THE EFFECTS OF REPEATED-LYSERGIC ACID DIETHYLAMIDE INJECTIONS ON CATECHOLAMINE LEVELS AND TYROSINE HYDROXYLASE ACTIVITY IN RAT BRAIN REGIONS

Daily injections of 100 μg/kg of d -lysergic acid diethylamide (LSD) for 14 days produced a significant decrease in the dopamine level in rat brain corpus striatum which was still apparent 15 days after the last LSD treatment. Further LSD injections did not change the amount of dopamine depletion. In cerebral cortex, 14 days of LSD injections produced a significant decrease in the norepinephrine level and a significant increase in tyrosine hydroxylase activity. The elevated tyrosine hydroxylase activity was still present 15 days after the final LSD injection but only in those animals receiving daily vehicle injections during this period. Pre-treatment of rats with daily saline injections for 2 weeks before the 2 week period of LSD treatment prevented both the reduced norepinephrine content and elevated tyrosine hydroxylase activity usually found 24 h after the last LSD injection.     

Extinction-dependent alterations in corticostriatal mGluR2/3 and mGluR7 receptors following chronic methamphetamine self-administration in rats

Methamphetamine (meth) is a highly addictive and widely abused psychostimulant. Repeated use of meth can quickly lead to dependence, and may be accompanied by a variety of persistent psychiatric symptoms and cognitive impairments. The neuroadaptations underlying motivational and cognitive deficits produced by chronic meth intake remain poorly understood. Altered glutamate neurotransmission within the prefrontal cortex (PFC) and striatum has been linked to both persistent drug-seeking and cognitive dysfunction. Therefore, the current study investigated changes in presynaptic mGluR receptors within corticostriatal circuitry after extended meth self-administration. Rats self-administered meth (or received yoked-saline) in 1 hr/day sessions for 7 days (short-access) followed by 14 days of 6 hrs/day (long-access). Rats displayed a progressive escalation of daily meth intake up to 6 mg/kg per day. After cessation of meth self-administration, rats underwent daily extinction or abstinence without extinction training for 14 days before being euthanized. Synaptosomes from the medial PFC, nucleus accumbens (NAc), and the dorsal striatum (dSTR) were isolated and labeled with membrane-impermeable biotin in order to measure surface mGluR2/3 and mGluR7 receptors. Extended access to meth self-administration followed by abstinence decreased surface and total levels of mGluR2/3 receptors in the NAc and dSTR, while in the PFC, only a loss of surface mGluR2/3 and mGluR7 receptors was detected. Daily extinction trials reversed the downregulation of mGluR2/3 receptors in the NAc and dSTR and mGluR7 in the PFC, but downregulation of surface mGluR2/3 receptors in the PFC was present regardless of post-meth experience. Thus, extinction learning can selectively restore some populations of downregulated mGluRs after prolonged exposure to meth. The present findings could have implications for our understanding of the persistence (or recovery) of meth-induced motivational and cognitive deficits.     

Melatonin attenuates methamphetamine-induced reduction of tyrosine hydroxylase, synaptophysin and growth-associated protein-43 levels in the neonatal rat brain

Methamphetamine (METH) is a most commonly abused drug which damages nerve terminals by causing formation of reactive oxygen species (ROS), apoptosis, and finally neuronal damage. Fetal exposure to neurotoxic METH causes significant behavioral effects. The developing fetus is substantially deficient in most antioxidative enzymes, and may therefore be at high risk from both endogenous and drug-enhanced oxidative stress. Little is known about the effects of METH on vesicular proteins such as synaptophysin and growth-associated protein 43 (GAP-43) in the immature brain. The present study attempted to investigate the effects of METH-induced neurotoxicity in the dopaminergic system of the neonatal rat brain. Neonatal rats were subcutaneously exposed to 5–10 mg/kg METH daily from postnatal day 4–10 for 7 consecutive days. The results showed that tyrosine hydroxylase enzyme levels were significantly decreased in the dorsal striatum, prefrontal cortex, nucleus accumbens and substantia nigra, synaptophysin levels decreased in the striatum and prefrontal cortex and growth-associated protein-43 (GAP-43) levels significantly decreased in the nucleus accumbens of neonatal rats. Pretreatment with 2 mg/kg melatonin 30 min prior to METH administration prevented METH-induced reduction in tyrosine hydroxylase, synaptophysin and growth-associated protein-43 protein levels in different brain regions. These results suggest that melatonin provides a protective effect against METH-induced nerve terminal degeneration in the immature rat brain probably via its antioxidant properties.     

