Differences in the characteristics of opiate and catecholaminergic receptors of the striatum and cerebral cortex of rats of Fisher-344 and WAG/GSto strains may cause differences in reinforced action of morphine]

It has been shown that Fischer-344 rats more than WAG/GSto inbred rats preferred to consume the solution of morphine. In intravenous self-administration testing, Fischer-344 rats had a higher rate of reinforced responses that resulted in morphine infusion. Bmax values for mu- and alpha 2-adrenoreceptors were significantly higher in the cortex of WAG/GSto rats. The sensitivity of the serotonin and dopamine receptors in the cortex and striatum of WAG/GSto rats was lower than that in Fischer-344 rats. These findings suggest that the difference between morphine consumptions in two inbred rat strains may be due to individual genetic patterns determining opioid and catecholamine receptors binding in the brain.     

Strain differences in kidney copper concentrations of male rats

The copper concentrations of the kidneys of male rats of six inbred (BN, F344, LEW, SHR, WAG/Cpb, and WAG/Rij) and one random-bred Wistar strain were determined. In inbred rats the mean concentration varied between strains and ranged from 7.10 μg/g for F 344 to 23.48 μg/g for WAG/Cpb. The calculated coefficient of genetic determination (g²) was 0.88. A remarkable discrepancy was found between the two WAG inbred strains; the WAG/Cpb had a 2.5 times higher kidney Cu concentration than the WAG/Rij. Kidney Cu concentrations of random-bred rats varied considerably; the coefficient of variation of the means was 28 and 34% in two samples taken with a 1-yr interval, respectively, indicating inhomogeneity within the population. The results indicate that the individual differences in kidney Cu concentration have a genetic basis.     

Impact of Swimming Exercise Training on the Effects of Modulation of Mitochondrial Permeability Transition and NOS-1 Activation in Medullary Cardiovascular Neurons of Rats

Physical inactivity can be considered one of the major risk factors related to cardiovascular diseases. There are reasons to believe that the positive effect of exercise training is, to a large extent, mediated by modulation of the nervous control of the circulation system. In our previous studies, we showed that modulation of mitochondrial permeability transition in medullary cardiovascular neurons significantly contributes to the hemodynamic reactions in both the norm and a number of pathological states. In this study, we examined in acute experiments on urethane-anesthetized rats the hemodynamic effects mediated by either modulation of mitochondrial permeability transition in medullary neurons, or activation of neuronal NO synthase (NOS-1) in these neuronal populations after preliminary moderate exercise training (everyday swimming sessions of increased duration carried out for four weeks). It was shown that, after exercise training had been completed, the effects of injections of an inductor of mitochondrial permeability transition pore (MPTP) opening, phenylarsine oxide (PAO, 0.5 to 1.5 nmol), into populations of cardiovascular neurons in the medullary autonomic nuclei (nucl. tractus solitarius and paramedian and lateral reticular nuclei) were less expressed, as compared with those in control (untrained) animals. The data obtained suggest that exercise training can exert a protective action on functional activity of medullary neurons due to the decreased sensitivity of MPTPs to their opening. Injections of an inhibitor of MPTP opening, melatonin (0.7 to 2.1 nmol), into populations of medullary neurons under study in trained rats induced a decrease in the systemic arterial pressure (SAP), in contrast to untrained animals demonstrating mostly hypertensive responses following injections of melatonin into the above nuclei. Injections of an activator of neuronal NO synthase (NOS-1), L-arginine, into the medullary nuclei of swimming-trained rats resulted in more expressed hemodynamic shifts than in control animals, which suggests an increase in the activity of neuronal NO synthase in medullary neurons of such animals.     

Prophylactic effect of melatonin in reducing lead-induced neurotoxicity in the rat

Oxidative stress is a likely molecular mechanism in lead neurotoxicity. Considering the antioxidant properties of melatonin, this study investigated the neuroprotective potential of melatonin in the hippocampus and corpus striatum of rats treated with lead. Three groups of male rats (control, lead acetate-treated [100 mg/kg], and lead acetate plus melatonin [10 mg/kg] for 21 consecutive days) were used. Levels of products of lipid peroxidation (LPO), glutathione (GSH) and superoxide dismutase (SOD) activity were measured in brain homogenates. Histological changes in the pyramidal cells of the hippocampus and the putamen of the corpus striatum were examined. The results documented increased LPO and decreased GSH and SOD activity in the brain homogenates of lead-treated rats. Histological observations revealed severe damage and a reduction in neuronal density in the hippocampus and corpus striatum. When melatonin was given to lead-treated rats, it almost completely attenuated the increase in LPO products and restored GSH levels and SOD activity. Also, the morphological damage was reduced and neuronal density was restored by melatonin. Considering the ease with which melatonin enters the brain, these results, along with previous observations, suggest that melatonin may be useful in combating free radical-induced neuronal injury that is a result of lead toxicity.     

