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R L Patrick

Publications and source records attributed to R L Patrick.

At least 19 recordsLinked to original sources
PubMed1995

Stimulation of rat striatal tyrosine hydroxylase activity following intranigral administration of sigma receptor ligands.

The effects of sigma ligands on turning behavior and striatal tyrosine hydroxylase activity were determined following microinjection of two chemically dissimilar sigma ligands into the rat substantia nigra. Striatal tyrosine hydroxylase activity was monitored by measuring the amount of 3,4-dihydroxyphenylalanine (DOPA) formed following inhibition of DOPA decarboxylase activity with m-hydroxybenzylhydrazine (NSD-1015). The sigma ligands, 1,3-di-o-tolylguanidine (DTG) and (-)-deoxy-N-benzylnormetazocine, produced a significant increase both in contralateral turning and in tyrosine hydroxylase activity. The DTG-induced increase in tyrosine hydroxylase activity was not antagonized by intranigral injection of the NMDA receptor antagonist, 3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP). CPP alone produced significant contralateral turning that was not accompanied by an increase in striatal tyrosine hydroxylase activity, indicating that turning per se is not sufficient to activate striatal tyrosine hydroxylase. The DTG-induced increase in tyrosine hydroxylase activity was antagonized by general anesthetics such as halothane and chloral hydrate. These results indicate that occupancy of sigma receptors in the substantia nigra is associated with an activation of dopamine formation in dopaminergic terminals in the striatum and support the concept that sigma activity in the substantia nigra produces an activation of dopamine-mediated responses in the striatum.

Animals↗
PubMed1991

Concomitant sensitization of amphetamine-induced behavioral stimulation and in vivo dopamine release from rat caudate nucleus.

Rats were treated twice daily either with saline or d-amphetamine (5 mg/kg) for 5 days. When challenged approximately 15 days later with an injection of 0.5 mg/kg amphetamine, the chronic amphetamine animals showed (1) an augmented release of dopamine in the caudate nucleus in vivo and (2) an increase in stereotyped behavior compared to the chronic saline animals. These results suggest that an increase in dopamine release from the caudate may contribute to amphetamine-induced behavioral sensitization.

Animals↗
PubMed1990

Activation of striatal tyrosine hydroxylase by in vivo electrical stimulation: comparison with cyclic AMP-mediated activation.

These studies were carried out to characterize the activation of rat striatal tyroxine hydroxylase produced by depolarization of the medial forebrain bundle and to evaluate the possible role of cyclic AMP as a mediator of this activation. The enzymatic properties of tyrosine hydroxylase following in vivo depolarization were compared to those produced by treatment of striatal synaptosomes with dibutyryl cyclic AMP (dbcAMP). Similar effects were observed with regard to enzyme distribution, altered sensitivity to dopamine-induced inhibition, and activity as a function of tyrosine concentration. However, differences between the two treatments were also apparent. First, treatment with dbcAMP shifted the pH optimum from 6.2 to 7.0. In contrast, electrical stimulation decreased the rate of decline in activity as the pH was increased above the optimum, but did not shift the pH optimum. Second, plots of tyrosine hydroxylase activity versus cofactor concentration revealed two enzyme forms for both control and electrically stimulated preparations. However, dbcAMP treatment converted the enzyme to a single high affinity form. These results can be explained by one of the following: (1) cyclic AMP is the sole mediator of enzyme activation, but does not produce a maximally activated enzyme following in vivo depolarization, (2) cyclic AMP is only one of several mediators involved or (3) cyclic AMP is not involved in depolarization-induced activation, with activation occurring via the mediation of other intracellular messengers, such as calcium.

Animals↗
PubMed1990

Diacylglycerol-induced stimulation of neurotransmitter release from rat brain striatal synaptosomes.

