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R Kuczenski

Publications and source records attributed to R Kuczenski.

At least 73 records · Page 4Linked to original sources
PubMed1987

Individual differences in responsiveness to single and repeated amphetamine administration: behavioral characteristics and neurochemical correlates.

The administration of amphetamine to rats results in a relatively wide range of individual differences in responsiveness, both in the initial behavioral patterns as well as in the augmentation response to repeated administration. Therefore we examined the possibility that such differences might reflect intrinsic variation in neurochemical mechanisms regulating responsiveness to amphetamine. Animals were administered a transitional dose (1.75 mg/kg) of amphetamine with regard to the induction of locomotion and continuous stereotypy. On the basis of individual response profiles animals could be separated into two markedly different subgroups, one displaying continuous locomotion (S1), characteristic of lower amphetamine doses, and the other exhibiting a multiphasic pattern, including a prolonged focused stereotypy phase (S2), typically associated with higher amphetamine doses. Examination of regional brain monoamine and metabolite levels revealed distinguishing patterns between the subgroups only in the mesolimbic and mesocortical dopamine systems. With repeated amphetamine administration, the two prominent factors of the augmentation, the emergence of stereotypy and the enhancement of locomotion during the last half of the response, were dissociable between the subgroups. The emergence of stereotypy was confined to S1 animals, whereas only the S2 subgroup displayed the progressive increase in locomotion. Differences in the responsiveness of neurochemical systems to amphetamine rather than pharmacokinetic factors appear to underly the distinct behavioral profiles associated with the two subgroups. The results indicate that characterization of individual responses may be required to determine accurately the neurochemical mechanisms involved in the behavioral effects of amphetamine.

Amphetamine↗
PubMed1986

Evidence that amphetamine and Na+ gradient reversal increase striatal synaptosomal dopamine synthesis through carrier-mediated efflux of dopamine.

Amphetamine (AMPH) releases dopamine (DA) from striatal synaptosomes and concomitantly increases DA synthesis. Since AMPH may release DA through carrier-mediated diffusion via reversal of the DA uptake system, the increase in DA synthesis might depend on a functioning uptake carrier. Consistent with such a mechanism, the uptake inhibitors nomifensine (NMF) and benztropine (BZT) completely prevented the AMPH-induced increase in DA synthesis at concentrations known to inhibit DA uptake. Changes in the Na+ gradient across the synaptosomal membrane also promote DA release, since DA and Na+ are cotransported by the neuronal uptake carrier. Incubation of synaptosomes in medium containing decreasing Na+ increased DA synthesis inversely proportional to Na+ over the range 128 to 20 mM. Similarly, incubations in the presence of 10(-4) M ouabain to inhibit Na+, K+-ATPase and allow intracellular accumulation of Na+ also increased DA synthesis. These changes in DA synthesis could also be prevented by BZT and were non-additive with the AMPH-induced increase in DA synthesis. However, a concentration of ouabain (10(-6) M) which by itself did not increase DA synthesis, and does not promote DA release, potentiated the AMPH-induced increase in DA synthesis. Further, the increased DA synthesis promoted by all three manipulations was only marginally dependent on the presence of Ca2+ in the incubation medium. However, at 5 and 10 mM Na+, a second component of increased DA synthesis was observed which was insensitive to BZT, but was prevented by Ca2+ removal. These results suggest that the increase in DA synthesis, and presumably DA release promoted by AMPH, lowered Na+, and ouabain, depend on the availability of the DA carrier at the internal face of the neuronal membrane and the intracellular content of Na+. The second component of increased DA synthesis which is evident at 5 and 10 mM Na+ is discussed in terms of a possible Ca2+-mediated change in DA synthesis which is independent of the DA carrier.

Amphetamine↗
PubMed1986

Dose response for amphetamine-induced changes in dopamine levels in push-pull perfusates of rat striatum.

