Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.16.2 (tyrosine hydroxylase)
 14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied the molecular and cellular mechanisms underlying the acute and chronic effects of opiate on neurons of the rat locus coeruleus (LC). Acutely, opiates inhibit LC neurons by activating K+ channels and inhibiting a novel sodium-dependent inward current. Both of these actions are mediated via pertussis toxin-sensitive G-proteins, and regulation of the sodium current occurs through inhibition of the cyclic AMP pathway. In contrast to the acute effects of opiates, chronic treatment of rats with opiates increases levels of specific G-protein subunits, adenylate cyclase, cyclic AMP-dependent protein kinase, and a number of phosphoproteins (including tyrosine hydroxylase) in this brain region. Electrophysiological data have provided direct support for the possibility that this upregulation of the cyclic AMP system contributes to opiate tolerance, dependence, and withdrawal exhibited by these noradrenergic LC neurons. As the adaptations in G-proteins and the cyclic AMP system appear to occur at least in part at the level of gene expression, current efforts are aimed at identifying the mechanisms by which opiates regulate the expression of these intracellular messenger proteins in the LC. These studies will lead to an improved understanding of the molecular and cellular basis of opiate addiction.
 ...
PMID:Molecular and cellular mechanisms of opiate action: studies in the rat locus coeruleus. 785 10

We have studied the role of second messenger and protein phosphorylation pathways in mediating changes in neuronal function associated with opiate addiction in the rat locus coeruleus. We have found that chronic opiates increase levels of the G-protein subunits Gi alpha and Go alpha, adenylate cyclase, cyclic AMP-dependent protein kinase, and a number of phosphoproteins (including tyrosine hydroxylase) in this brain region. Electrophysiological data have provided direct support for the view that this up-regulation of the cyclic AMP system contributes to opiate tolerance, dependence, and withdrawal exhibited by these neurons. As the adaptations in G-proteins and the cyclic AMP system appear to occur at least in part at the level of gene expression, current efforts are aimed at identifying the mechanisms, at the molecular level, by which opiates regulate the expression of these intracellular messenger proteins in the locus coeruleus. These studies will lead to an improved understanding of the biochemical basis of opiate addiction.
 ...
PMID:Second messenger and protein phosphorylation mechanisms underlying opiate addiction: studies in the rat locus coeruleus. 838 77

The mesolimbic dopamine system, which arises in the ventral tegmental area (VTA), is an important neural substrate for opiate reinforcement and addiction. Chronic exposure to opiates is known to produce biochemical adaptations in this brain region. We now show that these adaptations are associated with structural changes in VTA dopamine neurons. Individual VTA neurons in paraformaldehyde-fixed brain sections from control or morphine-treated rats were injected with the fluorescent dye Lucifer yellow. The identity of the injected cells as dopaminergic or nondopaminergic was determined by immunohistochemical labeling of the sections for tyrosine hydroxylase. Chronic morphine treatment resulted in a mean approximately 25% reduction in the area and perimeter of VTA dopamine neurons. This reduction in cell size was prevented by concomitant treatment of rats with naltrexone, an opioid receptor antagonist, as well as by intra-VTA infusion of brain-derived neurotrophic factor. In contrast, chronic morphine treatment did not alter the size of nondopaminergic neurons in the VTA, nor did it affect the total number of dopaminergic neurons in this brain region. The results of these studies provide direct evidence for structural alterations in VTA dopamine neurons as a consequence of chronic opiate exposure, which could contribute to changes in mesolimbic dopamine function associated with addiction.
 ...
PMID:Chronic morphine induces visible changes in the morphology of mesolimbic dopamine neurons. 885 33

Interactions between dopamine and glutamate play prominent roles in memory, addiction, and schizophrenia. Several lines of evidence have suggested that the ventral midbrain dopamine neurons that give rise to the major CNS dopaminergic projections may also be glutamatergic. To examine this possibility, we double immunostained ventral midbrain sections from rat and monkey for the dopamine-synthetic enzyme tyrosine hydroxylase and for glutamate; we found that most dopamine neurons immunostained for glutamate, both in rat and monkey. We then used postnatal cell culture to examine individual dopamine neurons. Again, most dopamine neurons immunostained for glutamate; they were also immunoreactive for phosphate-activated glutaminase, the major source of neurotransmitter glutamate. Inhibition of glutaminase reduced glutamate staining. In single-cell microculture, dopamine neurons gave rise to varicosities immunoreactive for both tyrosine hydroxylase and glutamate and others immunoreactive mainly for glutamate, which were found near the cell body. At the ultrastructural level, dopamine neurons formed occasional dopaminergic varicosities with symmetric synaptic specializations, but they more commonly formed nondopaminergic varicosities with asymmetric synaptic specializations. Stimulation of individual dopamine neurons evoked a fast glutamatergic autaptic EPSC that showed presynaptic inhibition caused by concomitant dopamine release. Thus, dopamine neurons may exert rapid synaptic actions via their glutamatergic synapses and slower modulatory actions via their dopaminergic synapses. Together with evidence for glutamate cotransmission in serotonergic raphe neurons and noradrenergic locus coeruleus neurons, the present results suggest that glutamatergic cotransmission may be the rule for central monoaminergic neurons.
 ...
PMID:Dopamine neurons make glutamatergic synapses in vitro. 961 34