Evidence for the role of brain biogenic amines in depressed motor activity seen in chemically thyroidectomized rats.

Abstract— The effects of exposure to an antithyroid drug, methimazole, on brain tyrosine hydroxylase and tryptophan hydroxylase activity, as well as the levels of norepinephrine, dopamine, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid have been investigated in maturing brain. Daily treatment of neonatal rats with methimazole for 30 days induced chemical thyroidectomy as evidenced by significant impairment of body and brain growth. The activities or brain tyrosine hydroxylase and tryptophan hydroxylase and the levels of norepinephrine, dopamine and 5-hydroxytryptamine were markedly altered in a dose- and time-dependent manner in methimazole-treated rats. Conversely, the concentration of brain 5-hydroxyindoleacetic acid was elevated (46%) by methimazole administration. Treatment with the antithyroid drug failed to exert any significant effect on the endogenous levels of brain tryptophan, as well as on the activity of the deaminating enzyme, monoamine oxidase. Administration of triiodothyronine (25 or 100 μg/100 g) to hypothyroid rats for 30 days did not produce any appreciable effect upon the neurochemical parameters related to either norepinephrine or 5-hydroxytryptamine mctabolism. However, increasing the dose of triiodothyronine to 250 μg/100 g significantly elevated the levels of norepinephrine and 5-hydroxytryplamine as well as the activities of the two synthesizing enzymes, tyrosine hydroxylase and tryptophan hydroxylase. Brain 5-hydroxyindoleacetic acid levels were restored to normal values in thyroid hormone-deficient rats treated with this higher dose of triiodothyronine. Evidencc also was obtained to show that chemical thyroidectomy suppressed the spontancous locomotor activity in neonatal rats; the changes being apparent at 15 days of age. Our data support the view that thyroid hormone in neonatal life displays an important regulatory effect on the metabolism of norepinephrine, dopamine and 5-hydroxytryptamine. Since certain amines have been known to be implicated as the neurochemical substrates for behavioural arousal, it is conceivable that the observed hypoactivity in methimazolc-treated rats may, at least in part, be related to impaired maturation of norepinephrine and dopamine-synthesizing systems in brains of cretinous rats.     

Dicyclohexylphthalate causes hyperactivity in the rat concomitantly with impairment of tyrosine hydroxylase immunoreactivity

Endocrine disruptors possibly exert effects on neuronal functions leading, in particular, to behavioural alterations. In this study, we examined the effects of dicyclohexylphthalate (DCHP), an endocrine disruptor, on rat behavioural and cellular responses. Single intracisternal administration of DCHP (0.87-87 nmol) into 5-day-old male Wistar rats caused significant hyperactivity at 4-5 weeks of age. It was about 1.4-fold more active in the nocturnal phase after administration of 87 nmol of DCHP than control rats (p < 0.001). The response had a tendency to be dose-dependent. Based on DNA macoarray analyses, DCHP down-regulated the levels of gene expression of the dopamine D4 receptor at 4 weeks old in both the midbrain and the striatum, and the dopamine transporter in the midbrain at 8 weeks old 1.7- to 2-fold. The gene expression of several subtypes of glutamate receptors was facilitated in the striatum at 4 weeks old and in the midbrain at 8 weeks old. Some normalization and/or compensatory changes seemed to occur in gene expression of GABA or glycine transmission. Furthermore, DCHP abolished immunoreactivity of tyrosine hydroxylase in the substantia nigra at 8 weeks of age, where TUNEL-positive cells were seen. We conclude that DCHP affected the developing rat brain, resulting in hyperactivity, probably as a result of degeneration of mesencephalic tyrosine hydroxylase rather than alteration of the level of gene expression.     

