Effects of morphine in rats withdrawn from repeated nifedipine administration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 Further, the antinociceptive potency of acute morphine (2.5 mg/kg s.c.) was significantly reduced in rats withdrawn for 24 h from repeated nifedipine treatment.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.     

Effect of morphine on striatal dopamine metabolism and ascorbic and uric acid release in freely moving rats

Recent ex vivo findings have shown that morphine increases dopamine (DA) and xanthine oxidative metabolism and ascorbic acid (AA) oxidation in the rat striatum. In the present study, we evaluated the effects of subcutaneous daily morphine (20 mg/kg) administration on DA, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), AA and uric acid in the striatum of freely moving rats using microdialysis. Dialysates were assayed by high performance liquid chromatography with electrochemical detection. On the first day, morphine administration caused a significant increase in extracellular DA, DOPAC, HVA, AA and uric acid concentrations over a 3 h period after morphine. In all treated rats (n = 7), individual concentrations of DOPAC + HVA were directly correlated with individual AA and uric acid concentrations. Last morphine administration on the 4th day increased DOPAC, HVA, AA and uric acid concentrations but failed to increase those of DA. Individual DOPAC + HVA concentrations were still directly correlated with individual AA and uric acid concentrations. These results suggest that systemic morphine increases both striatal DA release and DA and xanthine oxidative metabolism. Only the former effect undergoes tolerance. The increase in DA oxidative metabolism is highly correlated with that of xanthine. The subsequent enhancement in reactive oxygen species production may account for the increase in extracellular AA.     

Sertraline induced parkinsonism. A case report and an in-vivo study of the effect of sertraline on dopamine metabolism

We report a patient with a parkinsonian syndrome induced by sertraline (Zoloft), an SSRI antidepressant, whose symptoms resolved after the drug was discontinued. This case prompted us to investigate the effect of sertraline on dopamine metabolism in animals. Sertraline (30 mg/kg, i.p.) or placebo (vehicle) was administered to two groups of six normal, anesthetized rats and using cerebral microdyalisis extracellular striatal levels of dopamine, the dopamine metabolites (HVA and DOPAC), as well as the serotonin metabolite 5-HIIA were monitored. In animals pre-treated with sertraline, DOPAC, HVA, and 5-HIAA levels were significantly decreased compared to control animals (p < 0.01). These data indicate that sertraline has an effect on dopamine metabolism, which may alter function in the striatum and induce a parkinsonian syndrome.     

Antibody reactivity to conserved linear epitopes of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1)

High concentrations of diazepam-binding inhibitor (DBI) have been detected in brain areas containing dopaminergic cell bodies and nerve terminals. In the present study, we have investigated the effect of a proteolytic fragment of DBI, the octadecaneuropeptide ODN, on apomorphine-induced yawning in Sprague-Dawley rats. Injection of graded doses of ODN (12.5 to 100 ng i.c.v.) caused a dose-dependent inhibition of apomorphine-induced yawning and penile erections. At a dose of 100 ng, intracerebroventricularly administered ODN was able to inhibit, during more than 3 h, the apomorphine-evoked yawning. ODN also inhibited pilocarpine-induced yawning. Apomorphine induces a bell-shaped dose-dependent effect on yawning with a maximum response at the dose of 100 microg/kg and a much lower effect at a dose of 200 microg/kg. Injection (i.c.v.) of 100 ng ODN markedly attenuated the number of yawns induced by 100 microg/kg apomorphine but partially restored the yawning behavior in rats treated with a 200 microg/kg dose of apomorphine. At doses of 0.5 or 5 mg/kg s.c., diazepam did not modify the inhibitory effect of ODN on the apomorphine-induced yawning. Taken together, the present data suggest that ODN inhibits yawning downstream dopaminergic as well as cholinergic synapses involved in yawning. In addition, the effect of ODN cannot be ascribed to an inverse agonistic activity on central-type benzodiazepine receptors.     

