Confirmation of the efficacy of a novel formulation of metaflumizone plus amitraz for the treatment and control of fleas and ticks on dogs.

A novel spot-on formulation containing metaflumizone plus amitraz (ProMeris/ProMeris Duo for Dogs, Fort Dodge Animal Health, Overland Park, KS) was evaluated in four laboratory studies to confirm efficacy against fleas and ticks on dogs for 1 month. Three different strains of cat flea (Ctenocephalides felis felis) and four tick species were used. Rhipicephalus sanguineus and Dermacentor variabilis were evaluated concurrently in two studies and Ixodes scapularis and Amblyomma americanum in one study each. In all studies, dogs were randomly allocated to treatment groups and compared with nontreated dogs. One study also included a placebo treatment and a commercial product containing fipronil plus S-methoprene. All treatments were applied to the skin at a single spot between the scapulae on Day 0. Dogs were infested with fleas and/or ticks prior to treatment and then reinfested at weekly intervals for 6 weeks after treatment and evaluated for efficacy at 1 or 2 days after treatment and each reinfestation. These studies confirmed that treatment with ProMeris for Dogs at the proposed commercial dose rate rapidly controlled existing infestations of fleas and ticks on dogs. Treatment provided control of reinfesting fleas for up to 6 weeks and at least 4 weeks control of ticks. Efficacy was confirmed in a variety of dog breeds against three different flea strains and four common species of ticks found on dogs in the United States.

Brain-derived neurotrophic factor is released in the dorsal horn by distinctive patterns of afferent fiber stimulation.

Brain-derived neurotrophic factor (BDNF) is synthesized by small neuron cell bodies in the dorsal root ganglia (DRG) and is anterogradely transported to primary afferent terminals in the dorsal horn where it is involved in the modulation of painful stimuli. Here we show that BDNF is released in the rat isolated dorsal horn after chemical stimulation by capsaicin or electrical stimulation of dorsal roots. Capsaicin superfusion (1-100 microm) induced a dose-dependent release of BDNF, measured using ELISA. The highest dose of capsaicin also induced a depletion of BDNF protein in the dorsal horn. BDNF release was also seen after electrical stimulation of the dorsal roots at C-fiber strength. This release was encoded by specific patterns of afferent fiber stimulation. Neither continuous low-frequency (480 pulses, 1 Hz) nor tetanic high-frequency (300 pulses in 3 trains, 100 Hz) stimulation evoked release of BDNF, although substance P (SP) release was observed under both of these conditions. However, BDNF was released after short bursts of high-frequency stimulation (300 pulses in 75 trains, 100 Hz) along with SP and glutamate. The NMDA antagonist d-AP-5 inhibited electrically evoked BDNF release. BDNF release was also measured after systemic or intrathecal NGF treatment. This upregulated BDNF content in the DRG and increased the capsaicin-evoked release of BDNF. Similarly, the amount of BDNF released by burst stimulation was increased after NGF treatment. This activity-dependent release continued to be encoded solely by this stimulation pattern. These experiments demonstrate that BDNF release in the dorsal horn is encoded by specific patterns of afferent fiber stimulation and is mediated by NMDA receptor activation.

Development of computer algorithms for radiation treatment planning.

As a result of an analysis of data relating tissue response to radiation absorbed dose the ICRU has recommended a target for accuracy of +/- 5 for dose delivery in radiation therapy. This is a difficult overall objective to achieve because of the many steps that make up a course of radiotherapy. The calculation of absorbed dose is only one of the steps and so to achieve an overall accuracy of better than +/- 5% the accuracy in dose calculation must be better yet. The physics behind the problem is sufficiently complicated so that no exact method of calculation has been found and consequently approximate solutions must be used. The development of computer algorithms for this task involves the search for better and better approximate solutions. To achieve the desired target of accuracy a fairly sophisticated calculation procedure must be used. Only when this is done can we hope to further improve our knowledge of the way in which tissues respond to radiation treatments.

Quality assurance in radiation therapy: clinical and physical aspects. Quality assurance in dosimetry and treatment planning.

The considerations of tissue response to radiation absorbed dose suggest a need for an accuracy of +/- 5% in its delivery. This is very demanding and its regular achievement requires careful quality control. There are three distinct phases to the delivery of the planned treatment: calibration of the radiation beam in a reference situation, calculation of the dose distribution for a patient relative to the reference dose and the delivery of the radiation to the patient as planned. Each has distinctly different quality assurance requirements and must be diligently observed if the desired accuracy is to be achieved.