CADMIUM ALTERS BEHAVIOUR AND THE BIOSYNTHETIC CAPACITY FOR CATECHOLAMINES AND SEROTONIN IN NEONATAL RAT BRAIN1

Abstract— Daily exposure to cadmium (10 μg/100g) for 30 days since birth significantly increased spontaneous locomotor activity as well as striatal tyrosine hydroxylase and mid-brain tryptophan hydroxylase. The endogenous levels of norepinephrine, dopamine and serotonin failed to change in various brain regions of cadmium-treated rats. In contrast, the concentration of 5-hydroxyindoleacetic acid tended to rise but was significantly different from controls only in the mid-brain region. The data suggest that cadmium treatment in early life increased the synthesis and physiological utilization of these putative transmitters which in turn probably altered locomotor performance. Increasing the dose of cadmium to 100 μg/100 g for 30 days decreased body weight (by 19%) and produced slight increases in the turnover of brain amines. However, the rise was not dose-dependent. Furthermore, the locomotor activity remained the same as that seen in rats treated with the low dose of cadmium. The levels of dopamine in hypothalamus and that of norepinephrine in several brain regions examined were enhanced. This could in part, be attributed to decreased (12%) activity of catechol-O-methyl transferase enzyme. Administration of the high dose of cadmium produced significant increases in 5-hydroxyindoleacetic acid level. Data suggest that cadmium acts at some step in the sequence of intracellular events that leads to increased synthesis and presumably turnover of brain catecholamines and serotonin. Since high dosage of this heavy metal failed to produce a dose-dependent change in locomotor activity, it is not possible to impute any casual role for these amines in the production of hyperactivity seen in cadmium-treated rats.     

Increased uptake sites for serotonin and dopamine with decreased S2 serotonin receptors in microencephalic rat brain

Methylazoxymethanol (MAM)-induced cerebral hypoplasia resulted in a significant increase in densities of both serotonin uptake sites in frontal cortex and dopamine uptake sites in striatum, suggesting serotonergic and dopaminergic axon terminals were compressed in the smaller brain volumes. The density of S2 serotonin receptors in MAM-lesioned frontal cortex was decreased probably due to down-regulation, while densities of D1 and D2 dopamine receptors in striatum were identical between MAM-lesioned rats and control rats.     

Region - specific alterations in tyrosine hydroxylase activity in rats exposed to lead

Previous studies from our laboratory showed that subchronic exposure to low levels of Pb resulted in significant decrease in dopamine (DA) content, attenuation of stimulus-induced release of DA in the dopaminergic projection area of nucleus accumbens (NA), and alterations in tyrosine hydroxylase (TH) activity in rat whole brain homogenates. The present study reported here was conducted to assess the functional integrity of DA synthesis in different brain regions of rats subchronically (90-days) exposed to 50 ppm Pb by measuring the activity of the rate limiting enzyme, tyrosine hydroxylase, in seven brain regions. In Pb-exposed rats, TH activity was reduced in two of the seven brain regions investigated, i.e., nucleus accumbens (42% reduction) and frontal cortex (61% reduction) when compared to controls. In contrast, Pb exposure did not affect the TH activity in cerebellum, brainstem, hippocampus, hypothalamus and striatum. The changes in TH activity in nucleus accumbens (NA) and frontal cortex (FC) in Pb-exposed rats were further confirmed by Western blot analysis using TH polyclonal antibody. Collectively, these results indicate that low level subchronic Pb exposure may affect TH protein in these brain regions.     

Methamphetamine-induced spectrin proteolysis in the rat striatum

Methamphetamine (METH) is a widely abused psychostimulant. Multiple high doses of METH cause long-term toxicity to dopamine (DA) and serotonin (5-HT) nerve terminals in the brain, as evidenced by decreases in DA and 5-HT content, decreases in tyrosine and tryptophan hydroxylase activities, decreases in DA and 5-HT re-uptake sites, and nerve terminal degeneration. Multiple high doses of METH are known to elicit a rapid increase in DA release and hyperthermia. Although METH also produces a delayed and sustained rise in glutamate, no studies have shown whether METH produces structural evidence of excitotoxicity in striatum, or identified the receptors that mediate this toxicity directly, independent of alterations in METH-induced hyperthermia. These experiments investigated whether METH can cause excitotoxicity as evidenced by cytoskeletal protein breakdown in a glutamate receptor-dependent manner. METH increased calpain-mediated spectrin proteolysis in the rat striatum 5 and 7 days after METH administration without affecting caspase 3-dependent spectrin breakdown. This effect was completely blocked with the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, GYKI 52466, but not the NMDA receptor antagonist, MK-801. However, AMPA or NMDA receptor antagonism did not attenuate the METH-induced depletions of the dopamine transporter (DAT). Independent mechanisms involved in mediating spectrin proteolysis and DAT protein loss are discussed.     