Naloxone-precipitated changes in biogenic amines and their metabolites in various brain regions of butorphanol-dependent rats

Influence of a naloxone (an opioid receptor antagonist) challenge (5 mg/kg, IP) on levels of biogenic amines and their metabolites in various brain regions of rats infused continuously with butorphanol (a mu/delta/kappa mixed opioid receptor agonist; 26 nmol/microliter/h) or morphine (a mu-opioid receptor agonist; 26 nmol/microliter/h) was investigated using high-performance liquid chromatography with electrochemical detection (HPLC-ED). Naloxone precipitated a withdrawal syndrome and decreased the levels of: dopamine (DA) in the cortex and striatum, 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum, homovanilic acid (HVA) in the striatum, limbic, midbrain, and pons/medulla regions in butorphanol-dependent rats. However, the levels of norepinephrine (NE), serotonin (5-hydroxytryptamine; 5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) in the regions studied were not affected by naloxone-precipitated withdrawal. In addition, naloxone increased the HVA/DA ratio in the cortex, while this ratio was reduced in the limbic, midbrain, and pons/medulla. The reduction of 5-HIAA/5-HT ratio was also detected in the limbic area. In the animals rendered dependent on morphine, the results obtained were similar to those of butorphanol-dependent rats except for changes of 5-HIAA levels in some brain regions. These results suggest that an alteration of dopaminergic neuron activity following a reduction of DA and its metabolites in specific brain regions (e.g., striatum, limbic, midbrain, and pons/medulla) play an important role in the expression of the opioid withdrawal syndrome.     

A hemagglutinin-based multipeptide construct elicits enhanced protective immune response in mice against influenza A virus infection

The effect of the muscarinic antagonist, scopolamine, was examined for a change in the increase in extracellular dopamine, dihydroxyphenyl acetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA), induced by haloperidol or clozapine in the striatum and nucleus accumbens of anaesthetised and awake rats, monitored using in vivo cerebral microdialysis. Rats received scopolamine (1 mg kg(-1); s.c.) or vehicle followed by haloperidol (1 mg kg(-1); s.c.) or clozapine (20 mg kg(-1); s.c.). Dopamine, DOPAC, HVA and 5-HIAA overflow into striatal or accumbens perfusates was determined using high performance liquid chromatography with electrochemical detection (HPLC-ECD). Scopolamine failed to modify the clozapine- or haloperidol-induced efflux of dopamine or its metabolites in either the striatum or nucleus accumbens following systemic administration in anaesthetised or awake rats. Although pretreatment with scopolamine tended to produce a smaller increase in the clozapine-induced efflux of DOPAC in striatal perfusates than following clozapine treatment alone, this was not statistically significant. Furthermore, local infusion of scopolamine (100 microM) with clozapine (1 mM) via the microdialysis probe did not attenuate the elevated efflux of dopamine observed following clozapine alone, in either the striatum or nucleus accumbens, in anaesthetised rats. This treatment did prevent the clozapine-induced increase in DOPAC and HVA in the striatum but not the nucleus accumbens. Carbachol (50 microM) infused into the dorsolateral striatum or nucleus accumbens raised extracellular dopamine levels 200% and 150%, respectively above baseline. Our data suggest that the increased efflux of dopamine and its metabolites in the rat basal ganglia following clozapine administration is not significantly dependent upon the interaction of clozapine with muscarinic receptors.     

Dopamine 'D2-like' receptor agonists in combination with cocaine: absence of interactive effects on locomotor activity

This study examined interactions between cocaine and drugs that act as direct agonists at subtypes of "D2-like" dopamine receptors. The drugs 7-OH-DPAT, quinpirole and RU24213 were studied alone and in combination with cocaine for their effects on locomotor activity in non-habituated mice. Locomotor activity was measured by photobeam crossings over 140 min. At the doses given (7-OH-DPAT: 0.006-6.4 mg/kg; quinpirole: 0.001-1 mg/kg; RU24213: 0.008-8 mg/kg) all three direct agonists dose-dependently reduced locomotor activity throughout the test, whereas cocaine (0.6-20 mg/kg) produced dose-related hyperactivity. Next, for each direct agonist, a series of doses was selected (up to threshold behaviourally-active doses) as pretreatments to a sub-maximally stimulant dose of cocaine (15 mg/kg). 7-OH-DPAT and quinpirole did not modulate the effects of cocaine; RU24213 produced, at best, a very modest attenuation of the effects of cocaine. Finally, a series of cocaine doses (below stimulant threshold) was given before a single dose of each direct agonist (the lowest dose to reduce activity significantly). Cocaine did not reliably alter the hypoactivity produced by any of the D2-like agonists. By demonstrating negligible interactions between cocaine and D2-like agonists, the results fail to demonstrate any necessary involvement of D2-like receptors in one of the behavioural effects of cocaine.     