Matrix metalloproteinase-9 activity increased by two different types of epileptic seizures that do not induce neuronal death: A possible role in homeostatic synaptic plasticity

Matrix metalloproteases (MMPs) degrade or modify extracellular matrix or membrane-bound proteins in the brain. MMP-2 and MMP-9 are activated by treatments that result in a sustained neuronal depolarization and are thought to contribute to neuronal death and structural remodeling. At the synapse, MMP actions on extracellular proteins contribute to changes in synaptic efficacy during learning paradigms. They are also activated during epileptic seizures, and MMP-9 has been associated with the establishment of aberrant synaptic connections after neuronal death induced by kainate treatment. It remains unclear whether MMPs are activated by epileptic activities that do not induce cell death. Here we examine this point in two animal models of epilepsy that do not involve extensive cell damage. We detected an elevation of MMP-9 enzymatic activity in cortical regions of secondary generalization after focal seizures induced by 4-aminopyridine (4-AP) application in rats. Pro-MMP-9 levels were also higher in Wistar Glaxo Rijswijk (WAG/Rij) rats, a genetic model of generalized absence epilepsy, than they were in Sprague–Dawley rats, and this elevation was correlated with diurnally occurring spike-wave-discharges in WAG/Rij rats. The increased enzymatic activity of MMP-9 in these two different epilepsy models is associated with synchronized neuronal activity that does not induce widespread cell death. In these epilepsy models MMP-9 induction may therefore be associated with functions such as homeostatic synaptic plasticity rather than neuronal death.     

Enhanced Assymetrical Noradrenergic Transmission in the Olfactory Bulb of Deoxycorticosterone Acetate-Salt Hypertensive Rats

The ablation of olfactory bulb induces critical changes in dopamine, and monoamine oxidase activity in the brain stem. Growing evidence supports the participation of this telencephalic region in the regulation blood pressure and cardiovascular activity but little is known about its contribution to hypertension. We have previously reported that in the olfactory bulb of normotensive rats endothelins enhance noradrenergic activity by increasing tyrosine hydroxylase activity and norepinephrine release. In the present study we sought to establish the status of noradrenergic activity in the olfactory bulb of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Different steps in norepinephrine transmission including tyrosine hydroxylase activity, neuronal norepinephrine release and uptake were assessed in the left and right olfactory bulb of DOCA-salt hypertensive rats. Increased tyrosine hydroxylase activity, and decreased neuronal norepinephrine uptake were observed in the olfactory bulb of DOCA-salt hypertensive rats. Furthermore the expression of tyrosine hydroxylase and its phosphorylated forms were also augmented. Intriguingly, asymmetrical responses between the right and left olfactory bulb of normotensive and hypertensive rats were observed. Neuronal norepinephrine release was increased in the right but not in the left olfactory bulb of DOCA-salt hypertensive rats, whereas non asymmetrical differences were observed in normotensive animals. Present findings indicate that the olfactory bulb of hypertensive rats show an asymmetrical increase in norepinephrine activity. The observed changes in noradrenergic transmission may likely contribute to the onset and/or progression of hypertension in this animal model.     

Protective effect of melatonin on 3-NP induced striatal interneuron injury in rats

To confirm the effect of melatonin on 3-nitropropionic acid (3-NP)-induced striatal interneuron injury in rats, behavioral test, histology, immunohistochemistry and Western blotting were respectively used to characterize the behavioral changes of experimental animals in motor and cognition, the morphological changes of striatal interneurons and the expression level of protein markers induced by 3-NP. The results showed that (1) 3-NP induced dysfunction of experimental animals in movement, motor coordination and cognition could be relieved by melatonin treatment; (2) The 3-NP-induced lesion area was unvaryingly in dorsolateral striatum, with almost all neuronal loss in the lesion core, however, lots of neurons survived after melatonin treatment; (3) Immunohistochemical staining of the four interneuron types (parvalbuminergic, cholinergic, calretinergic, and neuropeptide Y-neuronal nitric oxide synthase co-containing) showed that, in the lesion core of 3-NP group, loss of the four interneuron types was obvious, but in transition zone, the processes and varicosities of calretinergic, and neuropeptide Y- neuronal nitric oxide synthase co-containing interneurons increased significantly. Melatonin treatment reduced the loss of the four interneuron types in the lesion core, and inhibited the increase of processes and varicosities in the transition zone; (4) Consistent with above results, the expression level of five interneuron protein markers were significantly increased in the striatum after melatonin treatment. Notably, in both the transition zone and the lesion core induced by 3-NP, TUNEL-positive cells were detected, but decreased significantly after melatonin treatment. The present results indicate that melatonin effectively protects the striatal neurons against the injury induced by 3-NP in rats.     