Short-term effect of stress on tyrosine hydroxylase activity

The short-term influences of stress on the activities of tyrosine hydroxylase in vivo and in vitro were examined in mice. The in vivo tyrosine hydroxylase activity was estimated by the rate of dopa accumulation which was measured at 30 min after the injection of NSD-1015 (100 mg kg), an aromatic l-amino acid decarboxylase inhibitor, intraperitoneally and was compared with tyrosine hydroxylase activity measured in vitro. For the in vivo assay, both the accumulation of dopa (tyrosine hydroxylase activity) and that of 5-hydroxytryptophan (tryptophan hydroxylase activity) and the levels of monoamines and the metabolites (noradrenalin, adrenalin, dopamine, normetanephrine, 3-methoxytyramine and serotonin) and those of precursor amino acids, tyrosine and tryptophan, were investigated in ten different brain regions and in adrenals. The amount of dopa accumulation in the brain as a consequence of decarboxylase inhibition, in vivo tyrosine hydroxylase activity, was significantly increased by stress, in nerve terminals (striatum, limbic brain, hypothalamus, cerebral cortex and cerebellum) and also in adrenals. The effect of stress on tyrosine hydroxylase activity in vitro at a subsaturating concentration of 6-methyltetrahydropterin cofactor was also observed in nerve terminals (striatum, limbic brain, hypothalamus, and cerebral cortex). The amount of 5-hydroxytryptophan accumulation, the in vivo tryptophan hydroxylase activity, was also significantly increased in bulbus olfactorius, limbic brain, cerebral cortex, septum and lower brain stem. The influence of stress was also observed on the levels of precursor amino acids, tyrosine and tryptophan and monoamines in specific brain parts. These results suggest that the stress influences both catecholaminergic neurons and serotonergic neurons in nerve terminals in the brain. This effect was also observed on tyrosine hydroxylase activity in vitro in nerve terminals. However, in adrenals, the influence by stress was not observed on the in vitro activity, although dopa accumulation was increased.     

Neonatal hyperthyroidism: alterations in behavioural activity and the metabolism of brain norepinephrine and dopamine.

Daily administration of triiodothyronine (10 μg/100 g) to newborn rats for 30 days produced signs of hyperthyroidism which included accelerated development of physical and behavioural characteristics accompanying maturation. The hyperthyroid rats displayed progressive increases in spontaneous locomotor activity between 14–35 days, which remained elevated well above control levels even at 105 days. Exposure of developing rats to triiodothyronine increased the endogenous levels of striatal tyrosine and tyrosine hydroxylase as well as the concentration of dopamine in hypothalamus, pons-medulla, mid-brain, striatum and hippocampus. The concentration of striatal homovanillic acid and 3,4-dihydroxyphenylacetic acid was also increased in hyperthyroid rats. In contrast, the steady-state levels of norepinephrine remained unaltered resulting in a significant increase in dopamine to norepinephrine ratio in several regions of the brain examined. The elevated levels of dopamine metabolites (homovanillic acid and 3,4-dihydroxyphenylacetic acid) may be due to an increased turnover of dopamine. Our data suggest that increased thyroid hormone levels may lead to an enhanced synthesis as well as utilization of brain catecholamines which in turn may underlie the observed increases in spontaneous locomotor activity.     