Levels of dopamine were determined in push-pull perfusates of striatum in chloral hydrate-anesthetized rats as a function of increasing systemic doses of amphetamine over the range 0.5-5.0 mg/kg. In the absence of amphetamine administration, basal dopamine levels remained stable for at least 6 h. Perfusate levels of dopamine responded in a quantitatively predictable fashion to increasing doses of amphetamine: (1) the maximal increase in perfusate levels of dopamine after amphetamine, relative to predrug levels, was directly proportional to the dose of the drug up to 3 mg/kg (fivefold after 0.5 mg/kg to 30-fold after 3 mg/kg); (2) the duration over which perfusate levels of dopamine were significantly elevated, with respect to preamphetamine levels, was proportional to the dose of amphetamine up to 5 mg/kg; and (3) each successively higher dose of amphetamine significantly increased the perfusate level of dopamine over that observed at the next lower dose up to 3 mg/kg amphetamine. However, maximal levels of dopamine in striatal perfusates were achieved following 3 mg/kg amphetamine and were not increased further at higher doses of the drug. The data suggest that, at higher doses of amphetamine, extraneuronal metabolism of dopamine may be of sufficient capacity to limit increases in synaptic levels of dopamine. The absence of further increases in perfusate levels of dopamine as the dose of amphetamine is increased beyond 3 mg/kg is discussed in terms of potential relevance to mechanisms of amphetamine-induced stereotyped behaviors.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

Dopamine autoreceptor regulation of the kinetic state of striatal tyrosine hydroxylase.

Tyrosine hydroxylase isolated from striatal synaptosomes exhibits biphasic Lineweaver-Burk kinetics for its tetrahydrobiopterin cofactor, consistent with multiple Km forms of the enzyme. Incubation of striatal synaptosomes with forskolin (EC50 0.45 microM) or dibutyryl cyclic AMP (EC50 1.2 mM), results in activation of tyrosine hydroxylase, isolated from these synaptosomes via conversion of the enzyme to a single low Km form (Km 40 microM). The activation of synaptosomal tyrosine hydroxylase by forskolin or dibutyryl cyclic AMP is not additive and is similar to activation seen with cyclic AMP-dependent protein kinase phosphorylation of purified tyrosine hydroxylase. The addition of dopamine (IC50 1.0 microM) (with nomifensine and pargyline) or apomorphine (IC50 30 nM) to the synaptosomal incubation medium blocks the activation of tyrosine hydroxylase by forskolin. This effect of dopamine and apomorphine can in turn be blocked by preincubation of the synaptosomes with the dopamine receptor antagonist haloperidol (IC50 30 nM and 4.5 nM, respectively) or chlorpromazine (IC50 50 nM versus apomorphine). In contrast to the forskolin data above, dopamine failed to block the activation of tyrosine hydroxylase by dibutyryl cyclic AMP. Addition of dopamine to the tyrosine hydroxylase assay, in amounts equivalent to that carried over from the synaptosomal incubation with the tyrosine hydroxylase, had no effect on forskolin-activated enzyme. The observations that dopamine and apomorphine can block forskolin activation of tyrosine hydroxylase, that this blockade can in turn be prevented by preincubation with haloperidol or chlorpromazine, and that the amount of dopamine required for blockade of forskolin activation in synaptosomes has no effect on tyrosine hydroxylase when added to the enzyme assay constitute the first clear evidence of a presynaptic dopamine receptor (autoreceptor). This autoreceptor regulates the activity of tyrosine hydroxylase by preventing or reversing cyclic AMP-dependent activation of the enzyme, probably through a decrease in the phosphorylation state of tyrosine hydroxylase. Failure of dopamine to block dibutyryl cyclic AMP activation of tyrosine hydroxylase suggests that, if forskolin and dibutyryl cyclic AMP activate tyrosine hydroxylase through identical changes in phosphorylation state, then autoreceptor regulation of tyrosine hydroxylase must occur through a decrease in cyclic AMP levels.