Effect of scopolamine on the efflux of dopamine and its metabolites after clozapine, haloperidol or thioridazine

The extracellular concentrations of dopamine (DA) and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum and the nucleus accumbens were measured in awake, freely-moving rats. Clozapine (20 mg/kg, i.p.) increased extracellular DA and HVA in both regions but increased DOPAC only in the striatum. Scopolamine (1 mg/kg), although it had no effect by itself in the striatum or nucleus accumbens, inhibited the ability of clozapine to increase extracellular DA, DOPAC and HVA concentrations in the striatum. The clozapine-induced increase in DA in the frontal cortex was not blocked by scopolamine. Haloperidol (1 mg/kg, i.p.) and thioridazine (10 mg/kg, i.p.) also increased extracellular DA, DOPAC and HVA in the striatum, but scopolamine pretreatment did not inhibit these increases. The results suggest that clozapine differs from haloperidol and thioridazine in that the effect of clozapine, but not that of the two neuroleptic drugs, to increase DA release in the striatum acutely depends on muscarinic receptor stimulation. These results suggest that clozapine, despite its strong muscarinic antagonist properties, does not produce full blockade of muscarinic receptors in vivo in the striatum. The interaction of clozapine with the cholinergic system in the striatum could be relevant to its lack of ability to produce extrapyramidal symptoms or tardive dyskinesia.     

Glutathionyl hydroquinone: a potent pro-oxidant and a possible toxic metabolite of benzene

The effects of antidepressants given in a single dose or repeatedly (10 mg/kg p.o., twice daily, 14 days) on binding to dopamine D2 receptors in the striatum and limbic forebrain of Wistar male rats were studied. [3H]N-0437, (2-(N[2,3(n)-3H]propyl-N-(2-thiofuranyl)-2'-ethylamino) -5-hydroxy-1,2,3,4-tetrahydronaphthalene), a dopamine D2 receptor agonist, was used as a ligand. Already a single dose of imipramine and fluoxetine caused a statistically significant decrease in the affinity of the ligand for dopamine D2 receptors in the striatum, but only at 72 h after drug administration. Also at 72 h after the single dose of mianserin a significant increase in the density of dopamine D2 receptors was observed. Repeated imipramine, amitriptyline and mianserin increased the affinity for dopamine D2 receptors in the striatum and in the limbic forebrain. Repeated fluoxetine increased that affinity in the striatum, but decreased it in the limbic forebrain. The density of dopamine D2 receptors was increased by the repeated administration of the antidepressants studied in the limbic forebrain, but was not changed in the striatum. The results obtained in the present study are in good agreement with the previously reported enhancement of behavioural responsiveness to dopamine and dopamine stimulants (dopamine D2 up-regulation) evoked by repeated treatment with antidepressants.     

