Effects of chronic haloperidol and intermittent cocaine administration on behavior elicited by apomorphine.

Relatively little is known about the behavioral or neurophysiological effects resulting from the concurrent administration of haloperidol and cocaine. To investigate this drug interaction the effects of chronic, daily administration of haloperidol, intermittent cocaine injections, or the combination of both drug treatments on locomotion and stereotypy elicited by apomorphine in rats (Rattus norvegicus) were compared. The results indicated that, in comparison to treatment with either drug alone, the combination of daily haloperidol and intermittent injections of cocaine produced unique behavioral effects. Rats coadministered both drugs exhibited significant increases in apomorphine-induced locomotion that were maintained throughout the 64 days following suspension of drug treatment. These results are discussed in terms of the possible neurophysiological mechanisms underlying the observed behavioral changes and are related to the consequences of psychostimulant abuse in human neuroleptic treated populations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Influence of repeated levodopa administration on rabbit striatal serotonin metabolism, and comparison between striatal and CSF alterations

Parkinson's disease (PD) is characterized by decreased striatal dopamine, but serotonin (5-HT) is also reduced. Because 5-HT decreases following a single levodopa injection, levodopa has been suggested to contribute to PD's serotonergic deficits. However, in a recent study, rat striatal serotonin levels were reported to increase following 15-day levodopa administration. To address this issue, we administered levodopa (50 mg/kg) to rabbits for 5 days, then measured serotonin, its precursors tryptophan and 5-hydroxytryptophan (5-HTP), and its major metabolite 5-hydroxyindole-acetic acid (5-HIAA) in striatum and CSF. Striatal serotonin and tryptophan were unchanged, while 5-HTP and 5-HIAA increased 4- and 7-fold, respectively. CSF 5-HTP and 5-HIAA were also significantly increased. In levodopa-treated animals, 5-HTP concentrations were moderately correlated (r = 0.679) between striatum and CSF, while weak correlations were present between striatal and CSF concentrations of both serotonin and 5-HIAA. These results suggest that repeated levodopa treatment increases striatal serotonin turnover without changing serotonin content. However, levodopa-induced alterations in striatal serotonin metabolism may not be accurately reflected by measurement of serotonin and 5-HIAA in CSF.     

Effects of repeated questionnaire administration in longitudinal studies of adolescent males' sexual behavior

By comparing four similar groups of young adolescent males who completed questionnaires about their sexual behavior different numbers of times at various intervals, we explore the hypothesis that repeated questionnaire completion will affect sexual behavior. We find little support for the hypothesis even when the number of questionnaire administrations is very high.     

Ontogeny of striatal dopamine release in rats after acute administration of methamphetamine

In the present study, we examined the effects of acute MAP administration on striatal extracellular levels of dopamine (DA) and its metabolites in groups of rats on postnatal days (PNDs) 14, 21, 28, and 56. A single injection of 4 mg/kg MAP (IP) induced increase in extracellular DA and decrease in extracellular 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatal perfusates of rats on all PNDs examined. The magnitude of increase in DA concentrations at 20 min after the MAP injection was significantly smaller on PND 14 than PNDs 21, 28, and 56, whereas the magnitude of decrease in DOPAC concentrations after the MAP injection was significantly smaller on PND 14 than PNDs 21, 28, and 56. After the MAP injection, homovanillic acid levels decreased on PNDs 21, 28, and 56, but increased on PND 14. These results suggest that rats on PND 14 differ from those thereafter in MAP-induced DA release and changes in its metabolites, and that such developmental effect on MAP-induced DA release may be involved in the ontogeny of MAP-induced behavioral sensitization.     

The relationship between striatal and mesolimbic dopamine dysfunction and the nature of circling responses following 6-hydroxydopamine and electrolytic lesions of the ascending dopamine systems of rat brain