The Responses of Neurons of the Somatosensory Cortex to Stimulation of the Posterior Thalamus (PO) in WAG/Rij Rats Genetically Predisposed to Absence Epilepsy

In genetically predisposed WAG/Rij rats and healthy Wistar rats, we studied functioning of the paralemniscal region of the thalamo-cortical system. The responses of neurons of the somatosensory cortex to single electrical stimulation of the posterior nucleus of the thalamus were recorded in two- to three-monthold rats within the period when the epileptic activity was not developed. We revealed lower number of shortterm inhibitory responses in WAG/Rij rats as compared to Wistar rats. This may create preconditions for the spreading of spike-wave activity in the somatosensory cortex, which is an electrophysiological sign of absence epilepsy.     

Gastric electrical stimulation parameter dependently alters ventral medial hypothalamic activity and feeding in obese rats

Gastric electrical stimulation (GES) has been used to treat obesity with unclear mechanisms and limited parameter ranges. This study explores effects of GES parameters on ventral medial hypothalamic (VMH) activity, feeding, and body weight in diet-induced obese (DIO) rats. For experiment 1, discharge rates were recorded in 39 gastric distension-responsive (GD-R) neurons in 12 DIO rats. Basal rates were compared with rates under GES using varied pulse amplitudes, widths, frequencies, and train-on times. For experiment 2, a crossover experiment in 16 DIO rats measured food intake and weight effects of GES pulse width, the parameter with the steepest neuronal response gradient in experiment 1. Treatments were sham and 0.5-, 2.0-, and 5.0-ms pulse GES. In experiment 1, 11 of 13 GES parameter sets tested produced significantly (P < 0.05) altered discharge rates of GD-R neurons. Increases in pulse amplitude (P < 0.05) and width (P < 0.0001) produced significant upward linear trends in response over the range tested, with the trend being strongest for pulse width. In experiment 2, over 4 days of 0.5-, 2.0-, and 5.0-ms GES treatment, food intake was 9.6% (P < 0.05), 21.0% (P < 0.0001), and 47.3% (P < 0.0001) lower than under sham-GES, whereas body weight changes were 0.7 (P = 0.48), 2.2 (P < 0.05), and 3.5 (P < 0.002) percentage points lower, respectively. We concluded that GES pulse width increases had the largest effect on VMH neuronal activity, and these effects were paralleled by pulse width-dependent reductions in food intake and body weight. Lengthening pulse width beyond the range used in prior clinical studies may be critical to making GES a viable obesity treatment.     

Day-night differences in the response of the pineal gland to swimming stress

The effect of swimming stress on pineal N-acetyltransferase activity, hydroxyindole-O-methyltransferase (HIOMT) activity, and melatonin content was studied during the day and night in adult male rats. At night, elevated pineal activity was suppressed by light exposure before the animals swam. During the day, swimming for 2 hr did not stimulate NAT activity unless the animals were pretreated with desmethylimipramine (DMI), a norepinephrine uptake blocker. Pineal melatonin content after daytime swimming exhibited a weak rise, unless DMI was injected, in which case melatonin levels showed a highly significant increase. Swimming at night caused a greater (compared to daytime levels) increase in NAT activity in both noninjected and DMI-injected rats. Melatonin levels at night were highly significantly stimulated (compared to daytime values) even without pretreatment of the rats with DMI. The greater response of the rat pineal to swimming stress at night may relate either to an increase in the number of beta-adrenergic receptors in the pinealocyte membrane at night or to a reduced capacity of the sympathetic neurons in the pineal to take up excess circulating catecholamines. Pineal HIOMT activity was not influenced by swimming (with or without DMI) either during the day or at night.     