Dual-earner families: the importance of work stress and family stress for psychological well-being

The effect of neonatal hippocampal lesions on behavioral sensitivity to amphetamine (AMPH) and dopamine (DA) release in the nucleus accumbens (NAc) were examined. The ventral hippocampus was damaged bilaterally by ibotenic acid on postnatal day 7 (PD7). Spontaneous exploration and AMPH-stimulated locomotor activity were examined on postnatal day 35 (PD35) and day 56 (PD56). Extracellular DA, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were sampled using in vivo microdialysis while simultaneously AMPH-stimulated locomotion was examined in freely moving rats on PD56. Spontaneous exploration increased in rats with hippocampal lesions relative to controls on PD56 but not PD35. AMPH (0, 0.187, 0.375, 0.75, 1.5, and 3 mg/kg) enhanced locomotion dose-dependently in both control and lesioned groups. Locomotor activity was higher in lesioned rats than controls following AMPH at the dose of 0.75 mg/kg on PD35 and at the doses of 1.5 and 3.0 mg/kg on PD56. The basal level of DA in the NAc was not different between the hippocampal and control groups. AMPH (1.5 mg/kg) induced hyperlocomotion in lesioned rats relative to controls. DA release in the NAc for both groups was enhanced following injections of AMPH. However, neonatal hippocampal lesions had no further enhancement on AMPH-stimulated release of DA as compared to the control group. The levels of DOPAC and HVA in the NAc were altered by AMPH but not lesions. The level of 5-HIAA was not influenced by either lesions or AMPH. The results of neonatal lesion-induced hyperlocomotion suggest that an emergence of behavioral hyperresponsiveness to AMPH was dependent on an interaction of lesions, age of examination, and dose of the drug. A dissociation between the effect of AMPH on lesion-enhanced hyperlocomotion and a lack of a lesion-enhanced DA release in the NAc suggest that presynaptic release of DA had no major contribution to lesion-enhanced DA transmission in the mesolimbic DA system.     

Pharmacokinetic and pharmacodynamic studies of L-dopa in rats. II. Effect of L-dopa on dopamine and dopamine metabolite concentration in rat striatum

The purpose of this investigation was to quantitatively describe the time courses of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations in the striatum after L-dopa injection using a constructed dopamine metabolism model. The time courses of dopamine, DOPAC and HVA concentration in the striatum of rats was determined before and after the rapid i.v. injection of 10, 50 and 100 mg/kg using the same animals as in the previous report. The endogenous dopamine, DOPAC and HVA concentrations in the striatum before L-dopa administration were 5.9 +/- 0.7 micrograms, 3.6 +/- 0.4 micrograms and 1.0 +/- 0.2 micrograms/g, respectively. The dopamine concentration in the striatum increased immediately after L-dopa injection, with the peak concentration (15.9 +/- 0.5 micrograms/g) occurring at 3 min; then it returned to the pre-medication level until 2 h at 100 mg/kg dosing. The time course of dopamine concentration in the striatum was analyzed on a constructed dopamine metabolism model which has a zero-order production rate for the production of dopamine (i.e. release from the dopamine neuronal terminals) and two apparent first-order clearance terms, one from L-dopa to dopamine, which was estimated in the previous report, and the other from dopamine to dopamine metabolites (DOPAC and HVA). However, the time course of dopamine concentration in the striatum could not be described by this model.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dissociation of morphine-induced potentiation of turning and striatal dopamine release by amphetamine in the nigrally-lesioned rat

Morphine has been reported to increase extracellular levels of dopamine in the brain of intact rats and to potentiate turning induced by amphetamine in nigrally-lesioned rats. The present study tested the hypothesis that there is a causal relationship between these two effects of morphine. We tested morphine alone, amphetamine alone, and the combination in separate groups of nigrally-lesioned rats for effects on turning and, by microdialysis, on extracellular dopamine levels. Morphine (3.0 or 10 mg/kg) did not produce significant turning but amphetamine (1.0 mg/kg) did. The lower dose, but not the higher dose, of morphine potentiated amphetamine-induced turning. Amphetamine, but not morphine, produced increases in extracellular dopamine levels. In contrast to what occurred with turning, 10 mg/kg but not 3.0 mg/kg morphine potentiated amphetamine-induced increases in extracellular dopamine levels. These results show that the potentiation of amphetamine-induced turning by morphine in nigrally-lesioned rats is not due to the potentiation of dopamine release in the intact striatum.     