The importance of extrapyramidal and mesolimbic function for circling behaviour was investigated by placing 6-hydroxydopamine (6-OHDA) and electrolesions in the cell bodies, axons and terminals of each system. Circling behaviour was weak when 6-OHDA was placed at the centre of the substantia nigra (SN), but the characteristic contralateral/ipsilateral turning to apomorphine/amphetamine were recorded. Circling was more marked when 6-OHDA was placed anterior to the SN but was generally absent following injections posterior to the SN. However, 6-OHDA placed in the medial forebrain bundle in the lateral hypothalamus resulted in intense contralateral/ipsilateral turning to apomorphine/amphetamine. Generally, the intensity of circling responses was related to the degree of striatal dopamine (DA) depletion but the more effective lesions also caused reductions in mesolimbic DA content. However, circling was not observed following any 6-OHDA injection into the mesolimbic DA system and it is concluded that mesolimbic DA function is not essential for the initiation of circling. In contrast to the 6-OHDA lesions, rats circled ipsilateral to both apomorphine and amphetamine when the SN was damaged by electrocoagulation to cause marked depletion of striatal dopamine. Lesser depletions of striatal dopamine after electrocoagulation in different regions of the medial forebrain bundle were associated with a lower intensity of ipsilateral circling to both drugs. In general, the differences between 6-OHDA and electrolesions could not be explained by additional damage to ascending noradrenaline or 5-hydroxytryptamine pathways. Lower doses of apomorphine were effective in the 6-OHDA circling rats, and the ipsilateral striatum of such rats was more sensitive to directly applied DA. Higher doses of apomorphine were required to produce circling after chronic electrolesions which rendered the ipsilateral striatum insensitive to DA. The contralateral circling to apomorphine after 6-OHDA lesions was abolished by chronic but not by acute electrolesion of the SN. It is suggested that electrolesions of the SN cause different effects to 6-OHDA because they destroy neuronal pathways in addition to the dopaminergic nigrostriatal tract. These appear to be required for the expression of circling behaviour caused by stimulation of the denervated striatum. Whereas 6-OHDA lesions result in super-sensitivity of the denervated strital DA receptors, electrolesions may cause a hypo-sensitivity of the same receptor sites.     

Reduction of dopamine synthesis inhibition by dopamine autoreceptor activation in striatal synaptosomes with in vivo reserpine administration

In an attempt to clarify the mechanisms by which dopamine (DA) autoreceptor activation inhibits DA synthesis, the efficacy and potency of the D2 DA agonists bromocriptine, lisuride, and pergolide, and the D1-D2 DA agonist apomorphine were studied in rat striatal synaptosomes, in which the rate of DA synthesis (formation of 14CO2 from L-[1-14C]tyrosine) was increased 103% by treating the animals from which the synaptosomes were obtained with reserpine (5 mg/kg i.p. twice, 24 and 2 h before they were killed), using the striatal total homogenate as the standard synaptosomal preparation. The increase in DA synthesis evoked by reserpine was additive with that produced by treatment of the synaptosomes with dibutyryl cyclic AMP, suggesting that, not a cyclic AMP-dependent, but possibly a Ca(2+)-dependent mechanism was involved. The DA agonists showed a concentration-dependent inhibition of DA synthesis in the control synaptosomes, which was antagonized by the selective D2 DA antagonist (-)-sulpiride. In the synaptosomes with increased rate of DA synthesis obtained from the rats treated with reserpine, the concentration-response curves of DA synthesis inhibition for the other DA agonists were shifted to the right, and the effect of bromocriptine was completely eliminated, whereas bromocriptine antagonized the effect of apomorphine. The increased rate of DA synthesis was not preserved in the striatal P1 + P2 fraction obtained from the reserpine-treated rats, but the effects of the DA agonists were still reduced to the same degree as those in the total homogenate. (-)-Sulpiride did not enhance DA synthesis in synaptosomes from the reserpine-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes of behavior and monoamine metabolites in the rat brain after repeated methamphetamine administration: effects of duration of repeated administration

1. The authors studied the mechanism of the reverse-tolerance phenomenon caused by long-term administration of central stimulant drugs. Methamphetamine(MAP) was chronically administered to rats, and the reverse-tolerance phenomenon was studied in terms of behavioral changes and changes in monoamine metabolites, the latter being examined by in vivo microdialysis of the extracellular compartment of the corpus-striatum. The authors also studied [3H]SCH23390 and [3H]spiperone binding to striatal membranes after chronic MAP administration. 2. MAP(4 mg/kg) or saline was administered intraperitoneally once daily to male rats. In Groups 1 and 2, 10 and 30 injections of MAP were given, respectively. In Groups 3 and 4, animals received 10 and 30 injections of saline as controls. One week after the final injection, all rats were challenged with 4 mg/kg MAP. 3. Groups 1 and 2 displayed more intense stereotypy than Groups 3 and 4, indicating that behavioral sensitization had been achieved in the former. Dopamine(DA) levels increased rapidly in response to MAP challenge in all groups, with the increases in Groups 1 and 2 being more marked than that in Groups 3 and 4. Group 1 showed greater persistence and a higher rate of DA increase than Group 2. 4. The number of D1 and D2 dopamine receptors did not change after the repeated MAP administration. 5. The rate of increase in DA release induced by MAP was dependent on the duration of repeated administration, and there was no correlation between the intensity of stereotypy and the rate of increase in DA release induced by MAP. These findings suggest that enhancement in DA release is unlikely to be the sole cause of behavioral sensitization.     