Melatonin does not produce sedation in rats: A chronobiological study

ABSTRACT

Background: Melatonin has been associated with a wide variety of cellular, neuroendocrine, and neurophysiological processes. Clinical studies have reported the use of melatonin as an agent that exerts sedative-hypnotic effects. However, evidence of the sedative-hypnotic effects of different doses of melatonin is inconsistent, and available data regarding its night/day-time sedative effects are limited. The purpose of this study was to evaluate the effects of melatonin administered at different times of day on the magnitude of the sedative-hypnotic activity of different melatonin doses (5, 10, 30, and 50 mg/kg) in rats.

Methods: Sedation was assessed in Wistar rats behaviorally, using rota-rod, spontaneous locomotor activity, and fixed-bar tests at different times of day (ZT4, ZT10, ZT16, and ZT22).

Results: Our results showed that, compared to trazodone, acute and chronic dosing of ≤5 mg melatonin produced mild, transient sedative effects, mainly in the light period. Nevertheless, doses of ≥10 mg/kg did not cause sustained sedative effects.

Conclusion: These results suggest that melatonin may be used for sedation induction, mainly in preoperative patients.     

In vivo catechol activity in the rat locus coeruleus following different nociceptive stimuli and naloxone.

The nucleus locus coeruleus (LC) has been implicated in the processing of spinal reflexes following noxious stimuli. It has been demonstrated that noxious stimuli activate LC neuronal firing, but little is known about the neurochemical changes that might occur following such activation. To determine the effects of different noxious stimuli on LC neuronal activity, anaesthetized rats were exposed to mechanical (tail pinch), thermal (55 degrees C water), and chemical (5% Formalin injected in the hind paw) stimuli; the catechol oxidation current (CA.OC), an index of noradrenergic neuronal activity, in the locus coeruleus was monitored using differential normal pulse voltammetry. In addition, the effect of the opioid antagonist naloxone on the CA.OC in the LC was examined. Exposure to both mechanical and chemical stimuli significantly increased CA.OC indicating an increase in LC noradrenergic neuronal activity, while the thermal stimulus had no effect. Treatment with naloxone (1 mg/kg i.v.) had no effect on CA.OC in the LC. The results show a differential responsiveness of LC noradrenergic neurons to different modes of noxious stimuli and fail to demonstrate a tonic opioid regulation of these neurons in the anaesthetized rat.     

Age-related decrease in omega conotoxin binding to rat cardiac synaptosomes.

A cardiac synaptosomal preparation developed by this laboratory was used to study neuronal calcium channels in aging rat heart. Ca2+ channels were quantified by measuring binding of iodinated omega conotoxin, which is reported to specifically block neuronal Ca2+ channels. We determined the binding of [125I]-omega conotoxin GVIA to a synaptosomal preparation from the hearts of 6- and 24-month-old male Fisher 344 rats. The maximum number of binding sites (Bmax +/- SD, fmol/mg protein) is lower in preparations from 24-month (2.2 +/- 0.6) than from 6-month (3.4 +/- 0.7)-old rats. This decrease in number of binding sites suggests an age-related reduction in the number of neuronal calcium channels. Since calcium is essential for exocytotic release of norepinephrine and is made available intracellularly through neuronal calcium channels, the reduction in neuronal calcium channel number may explain, in part, our previous observations of diminished release of norepinephrine in senescent hearts.     

Analgesic activity of morphiceptin, beta-casomorphin-4, and deltakephalin in normotensive Wistar-Glaxo and spontaneously hypertensive rats

The effects of intraventricular injection of beta-casomorphin-4, morphiceptin and deltakephalin (DTLET) on hot water tail flick and tail compression responses were investigated in Wistar Albino Glaxo (WAG) and spontaneously hypertensive rats (SHR). The effects of the mu agonist morphiceptin (20 nmol/rat), as assessed by the tail compression test, were significantly greater in SHR rats but did not differ between both strains when measured by tail flick latency. Opioid agonist deltakephalin (2 nmol/rat) in both tests elicited stronger analgesic effects in SHR as compared to WAG and these effects were blocked by naloxone in both tests used. beta-Casomorphin-4 exhibits moderate activity for mu receptors. In the tail flick test peptide (60 nmol/rat) produced an increase in latencies in SHR rats that was significantly greater than was observed in WAG rats. Naloxone pretreatment abolished the analgesic activity of beta-casomorphin-4 solely in the tail compression test in SHR. Analysis of the slopes of the dose-response curves seems to suggest that differences between the activity of these opioid peptides in SHR and WAG rats are based on a difference in the density and affinity of the subpopulation of the opioid receptors in these strains of rats.     

