo microdialysis study

The objectives of the present study were to examine the effects of acute and chronic nicotine on dopamine (DA) release in the ventral tegmental area (VTA) of Long-Evans rats using in vivo microdialysis. Systemic application of acute nicotine (0.1-0.3 mg/kg, s.c.) significantly increased (145% of baseline) DA release in the VTA. Chronic exposure to nicotine (0.3 mg/kg, s.c.) for 5 days followed by a challenge dose of nicotine (0.3 mg/kg, s.c.) also produced significant enhancement (136% of baseline) of DA release in the VTA. The results suggest that both acute and chronic nicotine treatment exert stimulatory effects on somatodendritic DA release in the VTA. The enhancement of DA release to subsequent challenge nicotine may be susceptible to mild desensitization.     

Feeding and hypothalamic stimulation increase dopamine turnover in the accumbens

The hypothesis that the dopaminergic system plays a role in feeding behavior was tested in three experiments. First, microdialysis was performed in the nucleus accumbens (NAC) at 20 min intervals during free feeding in rats at 80% of normal body weight. Extracellular concentration of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) increased significantly during eating indicating an increase in DA turnover. Second, microdialysis samples were collected from the NAC during bar pressing with a) a signal light on and food available, b) the light on but no food available, c) neither light nor food. Only when food was available did extracellular DA, DOPAC and HVA increase significantly. This increase in DA turnover occurred in the accumbens but not in the ventral striatum. Third, electrical stimulation of the perifornical lateral hypothalamus (LH) that was capable of inducing feeding increased extracellular DA, DOPAC and HVA in the NAC. This occurred whether the animal had food to eat or not. The effect of LH stimulation on DA turnover resembled the effects of free feeding and operant feeding in Experiments 1 and 2. Perifornical LH stimulation did not increase dopamine turnover in the ventral striatum. The results show that perifornical LH stimulation activates the mesolimbic dopamine system and that dopamine release in the accumbens is involved in feeding. The increase in dopamine turnover outlasted the consummatory act. This suggests that accumbens dopamine may be related to sensory input, feeding reflexes, food reward or memory processes and not just to the consummatory act itself.     

Intrastriatal dialysis evidence for a direct inhibitory effect of benztropine on dopamine re-uptake

A direct inhibitory effect of benztropine on dopamine (DA) reuptake in the striatum was established by in vivo microdialysis of anesthetized rats. Benztropine was infused by means of a microdialysis probe positioned stereotaxically in the striatum. Extracellular DA collected from dialysate was measured by high-performance liquid chromatography using an electrochemical detector. Benztropine was found to cause a dose-dependent inhibition of re-uptake of DA in the nerve terminal area of the dopaminergic system.     

Mecamylamine decreases accumbal dopamine output in mice treated chronically with nicotine

The role of nicotinic acetylcholine receptor (nAChR) activation in accumbal dopamine (DA) release during chronic continuous nicotine treatment was studied by in vivo microdialysis in freely-moving mice. Nicotine was administered chronically to NMRI mice in their drinking water. On the 50th day of nicotine administration microdialysis samples were collected at 20 min intervals and their DA, 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindoleacetic acid contents were measured using a high-performance liquid chromatographic-electrochemical procedure. After collection of four baseline samples the nicotinic antagonist mecamylamine (2 mg/kg, s.c.) was given. The steady-state DA output was larger in the nicotine-treated mice than in the control mice. Mecamylamine reduced the DA output in the nicotine-treated but not in the control mice. Thus, after continuous 50-day administration nicotine still continues to activate nAChRs regulating accumbal DA release.     

Environmental lighting has a selective influence on ethanol intake in rats.

