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Experimental evidence suggests that dopamine (DA) modulates refractive eye growth. We evaluated whether increasing endogenous DA activity using pharmacological or genetic approaches decreased myopia susceptibility in mice. First, we assessed the effects of systemic L-3,4-dihydroxyphenylalanine (L-DOPA) injections on form deprivation myopia (FDM) in C57BL/6J (WT(C57)) mice. WT(C57) mice received daily systemic injections of L-DOPA (n=11), L-DOPA + ascorbic acid (AA, n=22), AA (n=20), or Saline (n=16). Second, we tested transgenic mice with increased or decreased expression of vesicular monoamine transporter 2 (VMAT2(HI) , n=22; WT(HI), n=18; VMAT2(LO), n=18; or WT(LO), n=9), which packages DA into vesicles under normal and form deprivation conditions, affecting DA release. At post-natal day 28 (P28), monocular FD was induced in each genotype. Weekly measurements of refractive error, corneal curvature, and ocular biometry were performed until P42 or P49. WT(C57) mice exposed to FD developed a significant myopic shift (treated-contralateral eye) in AA (−3.27±0.73D) or saline (−3.71±0.80D) treated groups that was significantly attenuated by L-DOPA (−0.73±0.90D, p=0.0002) or L-DOPA + AA (−0.11±0.46D, p=0.0103). The VMAT2(LO) mice, with under-expression of VMAT2, were most susceptible to FDM. VMAT2(LO) mice developed significant myopic shifts to FD after one week compared to VMAT2(HI) and WT mice (VMAT2(LO): −5.48 ± 0.54D; VMAT2(HI): −0.52 ± 0.92D, p

In chicks, the diurnal patterns of retinal dopamine synthesis and release are associated with refractive development. To assess the within-day patterns of dopamine release, we assayed vitreal levels of DOPAC (3,4-dihydroxyphenylacetic acid) using high performance liquid chromatography with electrochemical detection, at 4-hour intervals over 24 hours in eyes with experimental manipulations that change ocular growth rates. Chicks were reared under a 12 hour light/12 hour dark cycle; experiments began at 12 days of age. Output was assessed by modelling using the robust variance structure of Generalized Estimating Equations. CONTINUOUS SPECTACLE LENS-DEFOCUS OR FORM DEPRIVATION: One group experienced non-restricted visual input to both eyes and served as untreated “normal” controls. Three experimental cohorts underwent monocular visual alterations known to alter eye growth and refraction: wearing a diffuser, a negative lens or a positive lens. After one full day of device-wear, chicks were euthanized at 4-hour intervals over 24 hours (8 birds per time/condition). BRIEF HYPEROPIC DEFOCUS: Chicks wore negative lenses for only 2 daily hours either in the morning (starting at ZT 0; n=16) or mid-day (starting at ZT 4; n=8) for 3 days. Vitreal DOPAC was assayed. In chicks with bilateral non-restricted vision, or with continuous defocus or form-deprivation, there was a diurnal variation in vitreal DOPAC levels for all eyes (p

Purpose The hypothesis that outdoor exposure might protect against myopia has generated much interest, although available data find only modest clinical efficacy. We tested the effect of outdoor rearing on form-deprivation myopia in chicks, a myopia model markedly inhibited by high-intensity indoor laboratory lighting. Methods Unilaterally goggled cohorts of White Leghorn chicks were maintained in a species-appropriate, outdoor rural setting during daylight hours to the extent permitted by weather. Control chicks were reared indoors with incandescent lighting. Besides ocular refraction and ultrasound, we determined dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) content in retina and vitreous and measured mRNA expression levels of selected clock and circadian rhythm-related genes in the retina/RPE. Results Myopia developed in the goggled eyes of all cohorts. Whereas outdoor rearing lessened myopia by 44% at 4 days, a protective effect was no longer evident at 11 days. Outdoor rearing had no consistent effect on retinal or vitreous content of dopamine or DOPAC. Conforming to prior data on form-deprivation myopia, retina and vitreous levels of DOPAC were reduced in goggled eyes. Compared with contralateral eyes, the retinal expression of clock and circadian rhythm-related genes was modestly altered in myopic eyes of chicks reared indoors or outdoors. Conclusions Outdoor rearing of chicks induces only a partial decrease of goggle-induced myopia that is not maintained, without evidence that retinal dopamine metabolism accounts for the partial myopia inhibition under these outdoor conditions. Although modest, alterations in retinal gene expression suggest that studying circadian signals might be informative for understanding refractive mechanisms.