Evaluation of lung dose correction methods for photon irradiations of thorax phantoms.

Radiation absorbed dose in lung is measured and calculated using several algorithms available on commercial treatment planning systems. Phantoms resembling the human thorax are used and irradiated with small and large photon beams of 60Co, 4, 6, and 10 MV X ray energies. The applicability and usefulness of the different calculation methods in clinical situations is discussed.

The effects of GR127935, a putative 5-HT1D receptor antagonist, on brain 5-HT metabolism, extracellular 5-HT concentration and behaviour in the guinea pig.

Studies of neurotransmitter release in guinea pig and human brain indicate that the 5-HT terminal autoreceptor is the 5-HT1D subtype and that it regulates the depolarization evoked release of 5-HT. Thus, blockade of the terminal 5-HT autoreceptor should enhance 5-HT release in vivo. In the present study, we have used the recently described, selective and potent 5-HT1D receptor antagonist, GR127935, to determine if blockade of the terminal 5-HT autoreceptor enhanced 5-HT neurotransmission in the guinea pig. Neurochemical studies showed that GR127935 (0.1, 0.3 and 1.0 mg/kg i.p.) significantly increased 5-HT metabolism in forebrain regions but not in the raphe nucleus of the guinea pig. However, using in vivo dialysis, GR127935 did not significantly increase cortical 5-HT efflux when given either systemically (1 and 5 mg/kg i.p.) or by infusion via the probe directly into the cortex (10, 33 and 100 microM). Fast cyclic voltammetry studies in the guinea pig dorsal raphe slice in vitro failed to observe any significant effects of GR127935 (0.01-1 microM) on electrically evoked 5-HT release. Behavioural studies in the guinea pig were also unable to demonstrate any effects of GR127935 (0.1-3.0 mg/kg i.p.) per se or in combination with the 5-HT precursor 5-hydroxytryptophan. Taken together, results from the present neurochemical and behavioral studies in the guinea pig provide little substantial evidence that blockade of the terminal 5-HT autoreceptor following the acute administration of GR127935 increased brain 5-HT neurotransmission in vivo.

GABA release from Xenopus retina does not correlate with horizontal cell membrane potential.

The relationship between horizontal cell membrane potential and the release of GABA was explored in the retina of Xenopus laevis. The intracellularly recorded membrane potential of horizontal cells was monitored while the retina was exposed to different concentrations of depolarizing agents. The dose-response curves obtained revealed a rise from 5 to 95% maximum depolarization in 0.5-1.5 log unit concentration change. The molar concentrations that elicited a 20 mV depolarization were 40 mM (potassium), 0.8 mM (glutamate), 0.8 mM (glycine), 5 microM (kainate) and 1.3 microM (quisqualate). Autoradiography revealed that radiolabel was accumulated almost exclusively by horizontal cells when isolated retinas were incubated in medium containing 1 microM [3H]GABA. Thus, retinal release of radioactivity was used as a measure of [3H]GABA release from horizontal cells. Endogenous GABA released from retinas was measured using high performance liquid chromatography and was taken to reflect both amacrine and horizontal cell GABA pools. The release of both [3H]GABA and endogenous GABA was stimulated by glutamate, kainate and potassium, but not by glycine or quisqualate. Similar dose-response curves for GABA release and for depolarization were obtained in the case of potassium and kainate but not for glutamate. Potassium-evoked release either of endogenous GABA or [3H]GABA was both calcium- and sodium-dependent, whereas kainate- or glutamate-evoked GABA release was sodium-dependent but calcium-independent. The results indicate that depolarization per se is not necessarily associated with transmitter release in Xenopus retinal horizontal cells. It is suggested that the action of a given neurotransmitter upon the efflux of GABA from horizontal cells may depend on the degree to which it modifies the sodium conductance of the horizontal cell.

Release of endogenous ascorbic acid preserves extracellular dopamine in the mammalian retina.