Effects of GBR 12909 on locomotor activity and dopamine turnover in mice: comparison with apomorphine

31 patients with schizophrenic adolescent paranoid syndrome were treated by Leponex-Sandoz after the establishing of the therapeutic indications. We did not observe any considerable side effects. We observed the regression of positive symptoms at 19-day of the treatment and the regression of negative symptoms at 23-day of the therapy. We conclude that Leponex-Sandoz is effective and safe medication in the treatment of adolescent schizophrenic paranoid syndrome.     

Gestational exposure to cocaine or pharmacologically related compounds: effects on behavior and striatal dopamine receptors

Gestational cocaine (COC) exposure has been reported to alter behavior and possibly dopamine (DA) receptors. In this paper, we further examined the effects of prenatal COC (40 mg/kg, s.c.) on DA receptor binding and the behavioral response to quinpirole, a DA D2 receptor agonist. In an attempt to elucidate possible mechanisms of such effects, we exposed pregnant dams to specific reuptake blockers; fluoxetine 12.5 mg/kg, a serotonin reuptake blocker; desipramine 10 mg/kg, a norepinephrine reuptake blocker; GBR-12909 10 mg/kg, a DA reuptake blocker; or to a local anesthetic, lidocaine 40 mg/kg. Drugs were administered once daily over gestational days 8-20. Control dams were injected with saline (SAL) or pair-fed to the COC group. Quinpirole challenge was performed in the offspring on post natal day 19. Two pups per litter were injected (s.c.) with 0.03 or 0.09 mg/kg quinpirole-HCl on post-natal day 19. The remaining pups in each litter were sacrificed for analysis of striatal DA receptors. Results showed that only COC exposure altered the behavioral response to the quinpirole challenge by increasing quinpirole-induced stereotypy and motor activity relative to SAL controls. DA receptor analysis showed no alteration in K(D) or B(MAX) for striatal D1 or D2 sites in any group. These results suggest that prenatal COC exposure produces alterations in function of the D2 receptor complex which are not reflected in K(D) or B(MAX) and that these effects are not fully mimicked by exposure to specific monoamine reuptake blockers or a local anesthetic.     

Effects of unilateral striatal dopamine depletion on tongue force and rhythm during licking in rats.

To quantitatively assess the orolingual dysfunctions produced by unilateral striatal dopamine depletions, rats first received 6-hydroxydopamine injections into the nigrostriatal bundle and were then trained to lap water from a force-sensing disk in 2-min sessions. Compared with controls and rats with moderate (75%) dopamine depletions showed decreases in number of licks, lick rhythm, and lick peak force. Rats with substantial lesions were also impaired in making initial, within-session adjustments in lick peak force but not in lick rhythm. The results confirm the presence of Parkinson-like deficits in tongue dynamics during consummatory licking behavior in rats. The methods used here should prove useful in providing quantitative measures of the efficacy of experimental therapies in this rodent model of Parkinson's disease. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential effects of reserpine and tetrabenazine on rat striatal synaptosomal dopamine biosynthesis and synaptosomal dopamine pools

Rat striatal dopamine (DA) levels and synaptosomal DA synthesis were determined after the administration of the catecholamine-depleting agents reserpine (RES) and tetrabenazine (TBZ). Striatal synaptosomal DA synthesis remained unchanged from control levels after Res administration over a wide range of doses (0.5-5 mg/kg) and times (up to 48 hour). In contrast, after TBZ administration, DA synthesis rapidly increased to values greater than 200% of control values, then returned to control levels. The changes in DA synthesis inversely paralleled the depletion of and recovery of striatal DA levels. The increased levels of DA synthesis did not appear to originate with alterations either in the kinetic properties of tyrosine hydroxylase or in the availability of exogenous or endogenous tyrosine. To assess the contribution of synaptosomal DA pools to the regulation of DA synthesis in tissue preparations from RES-or TBZ-pretreated animals, synaptosomal DA synthesis was assessed in the presence of DA releasing agents and compared with analogous experimental manipulations on tissue preparations from animals pretreated with alpha-methyltyrosine or the monoamine oxidase inhibitor, clorgyline. The data are consistent with a differential in vivo interaction of RES and TBZ with a nerve ending pool of DA which participates in end-product inhibition of tyrosine hydroxylase.     