These studies were undertaken to test the hypothesis that alterations in phosphatidylinositol metabolism can modulate neurotransmitter release in the central nervous system. The effects of 1,2-diacylglycerols (DAGs) on dopamine release in the rat central nervous system were determined by measuring dopamine release from rat striatal synaptosomes in response to two DAGs (sn-1,2-dioctanoylglycerol and 1-oleoyl-2-acetylglycerol) that can activate protein kinase C and one DAG (deoxydioctanoylglycerol) that does not activate this kinase. Dioctanoylglycerol and 1-oleoyl-2-acetylglycerol, at a concentration of 50 micrograms/ml, stimulated the release of labeled dopamine from striatal synaptosomes by 35-50 and 17%, respectively. Dioctanoylglycerol-induced release was also demonstrated for endogenous dopamine. In contrast, deoxydioctanoylglycerol (50 micrograms/ml) did not stimulate dopamine release. Dioctanoylglycerol-induced dopamine release was independent of external calcium concentration, indicating a utilization of internal calcium stores. Dioctanoylglycerol (50 micrograms/ml) also produced a 38% increase in labeled serotonin release from striatal synaptosomes. The addition of dioctanoylglycerol to the striatal supernatant fraction increased protein kinase C activity. These results are consistent with the concept that an increase in phosphatidylinositol metabolism can stimulate neurotransmitter release in the central nervous system via an increase in DAG concentration. The data suggest an involvement of protein kinase C in the DAG-induced release, but other sites for DAG action are also possible.

Animals↗
PubMed1989

Tyrosine hydroxylase phosphorylation in rat brain striatal synaptosomes.

The present studies were carried out to determine if tyrosine hydroxylase phosphorylation in rat brain striatal synaptosomes is activated by dibutyryl cyclic AMP treatment. Incubation of synaptosomes with [32P]orthophosphate, followed by immunoprecipitation and sodium dodecyl sulfate polyacrylamide gel electrophoresis, produced a band of radioactivity associated with a 62 kDa polypeptide. Treatment with the catecholamine neurotoxin, 6-hydroxydopamine, produced parallel losses of: (1) tyrosine hydroxylase enzyme activity, (2) dopamine content, and (3) the 62 kDa band of radioactivity. These data support the identification of this band as a tyrosine hydroxylase-derived polypeptide. Incubation with dibutyryl cyclic AMP produced an increase in soluble tyrosine hydroxylase activity and phosphorylation. These results suggest that the increase in synaptosomal catecholamine synthesis produced by dibutyryl cyclic AMP is mediated by an increase in tyrosine hydroxylase phosphorylation.

Animals↗
PubMed1989

Motor effects of two sigma ligands mediated by nigrostriatal dopamine neurons.

(+)-Pentazocine, a potent sigma ligand that lacks affinity for PCP receptors, produced dose-dependent contralateral circling behavior following microinjections in the substantia nigra of rats. This effect was attenuated by 6-hydroxydopamine (6-OHDA) lesions of ascending dopamine neurons and enhanced by systemic injections of amphetamine, 6-OHDA lesions also attenuated the circling produced by another selective sigma ligand, 1,3-di-o-tolylguanidine (DTG). These findings suggest that sigma receptors are involved in the neural control of movement and the regulation of the ascending dopamine system. Since all typical antipsychotic drugs tested bind to sigma receptors with Ki values less than 1 microM, these findings further suggest that sigma receptors may mediate some of the motor side effects of antipsychotic drug therapy.

Amphetamines↗
PubMed1988

Dopamine-independent motor behavior following microinjection of rimorphin in the substantia nigra.

The motor-activating effects of rimorphin, an opioid peptide derived from prodynorphin, were examined in the substantia nigra pars reticulata of rats. Unilateral microinjections of rimorphin produced dose-dependent contralateral rotational behavior that was antagonized by naloxone, suggesting that these effects were mediated by opiate receptors. Lesions of midbrain dopamine cells with 6-hydroxydopamine (6-OHDA) produced a 95% or greater depletion of tyrosine hydroxylase in the striatum ipsilateral to the lesion, but failed to reduce the number of circles made by the rats. In addition to an overall preservation of rimorphin-induced circling in animals with 6-OHDA lesions, 50% of these rats exhibited circling that was at least 2 standard deviations above the mean of animals without lesions. The motor activating effects of rimorphin, thus, appear to occur independently of the nigrostriatal dopamine system; these effects may instead be mediated by GABAergic efferents in the pars reticulata.

Animals↗
PubMed1988

Rotational behavior mediated by dopaminergic and nondopaminergic mechanisms after intranigral microinjection of specific mu, delta and kappa opioid agonists.