PURPOSE: To investigate whether the inhibitory effect of nitric oxide (NO) on dopamine release from the retina is due to chemical oxidation of dopamine in the extracellular medium rather than to an inhibitory effect on dopamine release from retinal neurons. METHODS: Dopamine was incubated in Krebs bicarbonate medium and its rate of chemical degradation measured by high-performance liquid chromatography (HPLC). The effects of NO donors and antioxidants on dopamine were assessed by comparing dopamine degradation in the presence and absence of drug. The effects of NO donors on the K-evoked release of [3H]dopamine were measured from isolated superfused rabbit retinas. The release of ascorbic acid from the isolated rat retina and from an eyecup preparation in anesthetized rabbits was measured by HPLC. RESULTS: After 10 minutes' incubation in Krebs bicarbonate medium, the dopamine concentration decreased by 20%. This decline increased to 80% in the presence of S-nitroso-N-acetyl-DL-penicillamine (SNAP) or sodium nitroprusside (SNP). The increased rate of dopamine degradation was abolished if retina was incubated in the medium and then removed before the incubation of dopamine. The protective effect of preincubation with tissue was lost in the presence of ascorbate oxidase suggesting the release of ascorbic acid. HPLC analysis confirmed a substantial release of ascorbic acid from both rabbit and rat retinas. The K-evoked release of [3H]dopamine from the rabbit retina was inhibited by SNP. CONCLUSIONS: NO can rapidly, oxidize dopamine in physiological medium, but in the presence of retina, sufficient endogenous antioxidants (mainly ascorbate) are released to prevent this chemical reaction. Thus, the inhibitory action of NO on dopamine release results from an action on retinal neurons. Ascorbate release in the retina may have an important physiological role in prolonging the life of dopamine, which often has to diffuse long distances from axons in the inner plexiform layer to receptors in other retinal layers.

Effect of sulphur containing amino acids on [3H]-acetylcholine release from amacrine cells of the rabbit retina.

1. The effects of the sulphur containing amino acids, homocysteic acid, homocysteine sulphinic acid, cysteic acid and cysteine sulphinic acid on the release of [3H]-acetylcholine ([3H]-ACh) from the cholinergic amacrine cells of the rabbit retina were examined. 2. All the compounds stimulated the spontaneous resting release and abolished the light-evoked release of [3H]-ACh. Except for homocysteine sulphinic acid these actions occurred at concentrations that did not affect the erg b-wave amplitude, indicating a site of action at the inner retina. 3. N-methyl-D-aspartate (in Mg(2+)-containing medium) clearly blocked the effects of homocysteic acid and homocysteine sulphinic acid on the resting release of [3H]-ACh but had no effect on the actions of cysteic acid and cysteine sulphinic acid. 4. Since N-methyl-D-aspartate is an antagonist of the light-evoked endogenous bipolar cell transmitter released onto cholinergic cells, these results are consistent with the suggestion that homocysteic acid or homocysteine sulphinic acid may be a transmitter released from this subpopulation of bipolar cells. 5. The present experiments indicate the existence of excitatory amino acids that have closer pharmacological properties to a bipolar cell transmitter than glutamate but it remains to be seen whether homocysteic acid or homocysteine sulphinic acid occur in these particular bipolar cells.

Modulation of extracellular GABA levels in the retina by activation of glial P2X-purinoceptors.

1. In the rat retina, gamma-aminobutyric acid (GABA) released as a transmitter is inactivated by uptake mainly into glial cells (Müller cells). Activation of P2-purinoceptors in Müller cells increases [Ca2+]i and the present study was undertaken to see whether this action affected the glial release of [3H]-GABA from the superfused rat isolated retina. 2. Adenosine 5'-triphosphate (ATP) and the P2X-purinoceptor agonists, alpha,beta-methylene-ATP (alpha,beta-meATP) and beta,gamma-methyleneATP (beta,gamma-meATP) significantly increased the KCl-evoked release of [3H]-GABA from the retina. 3. Adenosine and the P2Y-purinoceptor agonist, 2-chloroATP, had no effect on the KCl-evoked release of [3H]-GABA from the retina. However, 2-methylthioATP (2-Me-S-ATP) significantly enhanced the evoked release of [3H]-GABA. 4. The effect of ATP on the glial release of [3H]-GABA was abolished by the P2-antagonist, pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS). 5. When the superfused retina was exposed to the GABA uptake inhibitor, SKF89976A, the enhancing effect of alpha,beta-meATP on the KCl-evoked release of GABA was abolished. 6. The KCl-evoked release of [3H]-GABA from the frog retina and rat cerebrocortical slices, which take up GABA mainly into neurones, was not affected by ATP or alpha,beta-meATP. 7. We concluded that the glial Müller cells in the rat retina possess P2-receptors, activation of which increases the 'release' of preloaded [3H]-GABA apparently by reducing uptake. On balance, the results suggest the involvement of P2X-purinoceptors, although we cannot exclude the possibility that P2Y-purinoceptors may be involved. Our results suggest that ATP, as well as being a conventional transmitter in the retina, may be involved in neuronal-glial signalling and modulate the extracellular concentration of GABA.