Place conditioning paradigms are widely used for determining the motivational properties of drugs. Phencyclidine (PCP) has been a common drug of abuse during the past two decades and has a rewarding effect in animals. However, PCP produces place aversion in the conditioned place preference (CPP) task in animals. Here, we report the possible neuronal mechanisms of PCP-induced place aversion and preference in the CPP task in rodents. In naive rats and mice, PCP dose-dependently produced place aversion and PCP had a significant effect at the doses of 4 and 8 mg/kg in rats and mice, respectively. The aversive effect of PCP (4 mg/kg) in rats was significantly attenuated by ritanserin (3 and 10 mg/kg), a serotonin 15-HT2) receptor antagonist whereas the lesion of serotonergic (5-HTergic) neurons by 5,7-dihydroxytryptamine (100 micrograms i.c.v.) and alpha-methyl-rho-tyrosine (AMPT; 100 mg/kg), a tyrosine hydroxylase inhibitor, did not affect the aversive effect of PCP. In rats pretreated with PCP (10 mg/kg/day) for 14 days, tolerance was developed to PCP (4 mg/kg)-induced place aversion. In rats and mice pretreated with PCP (10 mg/kg/day) for 28 days, however, PCP dose-dependently produced place preference but not aversion. The preferred effect of PCP (8 mg/kg) in mice preteated with PCP (10 mg/kg/day for 28 days) was significantly attenuated by AMPT (100 mg/kg) and 6-hydroxydopamine (100 micrograms i.c.v.) a dopaminergic (DAergic) neurotoxin, but not by DSP-4 (30 mg/kg), a noradrenergic neurotoxin and ritanserin. In mice pretreated with methamphetamine (1 mg/kg/day) for 14 days, PCP (8 mg/kg) produced place preference. These findings suggest that 5-HTergic and DAergic systems are involved in the PCP-induced place aversion and preference, respectively, and some changes in the neuronal systems including DAergic systems, induced by repeated PCP treatment play a critical role in the addiction of PCP.
 ...
PMID:Neuronal mechanisms of phencyclidine-induced place aversion and preference in the conditioned place preference task. 981 6

Cocaine- and amphetamine-regulated transcript (CART) is a novel mRNA whose level of expression was found to be increased in the striatum after acute administration of psychomotor stimulants in rats. To define better the potential role of CART peptides in behavioural and physiologic changes induced by psychomotor stimulants, we analyzed the distribution, ultrastructural features, synaptic connectivity, and transmitter content of CART peptide-immunoreactive neurones in the nucleus accumbens in monkeys. Medium-sized CART peptide-immunoreactive neurones within a rich plexus of labelled varicosities were found mostly in the medial division of the shell of the nucleus accumbens in monkeys. At the electron microscope level, CART peptide immunoreactivity was exclusively associated with neuronal structures that included perikarya, dendrites, spines as well as nerve terminals packed with electron-lucent and dense-core vesicles. Most CART peptide-containing somata displayed the ultrastructural features of striatal output neurones. The majority of labelled terminals formed symmetric axodendritic synapses and displayed gamma-aminobutyric acid (GABA) immunoreactivity. CART peptide-immunoreactive somata were not immunoreactive for parvalbumin and somatostatin, two markers of striatal interneurones, nor for calbindin D-28k, a marker of a subpopulation of projection neurones. In double-immunostained sections, CART peptide-immunoreactive dendrites were found to be contacted by tyrosine hydroxylase-positive terminals which displayed the ultrastructural features of dopamine-containing boutons. These findings strongly suggest that CART peptides may be a cotransmitter with GABA in a subpopulation of projection neurones in the monkey accumbens. Furthermore, the fact that CART peptide-immunoreactive neurones receive direct synaptic inputs from dopaminergic afferents and are particularly abundant in the caudomedial division of the shell of the nucleus accumbens suggest that CART peptides might be involved in neuronal and behavioural changes that underlie addiction to psychomotor stimulants and feeding in primates.
 ...
PMID:CART peptide-immunoreactive neurones in the nucleus accumbens in monkeys: ultrastructural analysis, colocalization studies, and synaptic interactions with dopaminergic afferents. 1023 41