The regulation of motor behavior by mu, delta and kappa opiate receptors in the substantia nigra was examined. Unilateral microinjections of specific mu (DAGO), delta (DPDPE) and kappa (U-50,488H) ligands into the substantia nigra pars reticulata of rats produced dose-dependent contralateral turning. The opiate antagonist naloxone blocked these effects, suggesting that the circling was mediated through opiate receptors. The involvement of midbrain dopaminergic systems in this behavior was tested in two ways. Unilateral 6-hydroxydopamine lesions of the medial forebrain bundle decreased the circling produced by DPDPE and DAGO but increased the circling produced by U-50,488H. In contrast, activating dopaminergic systems with systemic injections of amphetamine increased the circling produced by DAGO and DPDPE but had no effect on the circling produced by U-50,488H. These findings suggest that kappa opioids exert opposite effects on locomotion: motor activation through the SNR and motor inhibition through actions in the SNC. Furthermore, the data suggest that the actions of kappa opioids in the SNC are opposite to those produced by mu and delta opioids.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1986

Effects of propranolol on catecholamine synthesis and uptake in the central nervous system of the rat.

These studies were undertaken to determine the effects of propranolol on catecholamine synthesis and uptake in the rat central nervous system. The effects of propranolol on catecholamine synthesis were studied in vitro in striatal and hypothalamic synaptosomes, and also in vivo. In addition, the effects of propranolol on catecholamine uptake in striatal and hypothalamic synaptosomes were evaluated. Propranolol inhibited synaptosomal catecholamine synthesis and uptake in both tissues. Norepinephrine uptake in the hypothalamus was most sensitive to propranolol inhibition (IC50 = 5 microM). Dopamine synthesis in striatal synaptosomes was also inhibited markedly, with an IC50 = 8 microM. After in vivo administration, propranolol decreased the accumulation of dopa in the striatum, confirming propranolol's synthesis inhibiting effect in dopaminergic terminals. Studies of soluble striatal tyrosine hydroxylase revealed that propranolol has a direct inhibitory effect on the enzyme. These results indicate that propranolol administration may cause a potentiation of norepinephrine activity specifically at alpha receptors, due to concurrent beta receptor blockade and inhibition of norepinephrine reuptake and a decrease in dopamine activity at dopaminergic receptor sites due to an inhibition of dopamine formation.

Animals↗
PubMed1985

The projection of three extrathalamic cell groups to the cerebral cortex of the turtle Pseudemys.

Three extrathalamic subcortical inputs to the part of the cerebral cortex that is known to receive thalamic fibers in the turtle were examined in the present study. Direct projections from the locus coeruleus, the superior medial raphe nucleus, and a wide area of the basal telencephalon that lies ventromedial to the globus pallidus were demonstrated with the horseradish peroxidase method. Fluorescence histochemistry confirmed the presence of catecholamine-containing fibers in the rostral half of dorsal cortex and also demonstrated a dense network of serotoninergic fibers. Biochemical analysis showed the concentration of both monoamines to be relatively high; the norepinephrine concentration was 709 ng/g and the serotonin concentration was 1,750 ng/g. No evidence was found to suggest the existence of either a dopamine fiber projection to cortex comparable to that of mammalian neocortex or the presence of an epinephrine pathway to turtle cortex equivalent to the epinephrine-containing fibers in the pallium of amphibians. The coexistence of the projections from the thalamus with noradrenergic projections from the locus coeruleus, serotoninergic projections from the superior medial raphe nucleus, and presumably cholinergic projections from the basal telencephalon provide at least four distinct subcortical inputs to the reptilian dorsal cortex. Neither thalamic nor similar extrathalamic inputs have been demonstrated in the dorsal pallium of amphibia. Mammalian neocortex, in contrast, has even more elaborately differentiated inputs of both types. These results support the idea that thalamic and extrathalamic inputs to cortex appear at the same time in vertebrate evolution, and that both types of inputs are required for the normal development and function of neocortex.

Animals↗
PubMed1984

Differential effects of calcium on catecholamine synthesis regulation in olfactory tubercle and hypothalamic synaptosomes.