Relationship between myelin production and dopamine synthesis in the PKU mouse brain

Phenylketonuria is caused by specific mutations in the phenylalanine hydroxylase gene and is characterized by elevated blood phenylalanine levels, hypomyelination in forebrain structures, reduced dopamine levels, and cognitive difficulties. To determine whether brain tyrosine levels and/or myelination play a role in the up-regulation of dopamine, phenylketonuric mice were placed on a low phenylalanine diet for 4 weeks and as blood phenylalanine levels dropped to normal, the relationships between phenylalanine, tyrosine, dopamine, myelin proteins, and axonal proteins in frontal cortex and striatum were determined using gas chromatography mass spectrometry, histology, and western blotting techniques. Blood phenylalanine rapidly decreased from an eight-fold elevation to near control levels, and blood tyrosine gradually rose from about 50% to near normal values. In frontal cortex and striatum, phenylalanine levels dropped to 2- and 1.5-fold elevations above control, respectively, and tyrosine levels increased but remained less than 70% of control in both structures. In frontal cortex, increases in dopamine and myelin basic protein occurred in a similar biphasic pattern, reaching near normal levels by week 4. In striatum, dopamine and MBP dramatically increased to near normal levels in the first week. Myelination was confirmed histologically and by western blot quantification of phosphorylated neurofilaments. In summary, our results showed: (i) an increase in dopamine despite low brain tyrosine levels and (ii) similar recovery patterns for myelination and dopamine. Since myelin/axonal interactions trigger signaling pathways that result in axonal maturation, we speculate that this interaction also may trigger signals that up-regulate neurotransmitter synthesis.     

Attenuation of estradiol on the reduction of striatal dopamine by amphetamine in ovariectomized rats

Amphetamine (AMPH) is a highly addictive drug of abuse which exhibits toxicity to dopaminergic neurons in long‐term abusers. Estrogen seems to show neuroprotection in dopamine (DA) deficit caused by AMPH. The present study was to investigate the effects of estradiol on the levels of striatal DA in ovariectomized (Ovx) rats treated with or without AMPH. Female rats were Ovx for 2 weeks before administration of AMPH (5 mg/kg/day, i.p.) with or without 17β‐estradiol benzoate (EB) (25 µg/kg/day, s.c.) for 7 days. The striatal tissues were collected, homogenized with DA mobile phase, and centrifuged. The concentrations of DA in the supernatants were detected by HPLC. The protein expressions of dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT‐2), and tyrosine hydroxylase (TH) were analyzed by Western blotting. The results indicated that AMPH could attenuate DA level significantly in striatum (P < 0.01). Comparing to control groups, administration of either EB or EB plus AMPH increased DA level (P < 0.01). The protein expression of striatal DAT was significant greater (P < 0.01) in rats treated with AMPH plus EB than AMPH treated animals. These results suggest that the DA levels in striatum can be enhanced by EB via an increase of DAT expression following administration of AMPH. J. Cell. Biochem. 108: 1318–1324, 2009. © 2009 Wiley‐Liss, Inc.     

Molecular neuroadaptations in the accumbens and ventral tegmental area during the first 90 days of forced abstinence from cocaine self-administration in rats

Cocaine self-administration is associated with a propensity to relapse in humans and reinstatement of drug seeking in rats after prolonged withdrawal periods. These behaviors are hypothesized to be mediated by molecular neuroadaptations within the mesolimbic dopamine system. However, in most studies of drug-induced neuroadaptations, cocaine was experimenter-delivered and molecular measurements were performed after short withdrawal periods. In the present study, rats were trained to self-administer intravenous cocaine or oral sucrose (a control non-drug reward) for 10 days (6-h/day) and were killed following 1, 30, or 90 days of reward withdrawal. Tissues from the accumbens and ventral tegmental area (VTA) were assayed for candidate molecular neuroadaptations, including enzyme activities of cAMP-dependent protein kinase (PKA) and adenylate cyclase (AC), and protein expression of cyclin-dependent kinase 5 (cdk5), tyrosine hydroxylase (TH) and glutamate receptor subunits (GluR1, GluR2 and NMDAR1). In the accumbens of cocaine-trained rats, GluR1 and NMDAR1 levels were increased on days 1 and 90, while GluR2 levels were increased on days 1 and 30, but not day 90; PKA activity levels were increased on days 1 and 30, but not day 90, while AC activity, TH and cdk5 levels were unaltered. In the VTA of cocaine-trained rats, NMDAR1 levels were increased for up to 90 days, while GluR2 levels were increased only on day 1; TH and Cdk5 levels were increased only on day 1, while PKA and AC activity levels were unaltered. Cocaine self-administration produces long-lasting molecular neuroadaptations in the VTA and accumbens that may underlie cocaine relapse during periods of abstinence.     