Catecholaminergic and/or cyclic AMP (cAMP) systems have been demonstrated to be involved in the development of drug dependence. We investigated the involvement of both systems in psychological dependence on phencyclidine (PCP) by using tyrosine hydroxylase (TH) heterozygous (TH+/-) and cAMP response element binding protein (CREB) binding protein (CBP) heterozygous (CBP+/-) mice. PCP (8 mg/kg) induced place preference in wild-type mice pretreated with PCP (10 mg/kg once a day for 28 days). In these mice, the level of cAMP in the striatum, but not in the thalamus, was increased one day after the last injection of PCP (10 mg/kg). In TH+/- and CBP+/- mice pretreated with PCP (10 mg/kg per day for 28 days), however, no PCP (8 mg/kg)-induced place preference was observed. The level of cAMP in the striatum was increased in CBP+/- mice, but not TH+/- mice. Furthermore, we have demonstrated that the place preference induced by PCP is attenuated by 6-hydroxydopamine, a dopaminergic neurotoxin, and (+) SCH-23390, a dopamine-D1 receptor antagonist, but not by DSP-4, a noradrenergic neurotoxin, and (-) sulpiride, a dopamine-D2 receptor antagonist. These findings suggest that catecholamines and CBP are involved in the development of psychological dependence on PCP and that changes in dopaminergic and/or cAMP systems induced by repeated PCP treatment play an important role in the addiction to PCP.
 ...
PMID:Role of catecholaminergic and cyclic AMP systems in psychological dependence on phencyclidine: a study in mutant mice. 1092 19

Hypothesized risk factors for psychostimulant, amphetamine, and cocaine abuse include dopamine (DA) receptor polymorphisms, HIV infection, schizophrenia, drug-induced paranoias, and movement disorders; however, the molecular, cellular, and biochemical mechanisms that predispose to drug sensitivity or drive the development of addiction are incompletely understood. Using the Borna disease rat, an animal model of viral-induced encephalopathy wherein sensitivity to the locomotor and stereotypic behavioral effects of d-amphetamine and cocaine is enhanced (Solbrig et al., 1994, 1998), we identify a specific neurotrophin expression pattern triggered by striatal viral injury that increases tyrosine hydroxylase activity, an early step in DA synthesis, to produce a phenotype of enhanced amphetamine sensitivity. The reactive neurotrophin pattern provides a molecular framework for understanding how CNS viral injury, as well as other CNS adaptations producing similar growth factor activation profiles, may influence psychostimulant sensitivity.
 ...
PMID:Neurotrophic factor expression after CNS viral injury produces enhanced sensitivity to psychostimulants: potential mechanism for addiction vulnerability. 1105 Jan 46

To investigate the involvement of catecholamines and/or the cyclic AMP (cAMP) systems in the development of drug dependence, we examined whether morphine dependence was developed in tyrosine hydroxylase (TH) heterozygous (TH+/-) and cAMP response element binding protein (CREB) binding protein (CBP) heterozygous (CBP+/-) mice. Morphine (10 mg/kg) induced place preference in the wild-type mice. In the TH+/- and CBP+/- mice, however, we could not find any morphine-induced place preference. When the wild-type mice pretreated with morphine (10 mg/kg) twice a day for 5 days were challenged with naloxone (5 mg/kg), they showed increased numbers of jumping, rearing and forepaw tremor as a sign of withdrawal symptom and increased level of cAMP in the thalamus/hypothalamus, but not in the striatum. However, increased numbers of jumping and forepaw tremor in the TH+/- and CBP+/- mice and increased level of cAMP in the thalamus/hypothalamus of TH+/- mice were not observed. These results suggest that catecholamines and CBP are involved in the development of morphine dependence, and that some changes in the catecholaminergic and/or cAMP system induced by repeated morphine treatment play an important role in the addiction of morphine.
 ...
PMID:[The mechanisms of morphine dependence and it's withdrawal syndrome: study in mutant mice]. 1123 92

The expression of central cannabinoid (CB1) receptors in tyrosine hydroxylase (TH) containing neurones was demonstrated. Co-localisation was present in different brain areas responsible for reward-related mechanisms. The immunohistochemical investigations have shown that co-localisation is present in parts of mesolimbic-mesocortical dopaminergic system like nucleus accumbens (Nacb), ventral tegmental area (VTA), in the striatum, pyriform cortex, respectively. The results suggest a functional role of CB1 receptors in cannabis addiction by acting directly on reward-related structures.
 ...
PMID:Neuromorphological background of cannabis addiction. 1283 97


1 2 3 4 5 6 7 8 9 Next >>