Purpose.To study a potential role for muscarinic receptors in the inhibition of deprivation-induced excessive axial elongation and myopia in a monkey model.Methods.The right eyes of 20 newborn rhesus monkeys were occluded with a black contact lens. In seven monkeys each, either atropine or

Pineal organ of the lamprey, Lampetra japonica, is essential to keep the circadian locomotor activity rhythm as previously reported. In this paper, we tried to show that an endogenous oscillator is located and is working in the pineal organ. When the pineal organs were excised and cultured in a plastic tube with M199 medium at 20 degrees C, melatonin secretion rhythms were clearly observed under both light-dark and continuous dark conditions. The circadian secretion of melatonin continued for more than five cycles under the continuous dark condition. This indicates that the pineal organ has an endogenous oscillator and that the melatonin secretion rhythm is controlled by this oscillator. These findings suggest the possibility that the locomotor activity rhythm of the lamprey is under the control of the oscillator in the pineal organ.

The anti-alcoholism medication, disulfiram (Antabuse), decreases cocaine use in humans regardless of concurrent alcohol consumption and facilitates cocaine sensitization in rats, but the functional targets are unknown. Disulfiram inhibits dopamine β-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons. The goal of this study was to test the effects of chronic genetic or pharmacological DBH inhibition on behavioral responses to cocaine using DBH knockout (Dbh −/−) mice, disulfiram, and the selective DBH inhibitor, nepicastat. Locomotor activity was measured in control (Dbh +/−) and Dbh −/− mice during a 5 day regimen of saline+saline, disulfiram+saline, nepicastat+saline, saline+cocaine, disulfiram+cocaine, or nepicastat+cocaine. After a 10 day withdrawal period, all groups were administered cocaine, and locomotor activity and stereotypy were measured. Drug-naive Dbh −/− mice were hypersensitive to cocaine-induced locomotion and resembled cocaine-sensitized Dbh +/− mice. Chronic disulfiram administration facilitated cocaine-induced locomotion in some mice and induced stereotypy in others during the development of sensitization, while cocaine-induced stereotypy was evident in all nepicastat-treated mice. Cocaine-induced stereotypy was profoundly increased in the disulfiram+cocaine, nepicastat+cocaine, and nepicastat+saline groups upon cocaine challenge after withdrawal in Dbh +/− mice. Disulfiram or nepicastat treatment had no effect on behavioral responses to cocaine in Dbh −/− mice. These results demonstrate that chronic DBH inhibition facilitates behavioral responses to cocaine, although different methods of inhibition (genetic vs. non-selective inhibitor vs. selective inhibitor) enhance qualitatively different cocaine-induced behaviors.

Chicken retina contains autonomous circadian clocks in multiple cell types. Best studied of these clocks are the ones in photoreceptor cells. This article describes what is known about expression of clock genes, which form the molecular basis of circadian oscillators, as well as clock output pathways that regulate circadian rhythms in the chick retina. It focuses on clock-controlled regulation of cyclic AMP signaling, melatonin biosynthesis, phospholipid metabolism, and melanopsin and iodopsin expression.

Dopamine is a neuromodulator that acts on all cell types within the retina. It is synthesized and released by a small population of amacrine and interplexiform cells, and affects retinal physiology primarily through extrasynaptic mechanisms. Dopamine synthesis and release are stimulated by light. Within the retina, dopamine acts on four of the five known dopamine receptor subtypes, the D1, D2, D4, and D5 receptors. This article describes the circuitry controlling dopamine neuron activity, mechanisms regulating dopamine synthesis, the distribution of dopamine receptors within the retina, and the functions of this neuromodulator.