We have compared catecholamine synthesis regulation in rat brain olfactory tubercle and hypothalamic synaptosomes with regard to: calcium-dependency of stimulant drug-induced synthesis activation; tyrosine-dependency of amphetamine-induced synthesis stimulation, and the effects of the calcium chelator, ethylene glycol-bis-(beta-aminoethyl ether)N,N,N',N'-tetraacetic acid (EGTA). Amphetamine-induced synthesis stimulation was markedly calcium-dependent in the olfactory tubercle, but was completely calcium-independent in the hypothalamus. The effect of amphetamine on catecholamine synthesis in the olfactory tubercle was dependent upon the concentration of tyrosine in the incubation buffer; amphetamine produced a biphasic response, inhibiting synthesis at low tyrosine concentrations and activating synthesis at higher tyrosine concentrations. In contrast to the olfactory tubercle, amphetamine-induced stimulation of synthesis in the hypothalamus was observed at both low and high tyrosine concentrations. Distinct tissue differences in drug responsiveness were also observed following exposure to EGTA; synthesis was stimulated by EGTA in the olfactory tubercle but not in the hypothalamus. These data provide evidence for regional differences in catecholamine regulation in the brain, and suggest that some of these differences may be related to differential effects of calcium on catecholamine formation.

Amphetamine↗
PubMed1984

Dihydroxyphenylalanine production in rat brain striatal synaptosomes: stimulation by a calcium chelator.

By inhibiting aromatic L-amino-acid decarboxylase (EC 4.1.1.28) in rat brain striatal synaptosomes, we have been able to measure dihydroxyphenylalanine production via high performance liquid chromatography-electrochemical oxidation. This dihydroxyphenylalanine assay was compared to a standard radioisotopic assay of catecholamine synthesis (14CO2 production from L-[1-14C]tyrosine) in terms of (1) units of activity, (2) effects of known inhibitory and stimulatory agents, and (3) effects of the calcium chelator, EGTA. The units of activity in the dihydroxyphenylalanine assay were 40% greater than the units in the radioisotopic assay, indicating a mixing of labeled and endogenous tyrosine pools before conversion of the labeled tyrosine to labeled dihydroxyphenylalanine. The inhibition of synthesis produced by either 3-iodotyrosine or 3,4-dihydroxyphenylethylamine was similar in the two assays, as was the stimulation produced by 8-bromo cyclic AMP. The calcium chelator, EGTA, also activated synthesis to the same extent in the two assays, indicating that the increase observed in the radioisotopic assay is not an artifact of altered precursor specific activity. These data thus indicate the general utility of the synaptosomal dihydroxyphenylalanine synthesis assay, and also demonstrate the specific advantages of this assay for analyzing the effects of agents such as EGTA, which can alter tissue catecholamine precursor levels.

Animals↗
PubMed1981

Catecholamine synthesis regulation in hypothalamic synaptosomes.

In order to characterize the properties of synaptosomal catecholamine formation in a predominantly noradrenergic preparation, we have studied catecholamine synthesis in rat brain hypothalamic synaptosomes. Kinetic analysis revealed an apparent Km for tyrosine of 2.5 microM and an apparent Vmax of 2.1 nmol/h/g. In the hypothalamus, norepinephrine-induced synthesis inhibition was completely reversed by preincubation with desipramine, a blocker of catecholamine uptake into noradrenergic tissue. In contrast, desipramine was relatively ineffective in the predominantly dopaminergic striatum, indicating that most of the catecholamine synthesis observed in the hypothalamic synaptosomes was taking place in noradrenergic, as opposed to dopaminergic, terminals. Synthesis was stimulated approximately 30% in the hypothalamus by elevated (55 mM) potassium. This stimulation was markedly antagonized in a calcium-free buffer and by the addition of tetraethylammonium chloride. Phenylethylamine compounds could produce either stimulation (amphetamine) or inhibition (tyramine). The most effective synthesis stimulator was dibutyryl cyclic AMP (80% stimulation at 2 mM). Lowering the pH of the incubation buffer from 7.2 to 6.2 increased the basal rate but decreased the stimulatory response to elevated potassium. These data suggest that synaptosomal preparations from the hypothalamus offer a convenient system for studying drug effects on catecholamine synthesis in noradrenergic terminals.

Animals↗
PubMed1981

An ultrastructural and biochemical analysis of norepinephrine-containing varicosities in the cerebral cortex of the turtle Pseudemys.