Depression-like changes in behavior and c-fos gene expression in dopaminergic brain structures in WAG/Rij rats

In WAG/Rij rats with genetic absence epilepsy, inborn changes in behavior were observed such as decreased level of locomotion, exploratory activity, and grooming reactions in the open-field test, increased immobility in the forced-swimming test, and decreased sucrose consumption (anhedonia) as compared to Wistar rats completely lacking in seizure pathology. These behavioral alterations in WAG/Rij rats resemble the symptoms of human depression (psychomotor retardation, depressed mood, and anhedonia). No significant behavioral changes were found in the light-dark choice, social interaction, and elevated plus-maze tests. This suggests the absence of increased anxiety in WAG/Rij rats. In contrast to Wistar, WAG/Rij rats were sensitive only to chronic treatment with antidepressant imipramine like depressive patients. Behavioral "despair" induced by forced swimming led to C-fos gene expression in three brain structures (frontal cortex, nucleus accumbens, and striatum), which are, respectively, terminal regions of three dopaminergic brain systems (mesocortical, mesolimbc, and nigrostriatal). c-fos gene expression in the brain of WAG/Rij rats was substantially different from that in the brain of Wistar rats in both intensity (in WAG/Rij the c-fos gene expression was higher than in Wistar rats in all involved brain structures) and its distribution between the structures. The results suggest that WAG/Rij strain is a new experimental (genetic) model of absence epilepsy-related depression unassociated with increased anxiety.     

Does naloxone have functional significant activity on medial thalamic neurons? microiontophoretical study

Local administration (microiontophoretically) of naloxone was tested in 57 parafascicularis thalamic (PF) neurons of morphine-naive and morphine-dependent rats. In morphine-naive rats microiontophoretic applications of naloxone induced changes in 52% of the PF neurons. Reduction in neuronal activity was observed in the majority of them; this reduction phenomena exhibited dose response characteristics, i.e., each incremental naloxone dose caused further decrease of the neuronal discharges. In morphine-dependent animals, 64% of the PF neurons were affected. The changes seen after naloxone were mainly increases of electrical discharges (i.e. the opposite effects obtained in morphine-naive animals).     

Dynamic patterns of correlated activity in the prefrontal cortex encode information about social behavior

New technologies make it possible to measure activity from many neurons simultaneously. One approach is to analyze simultaneously recorded neurons individually, then group together neurons which increase their activity during similar behaviors into an “ensemble.” However, this notion of an ensemble ignores the ability of neurons to act collectively and encode and transmit information in ways that are not reflected by their individual activity levels. We used microendoscopic GCaMP imaging to measure prefrontal activity while mice were either alone or engaged in social interaction. We developed an approach that combines a neural network classifier and surrogate (shuffled) datasets to characterize how neurons synergistically transmit information about social behavior. Notably, unlike optimal linear classifiers, a neural network classifier with a single linear hidden layer can discriminate network states which differ solely in patterns of coactivity, and not in the activity levels of individual neurons. Using this approach, we found that surrogate datasets which preserve behaviorally specific patterns of coactivity (correlations) outperform those which preserve behaviorally driven changes in activity levels but not correlated activity. Thus, social behavior elicits increases in correlated activity that are not explained simply by the activity levels of the underlying neurons, and prefrontal neurons act collectively to transmit information about socialization via these correlations. Notably, this ability of correlated activity to enhance the information transmitted by neuronal ensembles is diminished in mice lacking the autism-associated gene Shank3. These results show that synergy is an important concept for the coding of social behavior which can be disrupted in disease states, reveal a specific mechanism underlying this synergy (social behavior increases correlated activity within specific ensembles), and outline methods for studying how neurons within an ensemble can work together to encode information.

Behaviorally-specific patterns of correlated activity between prefrontal neurons normally enhance the information that neuronal ensembles transmit about social behavior. This study shows that in a mouse model of autism, individual neurons continue to encode social information, but this additional information carried by patterns of correlated activity is lost.     