Enhancement of retinal acetylcholine release by DAMGO: possibly a direct opioid receptor-mediated excitatory effect.

1. An eye-cup preparation in anaesthetized rabbits was used to examine opioid modulation of acetylcholine (ACh) release from cholinergic neurones in the retina. 2. The mu-opioid receptor agonist, [D-Ala2, MePhe4, Gly-ol5]-enkephalin (DAMGO), when applied locally to the retina at concentrations between 1-30 microM significantly increased the light-evoked release of ACh. The effect of DAMGO was completely blocked by the selective mu-receptor antagonist CTOP but the kappa-receptor antagonist nor-binaltorphimine (norBNI) did not affect the action of DAMGO on ACh release indicating that the opioid produced its effect by activation of mu-receptors (the rabbit retina has negligible delta-receptors). 3. Blockade with bicuculline and strychnine of GABAergic and glycinergic inputs to the cholinergic neurones did not affect the action of DAMGO on ACh release. Also DAMGO did not reduce the potassium-evoked release of either GABA or glycine from rat isolated retinas. 4. Exposure of the rabbit retina to a combination of an A1-adenosine receptor antagonist, 8-cyclopentyl-1,3 dipropylxanthine (DPCPX), and adenosine deaminase did not affect the enhancing action of DAMGO on the light-evoked release of ACh. 5. When the retina in the rabbit eye-cup was exposed to kainate, the release of ACh was increased by approximately three times the resting release. In the presence of DAMGO the kainate-evoked release of ACh was enhanced by 44%. 6. These experiments show that activation of mu-opioid receptors by DAMGO increases the release of ACh elicited by physiological stimulation (flickering light). Since we could find no evidence thatDAMGO reduces inhibitory inputs to the cholinergic neurones, it seems that the enhancing action ofDAMGO on the light-evoked release of ACh involves a direct excitatory effect rather than disinhibition.This conclusion is supported by the enhancing action of DAMGO on the kainate-evoked release of ACh because kainate is thought to act directly on the cholinergic neurones.

Inhibition by nociceptin of the light-evoked release of ACh from retinal cholinergic neurones.

The retina possesses cholinergic amacrine cells which release acetylcholine (ACh) in response to flickering light. Using an eye-cup preparation in anaesthetized rabbits we found that when the retina was exposed to nociceptin, the light-evoked release of ACh was reduced in a concentration-dependent manner (IC50 = 100 nM), the maximum effect being 60% inhibition. Opioid receptors were not involved in the inhibitory effect of nociceptin because its action was not blocked by naloxone (1 microM) and furthermore mu-opioids enhanced the light-evoked release of ACh. Using rabbit retina homogenates we found that the retina possessed a substantial number of high-affinity binding sites for [3H]-nociceptin indicating the presence of ORL1-receptors. Since [des-Phe1]-nociceptin, which has no affinity for the ORL1-receptor, had no effect on the light-evoked release of ACh it is unlikely that the action of nociceptin was simply non-specific. We conclude that the inhibitory effect of nociceptin on retinal ACh release involves activation of the ORL1 receptors.

Overall cost in the treatment of otitis media.

BACKGROUND: Numerous antimicrobial agents are available for treatment of otitis media (OM); however, little is known about the relative cost effectiveness of these drugs. METHODS: We developed a noninvasive, observational model to assess the total costs (direct and indirect) associated with commonly used antibiotics in the therapy of OM. We also gathered data on recurrence rates, which can significantly affect costs. RESULTS: The average total cost of treating an episode of OM in this study was $115.80. Treatment of a recurrent OM episode was significantly more costly than treatment of an initial episode ($124.64 vs. $107.81, P = 0.0001). This study suggests that significant costs are associated with OM treatment and that antibiotic price constitutes only a small portion of this cost. Recurrence rates appeared to vary with various antibiotic treatments. CONCLUSION: We conclude that recurrence is a major determinant of OM treatment costs. Drugs associated with lower rates of recurrence will usually be the most cost-effective treatment options.