The attempt to restore lost neurological function through grafting of catecholaminergic tissue into the striatum is a dramatic new experimental treatment approach for parkinsonism. We have grafted autologous adrenal medullary tissue into the right caudate nucleus in 12 patients with advanced Parkinson's disease (10 males, 2 females, mean age 53 years, mean Hoehn and Yahr stage 'off' medications 4.2) applying a transcortical technique similar to that of Madrazo as modified by Allen using right adrenalectomy performed via a flank approach. There have been no deaths, surgical complications, or serious postoperative morbidity. Modified Columbia Parkinson's disease ratings of patients off all dopaminergic agents for 72 h revealed 22% improvement (p less than 0.01) 3-6 months postoperatively (n = 10) and 22% improvement (p less than 0.01) 7-12 months later (n = 9). Postoperative dyskinesias necessitated reduction of L-dopa by 11% and of carbidopa by 29%. Analysis of lumbar cerebrospinal fluid biogenic amine metabolites following a 4-day 'drug holiday' revealed that homovanillic acid increased to 159% of preoperative levels (p less than 0.01) 3-6 months (n = 9) and to 197% of preoperative levels (p less than 0.02) 7-12 months postoperatively (n = 5). We have observed a mild to moderate improvement persisting up to 1 year with this therapeutic approach, but further study is needed.

A vision-dependent feedback mechanism contributes to the regulation of postnatal eye growth and refraction; this mechanism is located at least in part in the retina. In chicks and rhesus monkeys, visual deprivation leads to ocular enlargement and a myopic refractive error, and it also reduces the retinal concentration of dopamine. In neonatal chicks, local application of the dopamine agonist apomorphine limits the excessive axial elongation that is associated with visual deprivation. Both D1 and D2 dopamine receptor mechanisms may participate. Remarkably, apomorphine is geometrically selective, not limiting the exaggerated equatorial growth that occurs during visual deprivation. Preliminary results in neonatal rhesus monkeys indicate that apomorphine eye drops also suppress exaggerated axial growth and myopic refractive error during visual deprivation; equatorial diameters were not measured. Our observations are consistent with a retinal hypothesis for emmetropization and suggest that retinal dopamine participates in a mechanism linking ocular growth control to vision. In addition, we conclude that axial and equatorial dimensions are independently regulated in the chick.

Bradykinesia and rigidity are the symptoms that most directly correlate with loss of striatal dopamine in Parkinson's disease. In the hemiparkinsonian (HP) monkey, this is represented by paucity of movement as measured by computerized movement analysis, diminished manual dexterity on clinical examination, and diminished performance on operant behavioral tasks. The present study used an MPTP-induced HP model in rhesus monkeys to evaluate the effectiveness of adrenal medullary and peripheral nerve co-grafts in diminishing parkinsonian symptoms. Unoperated controls (N = 4), surgical controls with caudate lesioning (N = 4), and caudate co-grafted (N = 4) HP monkeys demonstrated diminished movement in the home cage following MPTP. This behavior persisted in unoperated controls, but improved in both surgical control and co-grafted monkeys. Functional hand dexterity evaluations demonstrated similar impairment in all three groups, but only surgical controls and co-grafted monkeys demonstrated improvement. In general, rotational behavior in response to apomorphine was consistent with recovery of function in surgical controls and co-grafted monkeys, but marked between-subject variability precluded group statistical analyses. None of the monkeys could perform the operant task using the affected limb following MPTP. However, the performance of two co-grafted animals demonstrated partial recovery. L-dopa improved operant performance, demonstrating a dopaminergic component to the task. The results demonstrate recovery of behavioral function after surgical treatment, with adrenal co-grafted monkeys showing the greatest degree of improvement.

In dopamine D4 receptor knockout mice, the ultrastructure of the retina and fully dark adapted electroretinograms are normal, but the ERGs of light adapted retinae and the cAMP response to a dopamine agonist are abnormal.