Apparent thermodynamic parameters of ligand binding to the cloned rat mu-opioid receptor

This study examined the involvement of spinal dopamine D2 receptors in the cardiovascular effects induced by intravenous administration of the selective dopamine D2 receptor agonist quinpirole, as has been previously reported for the hypotensive action of systemic bromocriptine. In normotensive pentobartitone-anaesthetised rats, intravenous injection of quinpirole (25 to 1000 microg/kg) decreased mean aortic pressure and heart rate in a dose-related manner. The intravenous (0.5 mg/kg) or intrathecal (40 microg/rat at T9-T10) pretreatment with domperidone, a dopamine D2 receptor antagonist that does not cross the blood-brain barrier, significantly reduced the maximal hypotensive and bradycardic responses to intravenous quinpirole (1000 microg/kg). In contrast, the latter effects were fully abolished either by intravenous metoclopramide (5 mg/kg) or combined pretreatment with intravenous and intrathecal domperidone. In addition, when injected intrathecally at the T9-T10 level of the spinal cord, quinpirole (7.7 to 61.4 microg/rat) also produced dose-dependent depressor and bradycardic effects which could be blocked by intrathecal, but not intravenous, domperidone pretreatment. This suggests that, in anaesthetised normotensive rats, the hypotensive and bradycardic responses to intravenous quinpirole are fully mediated by dopamine D2 receptors, some of which are located in the peripheral circulation and some of which are located within the spinal cord. The latter finding is novel, suggesting that partial spinal mediation may not be peculiar to bromocriptine, as was previously thought. Rather, partial spinal mediation may be common to most dopamine D2 receptor agonists.     

Effect of morphine applied by intrapallidal microdialysis on the release of dopamine in the nucleus accumbens

The effect of morphine, administered intrapallidally, on extracellular concentrations of DA, DOPAC, and HVA in the nucleus accumbens and striatum was studied in the behaving rat using the in vivo microdialysis technique. Unilateral application of morphine hydrochloride was performed through microdialysis probes into the rat ventral pallidum (10 microliters of 0, 2.6, 4.0, 13.0, and 26.0 mM) or globus pallidus (10 microliters of 0 and 26.0 mM). The levels of DA, DOPAC, and HVA were measured using the HPLC with EC detection in dialysates collected from the nucleus accumbens, anteromedial, and anterolateral striatum. Samples were taken every 45 min over 3 h before and over 5 h after morphine or vehicle administration. Administration of morphine into the ventral pallidum resulted in increased DOPAC and HVA concentrations in the nucleus accumbens. Pretreatment with naloxone (1 mg/kg, SC) abolished this effect of morphine. Administration of morphine into the globus pallidus resulted in increased DA, DOPAC, and HVA concentrations in the nucleus accumbens and DA in the anteromedial striatum. The levels of DA and metabolites in anterolateral striatum remained rather unchanged following morphine administered into the ventral pallidum or the globus pallidus. The changes in DA neurotransmission into the nucleus accumbens induced by morphine application into the ventral pallidum and globus pallidus are reminiscent of a phasic and tonic release of DA respectively. The results show that intrapallidal morphine increases DA neurotransmission in nucleus accumbens and suggest that the effect of morphine is mediated by ventral pallidum/mesolimbic and globus pallidus/thalamocortical pathways, depending on the site of injection.     

Effects of acute and chronic morphine on rotational behavior in nigral-lesioned rats

Stimulation of mu-opioid receptors located on dopaminergic neurons in the striatum and the nucleus accumbens increases dopamine release, which may account for some of the behavioral effects of morphine. In this study, we examined the effects of acute and chronic morphine treatment on rotational behavior in rats with unilateral 6-hydroxydopamine dopamine (6-OHDA)-induced lesions of the nigrostriatal pathway. Rats receiving morphine acutely (0.3-10 mg/kg) did not show a significant bias toward contralateral or ipsilateral turning. Mini osmotic pumps dispensing morphine continuously (20-24 mg/kg/day) were implanted s.c. in these animals. This treatment induced tolerance to the behavioral depression produced by the highest dose of morphine (10 mg/kg) when it was given acutely. A slight but significant increase in ipsilateral turning occurred over the range of morphine doses examined. The effects of morphine on rotational behavior are slight, and do not correlate well with the reported increase in locomotor activity or extraneural dopamine in the striatum that are produced by doses of morphine similar to the ones tested in this study.     