Excitatory amino acid receptors and transmitter release in the retina.

The effects of excitatory amino acids and some analogues on the release of GABA and ACh from amacrine cells were studied. The release of endogenous GABA from the isolated rat retina was measured by HPLC. When animals were pretreated with ?-vinyl-GABA (GVG), glutamate evoked a large efflux of GABA but kainate, quisqualate and N- methyl- d -aspartate (NMDA) were relatively ineffective. The glutamate evoked release of GABA was calcium dependent and was blocked by the antagonist, piperidine-dicarboxylic acid (PDA) indicating that activation of excitatory amino acid receptors was involved in the response. The release of [(3)H]ACh from the rabbit retina was strikingly increased by homocysteate and this effect was blocked by NMDA. Since NMDA also blocked the light evoked release of [(3)H]ACh but not the effects of exogenous glutamate or aspartate, it is possible that homocysteate may be a bipolar cell transmitter released onto cholinergic amacrine cells.

Calcium dependent release of acetylcholine and gamma-aminobutyric acid from the rabbit retina.

The concurrent release of endogenous ACh and GABA from the retina (in the presence of physostigmine) was measured using either an eye-cup preparation in rabbits anaesthetized with urethane or isolated rabbit retinas. There was a spontaneous resting release of ACh and GABA from the dark adapted retina of ca 5 and 160 pmol min-1 respectively. Stimulation of the initially dark adapted retina in vivo with flickering light (0.1-20 Hz) increased the release of ACh by up to 5 times the spontaneous resting release but did not cause a detectable increase in GABA release. The maximum light-evoked release of ACh was about 24 pmol min-1/retina and occurred at a frequency of 10 Hz. However, the maximum release of ACh per flash occurred at 0.1 Hz at which frequency the average ACh release per flash from one amacrine cell was ca 2.35 x 10(-18) mol. Exposure of the retina to the potent inhibitors of GABA uptake, SKF89976A and SKF100330A markedly reduced the resting release of ACh and abolished the light-evoked release of ACh but did not enable a light-evoked release of GABA to be detected. Bicuculline blocked the inhibitory actions of both SKF89976A and SKF100330A on ACh release but the combination of bicuculline and uptake inhibitor did not result in a light-evoked release of GABA. In contrast, KCl (20 mM) applied locally to the retina in vivo resulted in the release of both ACh and GABA (61 and 2.6-fold respectively). KCl (20 mM) also evoked large increases in ACh and GABA release from isolated rabbit retinas in room light (13.5 and 3.4-fold respectively). The K-evoked release of ACh and GABA from the rabbit retina both in vivo and in vitro was calcium dependent. These experiments are the first in which endogenous ACh and GABA release from the retina have been simultaneously measured and suggest that the release mechanisms for these transmitters are fundamentally similar.

Abnormalities in expression of human retinal mRNA in retinitis pigmentosa.

The causative genetic defects of retinitis pigmentosa (RP) might be expected to affect the expression of messenger RNA in the retina. Total cellular RNA from retinas of normal and dystrophic individuals was therefore subjected to (i) in vitro translation and analysis by two-dimensional SDS polyacrylamide gel electrophoresis and (ii) Northern blot analysis using probes specific for ?-tubulin, interphotoreceptor retinoid-binding protein (IRBP) and glial fibrillary acidic protein (GFAP) mRNAs. Both methods revealed quantitative abnormalities in specific mRNA levels in RP. These differences appeared to reflect (i) the loss of photoreceptors in RP (decreased ?-tubulin and IRBP mRNA, and a reduced translation product comigrating with rhodopsin) and (ii) the proliferation of glial elements in the RP retinas (increased GFAP mRNA and its translation product). In addition, translation products of 21 and 39 kDa were consistently increased in RP retinas. These have not been previously detected in gliosis and their characterization may provide insight into the mechanisms of disease in RP.

The uptake and radioautographical localization in the frog retina of [3H](+/-)-aminocyclohexane carboxylic acid, a selective inhibitor of neuronal GABA transport.