The fine structure and norepinephrine content of small granular vesicle-containing profiles were studied in normal and norepinephrine-depleted cerebral cortex of the turtle, Pseudemys. The cortex was fixed for electron microscopy with the KMnO4 procedure of Koda and Bloom ('77), while the norepinephrine content was assayed wit the radioenzymatic method of Coyle and Henry ('73). Green fluorescent fibers have been described by Parent and Poitras ('74) as located almost exclusively in the outer half of the molecular layer in turtle cortex. Small granular vesicle-containing profiles are found down to 100 microns below the pial surface, but over 50% lie within 20 microns of the surface. Within the outer 100 microns of cortex, the frequency of labeled varicosities is 1.39/1,000 microns2. The average area of the norepinephrine-containing varicosities is 0.61 microns2, and there is a mean of 18.4 vesicles per single section. The average number of large plus small vesicles in an entire varicosity was estimated to be 72. Synaptic membranes are not well-preserved with KMnO4 fixation, but good examples were found of small granular vesicle-containing profiles forming both symmetrical and asymmetrical membrane differentiations. Only a small percentage of the small granular vesicle profiles were associated with a synaptic membrane differentiation in single sections. When norepinephrine-fiber synapses are seen, they usually share a postsynaptic element with another unlabeled vesicle-containing profile. Normal turtle cortex contains an average norepinephrine concentration of 1.95 micrograms/gr, which is about eight times higher than in rat cortex. The ratio of norepinephrine to dopamine is about 18 to one, suggesting that dopamine is present predominantly in a precursor pool for norepinephrine. Small granular vesicle-containing profiles were eliminated after treatment with reserpine and 6-hydroxydopamine in concentrations that were shown to reduce norepinephrine concentration by 94% and 86%, respectively. The labeled varicosities were partially depleted by midbrain hemisection and by an inhibitor of dopamine-beta-hydroxylase (FLA-63). The norepinephrine-containing varicosities are remarkably coextensive with the distribution of thalamic fibers, both in the total extent of cortex where they are found and in the depth of cortex where they terminate. The results support the idea that there is a close structural and functional association between locus coeruleus and thalamic fibers in cerebral cortex, and the apparent difference in frequency of synapses suggests that each fiber system exerts its influence on cortical cells in a different way.

Animals↗
PubMed1981

Effects of in vivo amphetamine administration on dopamine synthesis regulation in rat brain striatal synaptosomes.

The stimulation of dopamine synthesis in rat brain striatal synaptosomes produced by the depolarizing agent veratridine was markedly reduced by prior in vivo amphetamine administration. This effect did not appear to be due to an interference with the depolarization process, per se, since veratridine-induced inhibition of tyrosine uptake, a biochemical correlate of depolarization, was unaffected by amphetamine. Antagonism of veratridine-induced synthesis stimulation was not duplicated by in vivo treatment with pargyline, apomorphine, gamma-butyrolactone or haloperidol, suggesting that this effect may be due to a direct cellular action of amphetamine. In contrast to the inhibition of veratridine-induced synthesis stimulation produced by in vivo amphetamine administration, the synthesis stimulation produced by in vitro amphetamine treatment was not reduced. However, this stimulation was altered in character and was no longer calcium-dependent. A similar loss of calcium-dependency for amphetamine-induced synthesis stimulation was also observed after in vivo reserpine treatment. These results suggest that in vivo amphetamine administration can markedly alter the interactions between tyrosine hydroxylase and synaptosomal dopamine pools that may be involved in the regulation of catecholamine formation.

Animals↗
PubMed1979

Amphetamine- and phenylethylamine-induced alterations in dopamine synthesis regulation in rat brain striatal synaptosomes.

Amphetamine and phenylethylamine stimulate dopamine synthesis in rat brain striatal synaptosomes via a calcium- and tyrosine-dependent mechanism. The similarity of this stimulation to that produced by depolarizing concentrations of veratridine, along with the non-additivity of maximally stimulating concentrations of amphetamine and veratridine, suggests that these treatments may all share a common locus of action. Differences in exact modes of action can be seen, however, in the blockade only of the stimulation of veratridine by tetrodotoxin, and by the lack of effect of amphetamine or phenylethylamine on tyrosine uptake. At high concentrations, amphetamine and phenylethylamine lose their ability to stimulate dopamine synthesis and produce an antagonism of veratridine-induced synthesis stimulation.

Animals↗