Adenylyl Cyclases↗
PubMed1986

Desensitization of rat striatal dopamine-stimulated adenylate cyclase after acute amphetamine administration.

Catecholamine receptors positively coupled to adenylate cyclase (AC) have been shown to undergo rapid desensitization after excessive stimulation. Because amphetamine (AMPH) is known to enhance dopamine (DA) release and striatal D1 DA receptors are positively coupled to AC, the effect of acute AMPH on D1 DA receptor function was examined. Doses of AMPH were chosen for their contrasting behavioral effects: 1 mg/kg, which enhances locomotor activity, and 5 mg/kg, which promotes intense, focused stereotypies. AMPH was administered S.C. 45 min before killing. Assay of striatal AC activity was performed by following the conversion of [alpha-32P]ATP to [32P]cyclic AMP. A dose of 5 mg/kg of AMPH, but not 1 mg/kg of AMPH, caused a 2-fold shift to the right in the dose-response curve for DA in stimulating AC activity when compared with saline controls. Basal activity and GTP-, guanosine 5'-(beta-gamma-imido)-triphosphate- and NaF-stimulated activity did not change. As a function of time after administration of 5 mg/kg of AMPH, desensitization was also observed at 25 min but not at 90 or 180 min. At no time point tested (25, 45 or 60 min) did 1 mg/kg of AMPH alter DA-stimulated AC activity. Desensitization of the DA-stimulated AC was also observed after a stereotypy-producing dose of methylphenidate (50 mg/kg at 40 min). These data demonstrate D1 DA receptor desensitization. This desensitization occurs after a stereotypy-producing dose of either AMPH or methylphenidate. A possible role for D1 DA receptor desensitization in stereotypy is suggested.

Adenylyl Cyclases↗
PubMed1985

Purification and characterization of rat striatal tyrosine hydroxylase. Comparison of the activation by cyclic AMP-dependent phosphorylation and by other effectors.

Purification of rat striatal tyrosine hydroxylase in the presence of protease inhibitors effected a high yield of apparently homogeneous enzyme which is stable to prolonged storage. The purified enzyme migrates as a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis with a molecular weight of 61,300. Removal of protease inhibitors results in the appearance of additional bands with molecular weights of 59,800 and 57,000. Cyclic AMP-dependent protein kinase incorporates 1 mol of phosphate/61,000-Da subunit of tyrosine hydroxylase, and concomitantly decreases the apparent Km of the enzyme for cofactor. Phosphorylated tyrosine hydroxylase is unstable at 37 degrees C, exhibiting a 50% decrease in apparent Vmax in 40 min with no change in Km for cofactor. Levels of incorporated phosphate remain constant over this time period. Tyrosine hydroxylase activated by and in the presence of phosphatidylinositol or high concentrations of NaCl exhibited a similar loss of activity at 37 degrees C, whereas enzyme activated by heparin was relatively stable. The rate of phosphorylation of tyrosine hydroxylase is markedly increased in the presence of any of these effectors, suggesting that they promote a common conformation. Further, heparin appears to bind to tyrosine hydroxylase at a site distant from the phosphorylation site. Physiological effectors of tyrosine hydroxylase may act in concert with cyclic AMP-dependent phosphorylation, perhaps by binding to an allosteric site, to regulate enzyme activity in vivo.

Amino Acids↗
PubMed1983

Striatal dopamine metabolism in response to apomorphine: the effects of repeated amphetamine pretreatment.

The dose-dependent decrease in striatal dopamine (DA) metabolites following apomorphine (APO) administration was utilized as an index of changes in DA receptor sensitivity following the repeated administration of amphetamine (AMPH). The results suggest that: (a) repeated AMPH pretreatment does not alter DA autoreceptor sensitivity; and (b) interpretations of the decline in striatal DA metabolites at high doses of APO (greater than 50 micrograms/kg), in terms of activation of postsynaptic DA receptors, may require re-evaluation.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1983

Effects of phospholipases on the kinetic properties of rat striatal membrane-bound tyrosine hydroxylase.