The accumulation of [3H](+/-)-cis-3-aminocyclohexane carboxylic acid ([3H] ACHC) in frog retinae in vitro was highly localized in horizontal cells and their processes. [3H]GABA was also mainly accumulated within horizontal cells, but [3H]L-2,4-diaminobutyric acid ([3H]DABA) was taken up predominantly by the neuroglial Müller cells, whilst [3H]beta-alanine was localised largely within the photoreceptors. The uptake of [3H]ACHC (4.2 microM) was almost linear for 30 min and after 60 min a tissue/medium ratio of 5.25 was achieved. The uptake process was temperature sensitive highly dependent on sodium ions, and appeared to be mediated by a saturable transport process with an IC50 value of 0.83 mM. The accumulation of [3H]ACHC was inhibited by GABA and DABA (IC50 = 0.32 mM and 0.23 mM, respectively) whilst beta-alanine was a relatively weak inhibitor (IC50 = 9 mM) of ACHC uptake. In agreement with these results, the efflux of [3H]ACHC from the retina was increased by exposure to ACHC, GABA and DABA but not beta-alanine. In contrast, the efflux of [3H]DABA from the retina was not increased by GABA or ACHC, although DABA itself and potassium depolarization stimulated the release of [3H]DABA. These results strongly suggest that ACHC is accumulated in the frog retina by the same neuronal transport process as GABA. In contrast, the high affinity sites for DABA are localized mainly in glia, although inhibitor and release studies suggest that, at high concentration, DABA also interacts with the neuronal GABA (ACHC) transport process.

L-homocysteic acid--a possible bipolar cell transmitter in the rabbit retina.

The identity of the retinal bipolar cell transmitter(s) is unknown although there is much indirect evidence that suggests it may be glutamate or a related compound. Some bipolar cells synapse onto cholinergic amacrine cells and in the rabbit retina acetylcholine (ACh) release is increased by light flashes and by the excitatory amino acids glutamate, aspartate and homocysteic acid (HCA). In the retina, the amino acid agonist N-methyl-D-aspartate (NMDA) is unusual in that it sometimes acts as an antagonist, and in the present experiments it blocked the light-evoked release of ACh by acting as an antagonist of the bipolar cell transmitter. However, NMDA did not block the actions of glutamate or aspartate on amacrine cell ACh release, a result that argues against either of these amino acids being the bipolar cell transmitter. On the other hand, the HCA evoked release of ACh was clearly antagonised by NMDA suggesting that HCA may be the bipolar cell transmitter released onto cholinergic amacrine cells. This suggestion is supported by the finding that the rabbit retina possesses HCA at a concentration of 0.8 nmol/g wet wt.

Immunocytochemical evidence that vigabatrin in rats causes GABA accumulation in glial cells of the retina.

Vigabatrin (gamma-vinyl-GABA, GVG) is an irreversible inhibitor of GABA-aminotransferase (GABA-T) that is under clinical trial as an antiepileptic drug. Rats were injected (i.p.) with GVG and killed 18 h later. GVG administration reduced retinal GABA-T activity to undetectable levels and increased the GABA content 5-fold. Immunocytochemistry using a GABA antiserum clearly revealed the presence of GABA-IR in the glial Muller cells of retinas from GVG-treated rats but not from controls. This experiment indicates that the administration of drugs which inhibit GABA-T may cause the accumulation of GABA in retinal cells that do not normally possess enough endogenous GABA to be detected by immunocytochemistry.

Nitric oxide inhibits depolarization-induced release of endogenous dopamine in the rabbit retina.

The effect of nitric oxide donor compounds (sodium nitroprusside, hydroxylamine and S-nitroso-N-acetyl-D,L-penicillamine) on depolarization-induced release of endogenous dopamine in the light-adapted, isolated retina of the rabbit was studied by HPLC. All three compounds had the same effect, reducing the amount of dopamine released by up to 90%. The effect was concentration dependent, saturating at 300 microM; it was blocked by the nitric oxide scavenger, mannitol (50 mM), which by itself had no effect on the basal release of dopamine. GABAA receptors were not involved. Possible cellular mechanisms underlying the findings are discussed. It is suggested that the inhibitory interaction between dopamine and nitric oxide could represent a higher order function in the light adaptation process in the retina.