Effects of morphine in rats withdrawn from repeated nifedipine administration

The effects of withdrawal from repeated nifedipine treatment on morphine-induced analgesia, hyperthermia and catalepsy as well as on cerebral [3H]nitrendipine binding and on morphine-induced changes in striatal and limbic dopamine and 5-hydroxytryptamine metabolism were studied in rats. Repeated administration of nifedipine (5 mg/kg i.p., twice daily for 14 days) decreased [3H]nitrendipine binding in several brain areas of the rats at 24 h after the last dose but did not change the nociceptive response or rectal temperature of the animals. Further, the antinociceptive potency of acute morphine (2.5 mg/kg s.c.) was significantly reduced in rats withdrawn for 24 h from repeated nifedipine treatment. However, withdrawal from repeated nifedipine treatment failed to affect either the hyperthermia induced by this dose of morphine or the catalepsy and the elevation of dopamine or 5-hydroxytryptamine metabolites induced by 15 mg/kg of morphine. Taken together, these data show that withdrawal from repeated treatment with dihydropyridine calcium channel antagonists selectively reduces the effects of opioids on the nociceptive response.     

Fractal analysis of striatal dopamine re-uptake sites

Spatial variation in regional blood flow, metabolism and receptor density within the brain and in other organs is measurable even with a low spatial resolution technique such as emission tomography. It has been previously shown that the observed variance increases with increasing number of subregions in the organ/tissue studied. This resolution-dependent variance can be described by fractal analysis. We studied striatal dopamine re-uptake sites in 39 healthy volunteers with high-resolution single-photon emission tomography using iodine-123 labelled 2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([123I]beta-CIT). The mean fractal dimension was 1.15+/-0.07. The results indicate that regional striatal dopamine re-uptake sites involve considerable spatial heterogeneity which is higher than the uniform density (dimension=1.00) but much lower than complete randomness (dimension=1.50). There was a gender difference, with females having a higher heterogeneity in both the left and the right striatum. In addition, we found striatal asymmetry (left-to-right heterogeneity ratio of 1.19+/-0.15; P<0.001), suggesting functional hemispheric lateralization consistent with the control of motor behaviour and integrative functions.     

Effects of midazolam and propofol on dopamine release from rat striatal slice using a fast-cyclic voltammetry system

In order to evaluate the difference in pharmacological mechanism between midazolam and propofol, we focused on the interaction between dopaminergic and GABAergic neurons in the striatum because of its important role in the regulation of motor system and arousal response, and examined these inhibitory effects on dopamine (DA) release induced by high-K from the rat striatal slice using the fast-cyclic voltammetry method. Between 0.1 and 200 nmol, the standard curve of DA was linear. The peak and the sensitivity of DA oxidation were different from those of norepinephrine and DA main metabolites. The dosages between 0.1 and 10 micro M of propofol significantly blocked the high-K evoked DA release, although the dosage of larger than 50 micro M of propofol potentiated DA release. In case of midazolam, the dosages between 0.1 and 50 micro M markedly suppressed DA release induced by high-K in a dose-dependent manner. The recovery time of DA release after removal of midazolam from incubation medium was longer than that seen in the treatment of propofol. In conclusion, propofol and midazolam inhibited high-K evoked DA release from striatal slice, although these efficacies were dissimilar. Furthermore the pharmacological effects of larger dosage of propofol was different from those obtained by its smaller dosages. These results suggest that the anesthetic actions of propofol and midazolam are partially related to inhibition of DA neuron A1 activity and that the excitatory symptom induced by a larger dose of propofol may be related to its potantiation of DA release.     

Effects of cortical and striatal dopamine D1 receptor blockade on cued versus noncued behavioral responses.

Various lines of evidence suggest that disruptions in brain dopamine (DA) transmission produce behavioral impairments that can be overcome by salient response-eliciting environmental stimuli. We examined here whether D1 receptor blockade within striatal or frontal cortical DA target regions would differentially affect head entry responses elicited by an auditory cue compared with those occurring during noncued intertrial intervals. Rats received 2 drug-free 28-trial daily sessions in which an auditory cue was immediately followed by food delivery. On the following day, separate groups of rats received bilateral infusions of D1 antagonist SCH23390 to the dorsomedial striatum (DMS), nucleus accumbens (NAcc) core, or the medial prefrontal cortex (mPFC). SCH23390 infused into the DMS and NAcc core suppressed noncued head entries but had no effect on head entries in response to the auditory cue. SCH23390 infused to the mPFC did not reduce either cued or noncued approach responses. Systemic administration of the drug, in contrast, reduced the frequency of both cued and noncued approaches. The results are consistent with the notion that has emerged from the Parkinson's literature that reduced DA transmission produces behavioral suppression that can be overcome by salient environmental response elicitors, and extends this notion by showing that D1 receptor transmission within the striatum strongly suppresses noncued responses while leaving the identical behavior intact when cued by an environmental stimulus. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Influence of selective opiate antagonists on striatal acetylcholine and dopamine release