Rat striatal tyrosine hydroxylase can be isolated in both a soluble and a synaptic membrane-bound form. The membrane-bound enzyme, which exhibits lower Kms for both tyrosine (7 microM) and reduced pterin cofactor (110 microM) relative to the soluble enzyme (47 microM and 940 microM, respectively), can be released from the membrane fraction with mild detergent, and concomitantly its kinetic properties revert to those of the soluble enzyme. Treatment of membrane-bound tyrosine hydroxylase with C. perfringens phospholipase C increased the Km of the enzyme for tyrosine to 27 microM and the Vmax by 60% without changing the Km for cofactor. In contrast, treatment of membrane-bound tyrosine hydroxylase with V. russelli phospholipase A2 increased the Km for tyrosine to 48 microM, increased the Vmax, and increased the Km for cofactor to 560 microM. The enzyme remained bound to the membrane fraction following both phospholipase treatments. Addition of phospholipids to treated enzyme could partially reverse the effects of phospholipase A2 treatment, but not the effects of phospholipase C treatment. The kinetic properties of phospholipase-treated, detergent-solubilized tyrosine hydroxylase were identical to those of the control solubilized enzyme. Tyrosine hydroxylase appears to interact with synaptic membrane components to produce at least two separately determined consequences for the kinetic properties of the enzyme.

Animals↗
PubMed1982

Two dissociable components of behavioral sensitization following repeated amphetamine administration.

The acute administration of moderate to high doses (greater than 2 mg/kg) of amphetamine (AMPH) to rats produces a multiphasic behavioral response consisting of an initial period of locomotor activity followed by episodes of intense stereotyped behavior, and a period of post-stereotype locomotion. Repeated administration of the drug results in a sensitization with two components: more rapid onset of stereotypy and enhancement of the post-stereotype locomotor activity. The studies presented below provide converging evidence that the two components of the sensitization are dissociable. 1. Rats from ten different strains or suppliers all exhibited more rapid onset of stereotypy following repeated AMPH pretreatment, whereas only five of these strains or supplier groups exhibited significantly enhanced poststereotypy locomotion. 2. The time course differed for the development of these two components of the sensitization. 3. The recovery from sensitization differed for these two components of the behavioral response. Following withdrawal of the drug, post-stereotypy motor activity diminished within 2 months while the more rapid onset of stereotypy persisted for at least 3 months. These observations have particular relevance to future studies directed at specifying the biochemical substrates of the sensitization.

Animals↗
PubMed1982

Lack of behavioral evidence for dopamine autoreceptor subsensitivity after acute electroconvulsive shock.

A single electroconvulsive shock (ECS) delivered 7 days previously produced a significant decrease in spontaneous locomotion and rearing in non-habituated rats but did not alter the inhibition of these behaviors produced by low dose apomorphine administration. As such apomorphine effects are thought to be mediated by dopamine (DA) autoreceptors, these data are not consistent with previous reports that the ECS treatment produces a persistent subsensitivity of DA autoreceptors.

Animals↗
PubMed1982

Evidence that a behavioral augmentation following repeated amphetamine administration does not involve peripheral mechanisms.

Repeated administration of amphetamine (AMPH) to rats results in an augmentation of the drug-induced locomotion and stereotypy. The studies reported below were directed at examining the potential role for some dispositional and peripheral sympathomimetic factors in mediating the enhanced stereotypy response. These included three factors associated with repeated AMPH administration: (1) the possible accumulation of AMPH in a peripheral mobilizable pool; (2) repeated sympathetic activation; and (3) AMPH metabolite-induced depletion of peripheral stores of norepinephrine. The approach utilized was to selectively reduce or mimic the peripheral actions of AMPH through the use of non-pharmacological or pharmacological manipulations which are relatively lacking in AMPH-like central stimulant effects. The results indicate that these factors cannot account for the augmentation of the behavioral response to AMPH and suggest that these behavioral alterations reflect changes in the responsiveness of brain mechanisms which mediate the behavioral effects of the drug.