The effect of lighting condition on levels of absolute ethanol intake were systematically examined in the present study. Wistar rats were exposed to one of three lighting conditions: constant light, constant dark, and a standard 12/12 light/dark cycle. The animals were acclimatized to lighting conditions for 2 weeks prior to ethanol (EtOH) acquisition with water and food available ad lib. EtOH was then presented in increasing concentrations from 2% (v/v; 95% with tap water) to 10% on alternate days in free choice with water. Immediately following the acquisition phase, a maintenance period was initiated that began with everyday presentations of 10% EtOH solution in free choice with water. After 10 days, lighting conditions for the constant light and dark groups were switched to normal lighting (12/12 light/ dark). EtOH and water intake were recorded for an additional 10 days. Rats exposed to constant light during EtOH acquisition and maintenance consumed less EtOH during the maintenance period than rats exposed to normal lighting conditions. When lighting conditions were switched to a normal cycle, water consumption increased significantly but EtOH intake did not change. Rats living in constant dark during EtOH acquisition and maintenance consumed less EtOH during the acquisition period when compared with rats living in normal lighting conditions. Unlike animals trained under constant lighting, switching to normal lighting conditions had no effect on EtOH or water intake. There were no differences in water consumption levels among the groups during acquisition and maintenance, suggesting a specificity of the effects of lighting condition on EtOH intake. The present study, therefore, has attempted to show that an environmental variable such as lighting may exert a selective influence on EtOH self-selection in rats.     

Chronic treatment with clozapine selectively decreases basal dopamine release in nucleus accumbens but not in caudate-putamen as measured by in vivo brain microdialysis: further evidence for depolarization block

As measured using in vivo brain microdialysis in conscious freely-moving rats, chronic treatment (20 mg/kg/day i.p. for 21 days) with the clinically atypical neuroleptic clozapine selectively reduced basal dopamine (DA) release in the nucleus accumbens (Acb) but not in caudate-putamen (CPu). Apomorphine (100 micrograms/kg s.c.) enhanced presynaptic Acb DA release in clozapine-treated rats, but reduced Acb DA release in vehicle-treated rats. These findings provide further evidence that depolarization block of mesolimbic DA neurons projecting to Acb but not of nigrostriatal DA neurons projecting to CPu may underlie clozapine's unusual clinical efficacy and its lack of production of extrapyramidal motoric effects.     

Effects of thienorphine on release of dopamine and noradrenalin: an in vivo microdialysis study in rats

Thenorphine is a new potent long-acting partial opioid agonist. In present study, the effect of thienorphine on noradrenalin (NA) in the locus coeruleus (LC) and dopamine (DA) and its metabolites in the nucleus acumbens (NAc) and the striatum were examined in freely moving rats during acute and chronic thienorphine treatment followed by naloxone-precipitated withdrawal using the in vivo microdialysis technique. Acute thienorphine (1.0mg/kg, s.c.) treatment had no effect on the level of NA in the LC and the level of DA in the NAc and the striatum. Chronic thienorphine (1.0mg/kg, s.c.) third per day for continued 5 days treatment followed by naloxone-precipitated (5.0mg/kg, i.p.) had not alter the extracellular NA level in the LC and the extracellular level of DA in the NAc and the striatum, but significantly increased the level of DOPAC in the striatum. These changes are thought to reflect a direct effect of thienorphine on release of NA and DA. Thus thienorphine deserves further study as a new treatment for opioid dependence.     

Tyrosine prevents effects of hyperthermia on behavior and increases norepinephrine

Tyrosine (TYR) is the precursor of the catecholamine (CA) neurotransmitters, dopamine (DA) and norepinephrine (NE). Catecholamines, especially NE, participate in the response of the brain to acute stress. When animals are acutely stressed, NE neurons become more active and tyrosine availability may be rate-limiting. Tyrosine administration, before exposure to physical and/or environmental stressors including cold, reduces the adverse behavioral, physiological and neurochemical consequences of the exposure. In this study, the effects of tyrosine (400 mg/kg) were examined on rats exposed to heat stress, for which its effects have not been examined. Coping behavior and memory were assessed using the Porsolt swim test and the Morris water maze. Release of hippocampal NE and DA was assessed with in vivo microdialysis. In vehicle-treated animals, heat impaired coping and memory, and increased release of NE, but not DA. In heated animals receiving tyrosine, coping was not impaired and NE release was sustained, thus demonstrating tyrosine protects against the adverse effects of heat, and suggesting these effects result from increased central NE release. This study indicates the effects of tyrosine generalize across dissimilar stressors and that tyrosine administration may mitigate the adverse behavioral effects of heat and other stressors on humans. In addition, it demonstrates that moderate heat stress impairs coping behavior, as well as working and reference memory.