The purpose of this study was to assess the role of catecholamines in brain, in the stimulation of locomotor activity, induced by caffeine, as compared to the psychomotor stimulants d -amphetamine and methylphenidate. Adult male rats were pretreated with either (1) 2.5 mg/kg (i.p.) reserpine, 24 hr prior to testing of locomotor activity, (2) 50 mg/kg (i.p.) alpha-methyl-para-tyrosine (AMPT) 6 hr and 2 hr prior to testing of locomotor activity, (3) 200 μg/rat (i.c.v.) 6-hydroxydopamine (6-OHDA), or 25 mg/kg (i.p.) desmethylimipramine (DMI) and 200 μg/rat 6-OHDA (i.c.v.), 6–8 weeks prior to testing. Each treatment group had a matched control group. Levels of catecholamines in the forebrain were determined in each of the treatment and corresponding control groups. All rats were tested with doses of caffeine, d -amphetamine and methylphenidate (excluding the 6-OHDA-treated animals), administered in random order intraperitoneally 35 min before locomotor activity was measured for 30 min. Pretreatment with either reserpine or AMPT attenuated the stimulation of locomotor activity induced by caffeine and d -amphetamine but not that induced by methylphenidate. The dose-response curve for amphetamine was shifted downward and to the right by reserpine but was flattened by AMPT. The dose-response curve for caffeine was displaced downward in a similar manner by both reserpine and AMPT. Treatment with 6-OHDA or DMI + 6-OHDA produced the expected changes in the content of catecholamines in brain, but failed to modify dose-response curves for caffeine or amphetamine. Reversible depletion of catecholamines in brain with reserpine and AMPT differentiated the locomotor stimulant actions of caffeine from those of d -amphetamine and methylphenidate and confirmed previously reported differences between amphetamine and methylphenidate.

Publisher Summary This chapter examines the preliminary report on adrenal medullary grafting and cografting with sural nerve in the treatment of hemiparkinson monkeys. In the study described in the chapter, 11 juvenile rhesus monkeys (Macaca mulatta) were enrolled. A battery of testing was performed at 3 stages: (1) baseline, (2) post- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injection, and (3) post-transplantation. Baseline testing started with a clinical examination of the monkeys to ensure neurological normalcy. Cerebrospinal fluid (CSF) levels of the dopamine metabolite, homovanillic acid (HVA), and the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were determined by high performance liquid chromatography with electrochemical detection. Clinical behavior was assessed in a quantitative manner by a two-dimensional computerized movement analysis, indicating the following parameters: the percent of time moving, total distance traversed, and the graphical display of tracking of monkey's movements. The quantitation of drug induced rotation was used to measure the severity of the lesion and as a measure of graft effectiveness. Following the administration of MPTP, all of the animals demonstrated an altered behavior characteristic of parkmsonism. Hypokinesia, bradykinesia, and rigidity of the affected side were quite prominent, while a true tremor at rest was notably absent. The hemiparkinson monkeys demonstrated spontaneous rotation toward the side of the lesion within days following their MPTP injections. In a dose-dependent manner, rotation was accelerated using amphetamine or reversed using apomorphine.

Brief (15 min) and prolonged (96 h) exposure to light increases the activity of retinal tyrosine hydroxylase (TH) in vivo. Brief exposure decreases the apparent Km of TH for DMPH4 but not the Vmax, while prolonged exposure increases the apparent Vmax but not the Km for DMPH4. Retinal TH of rats that have been dark-adapted or dark-adapted plus exposure to light for 15 min is activated in vitro by cAMP-dependent phosphorylating conditions. Experimental evidence suggest that a cAMP-dependent phosphorylation reaction may be responsible for activation of TH after brief exposure to light.

The effects of hippccampal and neocortical lesions on open field locomotor activity and the levels of plasma corticosterone immediately after the activity testing session were examined. Rats with hippocampal lesions had significantly higher locomotor activity and lower corticosterone levels than sham-operated control, while rats with neocortical lesions were not significantly different from the controls. The results are discussed with respect to reduced fear and the perception of aversive stimuli by rats with hippocampal lesions.