Amphetamine↗
PubMed1981

Chronic amphetamine: tolerance and reverse tolerance reflect different behavioral actions of the drug.

Chronic administration of amphetamine (AMPH) has been reported to produce tolerance to the drug's behavioral effects in some paradigms (self-stimulation, discriminative stimulus, self-administration) and an enhanced effect or reverse tolerance when other behaviors are monitored (locomotor activity, stereotypy). The present study investigated whether the two phenomena are, in fact, related to the particular behavior monitored or reflect the marked differences in the injection regimens (1X vs. 3X daily injections) used to produce the phenomena. The effects of chronic AMPH administered once or three times daily on AMPH facilitation of self-stimulation responding and on the locomotor stimulant and stereotypy-producing effects of the drug were assessed. Regardless of the injection regimen used, chronic AMPH resulted in an enhancement of the locomotor stimulant effects of the drug as well as a more rapid onset and greater intensity of the stereotypy produced. In the self-stimulation paradigm, only the 3X daily regimen significantly reduced the effectiveness of a challenge dose of AMPH (tolerance), although the 1X regimen produced effects that were qualitatively similar but quantitatively less. Perhaps behavioral tasks in which tolerance develops reflect the mood-altering properties of the drug in humans whereas a process similar to reverse tolerance may underlie the increased susceptibility to psychoses elicited by the drug with repeated use.

Amphetamine↗
PubMed1981

Chronic amphetamine: is dopamine a link in or a mediator of the development of tolerance and reverse tolerance?

Rats were administered chronic multiple injections of amphetamine (AMPH) using dosage regimens which produce tolerance to the AMPH facilitation of self-stimulation responding, or reverse tolerance (sensitization) to the locomotor stimulant and stereotypy-producing effects of the drug. Subsequently rats were challenged with AMPH at behaviorally relevant doses and times and striatal and mesolimbic dopamine (DA) dynamics were assessed using the conversion of 3H-tyrosine to 3H-DA, and endogenous levels of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) as indices of dopaminergic function. Acute administration of AMPH produced dose and time related changes in all indices of DA function in both the striatal and mesolimbic brain regions. Co-administration of haloperidol during chronic AMPH pretreatment prevented the appearance of most of the behavioral changes induced by chronic AMPH, suggesting an important role for DA systems. However, following chronic AMPH treatment, no additional biochemical changes in striatal or mesolimbic DA metabolism could be detected which would parallel the development of tolerance to AMPH facilitation of self-stimulation behavior or reverse tolerance to AMPH as reflected in enhanced post-stereotypy locomotor activity or a suggested increased intensity of stereotypy. Challenge with AMPH after chronic AMPH pretreatment did accelerate the changes in striatal but not mesolimbic DA metabolism, correlating with the more rapid onset of stereotypy induced by chronic AMPH. Thus, while DA systems appear to be a critical link, not only in the acute effects of AMPH, but also in the development of tolerance and reverse tolerance, most of the behavioral differences between acutely and chronically treated animals are not reflected by comparable differences in DA synthesis and metabolism.

Amphetamine↗
PubMed1981

Monovalent cations and striatal tyrosine hydroxylase.

The kinetic properties of soluble tyrosine hydroxylase from rat striatum and the activation of the enzyme by the polyanion heparin were assessed as a function of the monovalent cations K+, Na+, tetramethylammonium (TMA+), and Tris. Substitution of K+ or Na+ for TMA+ or Tris can alter the kinetic properties of tyrosine hydroxylase in the absence of heparin the nature of the interaction of the enzyme with heparin and also the kinetic properties of the heparin-activated enzyme. The data suggest that monovalent cations can support unique conformational states of the enzyme.