Age-related changes in 24-hour rhythms of norepinephrine content and serotonin turnover in rat pineal gland: effect of melatonin treatment

The 24-hour rhythms of pineal norepinephrine (NE) content and serotonin (5-HT) turnover [estimated from the ratio of 5-hydroxyindoleacetic acid (5-HIAA) to 5-HT] were studied in young (2 months) and aged (18-20 months) Wistar rats killed at 6 different time points throughout a 24-hour cycle. In the first study, significant changes dependent on the time of day were identified, with acrophases in the first half of the activity span for both parameters. Old rats showed significantly smaller mesor and amplitude of the 24-hour rhythm of pineal NE content. They also showed decreased amplitude of the pineal 5-HT turnover rhythm, in the absence of changes in mesor. In old rats, pineal 5-HT and 5-HIAA concentrations were 41-47% of those found in young rats. In a second study, young and old rats received daily intraperitoneal injections of melatonin (30 microg) or vehicle for 11 days at 19.00 h (i.e. 11 h after light on). Analyzed as a main factor in a factorial analysis of variance, both pineal NE content and 5-HT turnover decreased in old rats while pineal 5-HT turnover increased after melatonin treatment. Melatonin treatment augmented the amplitude of the 24-hour rhythm of pineal NE content by 120 and 52% in young and old rats, respectively. The amplitude of the 24-hour rhythm of pineal 5-HT turnover almost doubled after melatonin treatment in young rats and did not change in old rats. Melatonin injection did not modify the rhythm's acrophase. The results indicate that old rats had lower amplitude and lower mesor values of 24-hour variations in pineal NE content and 5-HT turnover. Melatonin treatment only partly restored pineal NE content and was devoid of activity on pineal 5-HT turnover and 5-HT and 5-HIAA concentration in old rats. Impairment of pineal melatonin synthesizing capacity and intrapineal responses to melatonin may underlie pineal aging in rats.     

Effect of melatonin and epithalamin on activity of marker enzymes in the cell membrane in the forebrain of rats under acute hypoxia

The effects of a single-shot intraperitoneally administration of melatonin in a dose of 1 mg per kg body weight and epithalamin in a dose of 2.5 mg per kg body weight on the activities of Na+, K(+)-ATPase and 5'-nucleotidase were investigated in the forebrain of juvenile male white rats under the acute hypobaric hypoxia. The melatonin and epithalamin administration against the background of acute hypoxia prevented an acute hypoxia inducing decrease in the activity of Na+, K(+)-ATPase as well as increased in the activity of 5'-nucleotidase. Such effects of pineal hormones can promote antihypoxic protection of neurons.     

Short-term regulation of tyrosine hydroxylase in tonically-active and in tonically-inactive dopamine neurons: effects of haloperidol and protein phosphorylation

Dopamine (DA)-containing neurons of retina were employed as an experimental model for studying the short-term regulation of tyrosine hydroxylase (TH) in tonically-active and tonically-inactive neurons. These DA-containing neurons are trans-synaptically activated by light. Two mechanisms have been observed in this system for regulation of TH activity. A short-term activation of TH that is characterized by a decreased apparent Km for pteridine cofactors occurs in response to rapid increases of neuronal activity. A second mechanism occurs in response to prolonged, tonic changes of neuronal activity and is characterized by changes of Vmax. Both the Km changes and Vmax changes represent changes of specific activity of TH rather than enzyme induction. To determine the effects of short-term increases of neuronal activity on TH in tonically-active and tonically-inactive neurons, the effects of acute administration of haloperidol were examined in rats that were continuously light-exposed or light-deprived for 4 days. Haloperidol increased TH activity in both light-exposed and light-deprived retinas. The drug elicited the same percent stimulation in both experimental conditions. However, because the basal activity of TH was higher in the light-exposed than the light-deprived retinas, the absolute increase of TH specific activity was greater in the light-exposed samples. The effect of protein phosphorylation on TH activity in extracts of chronically light-exposed or light-deprived retinas was also examined to determine if the differences in the response to haloperidol might be due to a difference in the amount of TH available for short-term activation. Phosphorylation by endogenous cyclic AMP-dependent protein kinase (APK) or by purified catalytic subunit of APK resulted in larger increases of TH specific activity in extracts of light-exposed retinas than in those of light-deprived retinas. As was observed for haloperidol-induced activation, the percent stimulation elicited by phosphorylation was similar in extracts of light-exposed and light-deprived retinas. These observations suggest that more enzyme is available for short-term activation in tonically-active neurons than in those that are tonically inactive. A hypothetical model is proposed in which TH exists in active and inactive forms, the ratio of which depends on the tonic level of neuronal activity.