Ty3 is a retroviruslike element found in Saccharomyces cerevisiae. It encodes GAG3 and GAG3-POL3 polyproteins which are processed into mature proteins found in the Ty3 viruslike particle. In this study, the region encoding a protease that is homologous to retroviral aspartyl proteases was identified and shown to be required for production of mature Ty3 proteins and transposition. The Ty3 protease has the Asp-Ser-Gly consensus sequence found in copia, Ty1, and Rous sarcoma virus proteases, rather than the Asp-Thr-Gly found in most retroviral proteases. The Asp-Ser-Gly consensus is flanked by residues similar to those which flank the active sites of cellular aspartyl proteases. Mutations were made in the Ty3 active-site sequence to examine the role of the protease in Ty3 particle maturation and to test the functional significance of the Ser active-site variant in the consensus sequence. Mutation of the active-site Asp blocked processing of Gag3 and Gag3-Pol3 and allowed identification of a GAG3-POL3 polyprotein. This protein was turned over rapidly in cells expressing the mutant Ty3. Changing the active-site Ser to Thr caused only a modest reduction in the levels of certain Ty3 proteins. Five putative cleavage sites of this protease in Ty3 GAG3 and GAG3-POL3 polyproteins were defined by amino-terminal sequence analysis. The existence of an additional protein(s) of unknown function, encoded downstream of the protease-coding region, was deduced from the positions of these amino termini and the sizes of known Ty3 proteins. Although Ty3 protease cleavage sites do not correspond exactly to known retroviral protease cleavage sites, there are similarities. Residues P3 through P2' in the regions encompassing each of the five sites are uncharged, and no P1 position is occupied by an amino acid with a branched beta carbon.     

Peripheral and central pharmacokinetics of apomorphine and its effect on dopamine metabolism in humans

Apomorphine is a dopamine receptor agonist increasingly used in the treatment of Parkinson's disease (PD). In the present study, we examined the plasma and ventricular cerebrospinal fluid (CSF) pharmacokinetics of apomorphine as well as its effects on dopamine metabolism in six patients (one woman and five men, mean age 79.5 years) without evidence of PD who underwent 48-h intracranial pressure monitoring for suspected normal pressure hydrocephalus. Maximal plasma apomorphine concentration (25.04 ng/ml) is found 20 min after subcutaneous injection (50 micrograms/kg), and the mean area under the curve is 1,439.37 ng/ml for 120 min. In contrast to plasma values, the maximal ventricular CSF apomorphine concentration (1.08 ng/ml) is found 30 min after injection and the mean area under that curve is 7% of that of plasma (96.69 ng/ml for 120 min). Apomorphine administration causes a significant reduction in ventricular CSF concentrations of dopamine and of its major metabolites sulfoconjugated dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA). This effect starts 10 min after the injection of apomorphine, is maximal after 30 min (free dopamine, -30%; sulfoconjugated dopamine, -28%; HVA, -21%; DOPAC, -31%) and is still present, although to a lesser extent (-5 to -10%), 120 min after the injection of apomorphine. This study shows that in humans a dose of apomorphine commonly used in PD causes significant inhibition of dopamine metabolism lasting > 120 min. In addition to their symptomatic effects, dopamine agonists such as apomorphine may play a role in preventing or slowing the neurodegeneration in PD by autoreceptor-mediated inhibition of dopamine metabolism.     

Effects of repeated clarithromycin administration on the pharmacokinetic properties of pindolol in rats

The goal of the present work was to determine the effect of clarithromycin (CAM) administration on the pharmacokinetic properties of pindolol in rats. The binding of pindolol to serum components increases proportionally with increasing alpha1-acid glycoprotein (AGP) concentration, indicating that AGP might play a major role in the binding of pindolol. After intravenous administration of pindolol to rats, the CAM-treated group showed a decrease in the volume of distribution, an increase in AUC and no change in the half-life as compared to the control group. Treatment with CAM increased the AGP concentration only. The serum concentration of albumin and creatinine, as well as the metabolic activity of hepatic microsomes towards pindolol, were not altered. Good correlation was observed between the AUC of pindolol in rats and the AGP concentration in serum. Moreover, at 5 min after the administration of an intravenous bolus dose of pindolol to CAM-treated rats, the free concentration of pindolol was lower but the total concentration was higher, compared with the control rats. These results suggested that the influence of CAM on the pharmacokinetic properties of pindolol in CAM-treated rats can be explained by protein binding which, in turn, may be associated with variations in AGP concentration.