Animals↗
PubMed1980

Amphetamine-haloperidol interactions on striatal and mesolimbic tyrosine hydroxylase activity and dopamine metabolism.

Rat striatal and mesolimbic dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid levels and the activity of tyrosine hydroxylase (TOH) were determined as a function of dose of amphetamine (AMPH) or haloperidol (HAL). AMPH increases DA levels with an ED50 of 0.6 mg/kg and decreases DOPAC and homovanillic acid levels with an ED50 of 1.5 mg/kg, suggesting two sites of action for the drug. HAL increases DOPAC and homovanillic acid levels and activates TOH all with an ED50 near 0.05 mg/kg and maximal activation at 0.2 mg/kg. AMPH administered subsequent to 0.2 mg/kg of HAL has no effect on mesolimbic TOH activity or DA metabolism. In contrast AMPH after HAL still increases striatal DA levels and, in addition, partially reverses the HAL-induced increases in both DOPAC levels and TOH activity, all with an ED50 near 0.6 mg/kg. The maximal reversal by AMPH is near 25% of the HAL-induced increases with doses of AMPH to 10 mg/kg. The ED50 for AMPH reversal and the extent of reversal are independent of HAL dose. The equivalent reversal by AMPH of HAL-induced increases in striatal TOH activity and DOPAC levels suggest a neuronally mediated phenomenon involving a noncompetitive interaction between the two drugs on the nigrostriatal pathway. The data are discussed in terms of sites of action for AMPH in both the striatum and the substantia nigra.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1979

Effects of para-chlorophenylalanine on amphetamine and haloperidol-induced changes in striatal dopamine turnover.

Para-chlorophenylalanine (PCPA) was administered to rats, and the animals were sacrificed 48 h later. Animals received various doses of S(+)-amphetamine (AMPH) 31 min before sacrifice or of haloperidol (HAL) 46 min before sacrifice and an intracerebral injection of [3H]tyrosine 15 min prior to sacrifice. PCPA pretreatment potentiated the increased accumulation of striatal [3H]dopamine (DA) induced by doses of AMPH to 1.5 mg/kg, and inhibited the decrease in striatal [3H]DA accumulation observed at higher doses (greater than 2.5 mg/kg) of AMPH. Further, the AMPH-induced increase in endogenous levels of striatal DA was inhibited by PCPA pretreatment. Similarly, PCPA pretreatment potentiated the HAL-induced increase in striatal [3H]DA accumulation. The data are discussed with respect to an inhibitory serotonergic influence on nigrostriatal DA function, and the relationship of nigrostriatal biochemical events to AMPH-induced behavioral changes.

Amphetamine↗
PubMed1977

Biphasic effects of amphetamine on striatal dopamine dynamics.

S(+)-Amphetamine (AMPH) was administered to rats over the dose range 0.15-10.0 mg/kg (1.74(3)mumoles/kg) at various times before sacrifice. 15 min before sacrifice rats received an intraventricular injection of 3H-tyrosine, and the accumulation of striatal 3H-dopamine (DA) was assessed as an index of striatal DA formation and utilization. 3H-DA formation exhibited a biphasic dose response to AMPH. At 16 and 31 min after AMPH administration, 3H-DA accumulation increased linearly in response to AMPH to a maximal rate of 200% of control values at 1.0 mg/kg, then declined to less than 50% of control values at AMPH doses of 5 and 10 mg/kg. As a function of time, low doses of AMPH (to 2.0 mg/kg)) only increased 3H-DA accumulation, whereas high doses of AMPH (greater than 2.5 mg/kg) only decreased 3H-DA accumulation. All doses of AMPH increased endogenous levels of striatal DA. The data are discussed in terms of compensatory adaptive mechanisms of the nigrostriatal dopaminergic pathway.

Animals↗