Modulation of dopamine release in the nucleus accumbens by 5-HT1B agonists: involvement of the hippocampo-accumbens pathway

Changes in extracellular levels of dopamine (DA), DA metabolites DOPAC and HVA, and the serotonin metabolite 5-HIAA, were measured by microdialysis in the rat nucleus accumbens (n. acc) after treatments with serotonin (5-HT)1A (8-OH-DPAT) or 5-HT1B (RU 24969 and S-CM-GTNH2) receptor agonists. Subcutaneous injections of RU 24969 (0.02-2 mg/kg) dose-dependently decreased 5-HIAA levels (0 to -38%), and also induced long-lasting increases in DA levels (0 to +37%) and DOPAC (+11% at the dose 0.5 mg/kg) in the shell of the n. acc, whereas 8-OH-DPAT (0.25 and 0.5 mg/kg) reduced 5-HIAA levels (-25%) and very slightly increased DOPAC at the lower dose (+4%), but had no effect on DA levels. Three weeks after interruption of the subicular efferent projections, the increase in DA levels previously observed after systemic injections of RU 24969 was abolished. Microinjections of RU 24969 (10 micrograms/microliter) or S-CM-GTNH2 (3 micrograms/microliter) into the ventral subicular area reproduced the effects of systemic injections of RU 24969 cn DA levels and increased DOPAC (+13%; +19%, respectively) and HVA levels (+23%; +24%), with no significant change in 5-HIAA. It is concluded that: (1) serotonin interacts with the mesolimbic dopaminergic system through 5-HT1B, but not 5-HT1A, receptors: and (2) serotonin interaction with the mesolimbic dopaminergic system involves postjunctional 5-HT1B heteroreceptors located in the ventral subicular area, which modulate the activity of glutamatergic hippocampo-accumbens pathways and only secondarily alter DA levels in the n. acc. The possible relevance of these results for schizophrenia is discussed.     

Plasmodium falciparum: influence of malarial and host erythrocyte skeletal protein interactions on phosphorylation in infected erythrocytes

Striatopallidal output neurons, which coexpress D2-dopamine receptors and NMDA receptors, are logically a potential site of interaction between corticostriatal glutamatergic input and dopaminergic systems. Recent hypotheses about the etiology of schizophrenia have implicated both excitatory amino acid and dopamine systems. The present study was designed to examine, in vivo, the interaction between D2-dopamine receptors and NMDA receptors in the regulation of the expression of the early immediate genes (IEGs), zif 268 and jun B, in striatopallidal neurons. We tested whether coadministration of NMDA antagonists interacted with the actions of the D2 agonist, quinpirole, on IEG expression following dopamine depletion with reserpine. When rats were pretreated with the non-competitive NMDA receptor antagonists, MK 801 (1 mg/kg) or PCP (20 mg/kg), together with quinpirole, the quinpirole reversal of reserpine induction of zif 268 mRNA was potentiated in all regions examined. MK 801 alone had no significant effect on reserpine induction of zif 268 mRNA. Pretreatment with the competitive NMDA receptor antagonist, CPP (5 mg/kg), did not significantly alter the dose response of zif 268 mRNA expression to quinpirole in any region. There was no significant effect of MK 801 on jun B mRNA expression, either on the response to quinpirole or when administered alone with reserpine. Our findings provide evidence of an interaction between the NMDA receptor channel system and the D2-dopamine system on a molecular level in striatopallidal neurons carrying output from the basal ganglia.     