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.     

p53-Knockout Mice Are Protected Against the Long-Term Effects of Methamphetamine on Dopaminergic Terminals and Cell Bodies

Abstract: p53-knockout mice provide a useful model to test the role of p53 in the neurotoxic effects of drugs in vivo. To test the involvement of p53 in methamphetamine (METH)-induced toxicity, wild-type mice, as well as heterozygous and homozygous p53-knockout male mice, were administered four injections of three different doses (2.5, 5.0, and 10.0 mg/kg) of the drug given at 2-h intervals within the space of 1 day. METH caused a marked dose-dependent loss of dopamine transporters in both the striatum and the nucleus accumbens of wild-type mice killed 2 weeks after drug administration. However, this METH-induced decrease in dopamine transporters was attenuated in both homozygous and heterozygous p53-knockout mice, with homozygous animals showing significantly greater protection. The possibility for p53 involvement in METH-induced toxicity was also supported by the observation that METH caused marked increases in p53-like immunoreactivity in the striata of wild-type mice and very little change in heterozygous p53-knockout mice, whereas no p53-like immunostaining was detected in the homozygous p53-knockout mice. Further support for p53 involvement was provided by the fact that METH treatment caused significant decreases in dopamine transporter mRNA and the number of tyrosine hydroxylase-positive cells in the substantia nigra pars compacta and the ventral tegmental area of wild-type but not homozygous p53-knockout mice killed 2 weeks after cessation of METH administration. These results provide concordant evidence for a role of the tumor suppressor, p53, in the long-term deleterious effects of a drug acting on brain dopamine systems.     

Different roles of dopamine and serotonin in conditioned passive avoidance response of rats

Deamination of dopamine and serotonin by monoamine oxidase was studied in the prefrontal cortex, striatum, hippocampus and amygdaloid complex of the brain of rats during retrieval of conditioned passive avoidance response. Changes in the dopamine and serotonin metabolism were observed in different brain structures. A decrease in dopamine-deaminating activity of monoamine oxidase was found in the hippocampus, striatum and prefrontal cortex. At the same time, serotonin-deaminating activity of the enzyme was decreased in the striatum and increased in the amygdaloid complex, whereas it did not change in the prefrontal cortex and hippocampus. The observed changes in dopamine metabolism in the prefrontal cortex and hippocampus and serotonin metabolism in the amygdaloid complex indicate that dopamine and serotonin are involved in the regulation of two different processes mediating the memory trace retrieval. Dopamine is involved in neuronal mechanisms of information processes providing the strategy of behavior, whereas serotonin is related to emotional mechanisms of memory.     

Regulation of catecholamine synthesis in rat brain synaptosomes

Abstract— Catecholamine synthesis in synaptosomal preparations of rat striatum, cortex and brain stem was investigated. The striatum had much higher activity than either the cortex or brain stem. Equilibration of labelled tyrosine between tissue and incubation medium was completed within 2 min. The apparent K_m of tyrosine hydroxylase (EC 1.14.3a) and of the overall catecholamine synthetic pathway were both approximately 5 ± 10^?6m for tyrosine. The following amines were found to inhibit striatal dopamine synthesis: dopamine, 25% inhibition at 5 ± 10^?7m ; noradrenaline, 25% inhibition at 5 ± 10^?6m ;and serotonin, 30% inhibition at 10^?5m . The catecholamine-induced inhibition of synthesis was antagonized by pre-incubation with cocaine. Increasing the potassium concentration from 5 to 55 mm caused a release of amines into the medium which was accompanied by a 40% increase in dopamine synthesis, when synthesis was measured during the first 5 min of exposure to elevated potassium. These results indicate that synaptosomal catecholamine synthesis is inhibited by increases in intra-synaptosomal amine levels, and that short-term exposure to depolarizing concentrations of potassium can increase synthesis.