Behavioral and neurochemical effects of acute and repeated administration of triadimefon in the male rat

The effects of triadimefon (TDF) were examined in male Sprague-Dawley rats. In this study, the acute administration of TDF (100 mg/kg) was found to significantly increase locomotor activity and induce stereotyped behavior. Acute administration of TDF was also found to significantly increase dopamine (DA) and homovanillic acid (HVA) levels while the dihydroxyphenylacetic acid (DOPAC) level remained unchanged in both the nucleus accumbens (NA) and striatal (ST) tissues when compared to control. Furthermore, DOPAC:DA ratios were significantly reduced in both brain regions suggesting an increase in DA turn overrate. On the other hand, in animals receiving repeated TDF administration, only the HVA level was significantly increased in both the ST and NA. TDF neither competed for binding to D2, D3 or D4 DA receptors nor altered the Kd or the Bmax of [3H] SCH 23390 and [3H] spiperone recognition sites associated with striatal D1 and D2 receptors, respectively. Meanwhile, TDF competed with [3H] GBR 12935 for binding to DA transporter sites with strong affinity, but repeated treatment with TDF had no sustained or cumulative effect on the DA transporter system. These results clearly show that acute TDF-induced behavioral effects may not be via binding to DA receptors, but through the interaction with DA transporter binding sites. Also, TDF does not appear to produce cumulative effects in the parameters evaluated.     

Preferential involvement of D3 versus D2 dopamine receptors in the effects of dopamine receptor ligands on oral ethanol self-administration in rats

There is evidence that dopamine transmission is involved in reinforcement processes and the present study investigated the relative involvement of D3 versus D2 dopamine receptors in the effects of dopamine ligands on the reinforcing action of ethanol. Rats were trained to self-administer ethanol (10% v/v) orally in a free-choice two-lever operant task using a saccharin-fading procedure. When preference in responding for ethanol over water had developed the rats were tested with several dopamine agonists and antagonists. Pretreatment with the non-selective dopamine agonist, apomorphine (0.01-0.1 mg/kg), the preferential D2 agonist, bromocriptine (1-10 mg/kg) and the selective D3 agonists, 7-OH-DPAT (0.003-0.1 mg/kg), PD 128907 (0.1-3 mg/kg), (+)3PPP (0.3-3 mg/kg), quinelorane (0.0001-0.003 mg/kg) and quinpirole (0.003-0.03 mg/kg), resulted in dose-dependent decreases in responding for ethanol. The relative potencies of the dopamine agonists to decrease ethanol self-administration were highly correlated with their published potencies to produce in vitro functional D3 but not D2 responses. Active doses could be considered as those selectively stimulating receptors involved in the control of dopamine release, suggesting that reduction of dopamine transmission was associated with a decrease in ethanol-reinforced responding. This conclusion was further supported by the finding that pretreatment with the D2/D3 dopamine antagonists, haloperidol (0.1-0.4 mg/kg) and tiapride (10-60 mg/kg), decreased responding for ethanol at doses which have been shown previously to block dopamine transmission.     

Systemic administration of CCK-8S, but not CCK-4, enhances dopamine turnover in the posterior nucleus accumbens: a microdialysis study in freely moving rats

The present study was carried out to examine the effects of peripheral administration of sulfatedcholecystokinin octapeptide (CCK-8S) on dopamine (DA) turnover in the posterior nucleus accumbens (PNAc) and the caudate-putamen (CP) in awake rats. Microdialysis was used to quantify the extracellular concentrations of DA and its two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Intraperitoneal injections of CCK-8S (0.3 mg/kg b.wt.) caused a significant increase in DOPAC and HVA concentrations in the PNAc, but did not affect the DA level. Such increases in the metabolite contents were not found in the CP. Similar injections of vehicle (1% NaHCO3 solution, 1 ml/kg b.wt.) did not have an effect in either brain region. In an attempt to determine the type of receptor involved in the CCK-8S-induced changes, CCK tetrapeptide (CCK-4, 0.3 mg/kg b.wt.) known to have high affinity for CCKB subtype or vehicle (10% DMSO-saline, 1 ml/kg b.wt.) was administered intraperitoneally. Neither CCK-4 nor vehicle caused significant changes in any of extracellular DA, DOPAC and HVA contents in the PNAc. These results suggest that peripherally administered CCK-8S has stimulatory effects on the dopaminergic system in the PNAc, and raise the possibility that the effect appears to be mediated via CCKA receptors.