Comparison of chronic intermittent haloperidol and raclopride effects on striatal dopamine release and synaptic ultrastructure in rats.

The effects of chronic intermittent administration (7 months) of two neuroleptics, haloperidol (HAL) and raclopride (RAC), were compared using several different measures. Both drugs were administered weekly by subcutaneous injection at 7.0 mg/kg. Both neuroleptics consistently produced catalepsy throughout the treatment period, although HAL was generally more cataleptogenic than RAC. Assessment of dopamine (DA) release in the caudate putamen (CPu), through the use of in vivo microdialysis, showed that chronic HAL or RAC administration caused a prolonged decrease of DA release in response to a low dose of the DA D2 agonist quinpirole (0.03 mg/kg, sc). Injection of the muscarinic agonist pilocarpine (1.0 mg/kg, IP) did not have any significant within-group effects, although both neuroleptic treatment groups showed decreased DA release when compared to controls. Ultrastructural analysis of the dorsolateral CPu showed that both HAL and RAC treatment resulted in a significant increase in the number of perforated synapses, which contain a discontinuous density along the postsynaptic membrane. These results demonstrate that two different DA D2 receptor antagonists produce a similar effect on DA function and ultrastructural changes within the CPu following chronic, intermittent treatment.     

Differential regulation of striatal preproenkephalin mRNA by D1 and D2 dopamine receptors.

The effect of administration of subtype selective dopamine (DA) agonists on the 6-hydroxydopamine (6-OHDA) lesion-induced increase of striatal preproenkephalin (PPE) mRNA was examined by dot-blot hybridization. Eight days following a unilateral 6-OHDA lesion of the substantia nigra pars compacta (SNc), PPE mRNA levels in the ipsilateral striatum were increased approximately two-fold. Administration of the D2 DA agonist, quinpirole, dose-dependently attenuated the 6-OHDA lesion-induced increase in striatal PPE mRNA. The effect of quinpirole was blocked by coadministration of the D2 DA antagonist eticlopride. In contrast, administration of the D1 DA agonist, SKF 38393, either dose-dependently augmented or had no effect on the 6-OHDA lesion-induced increase in striatal PPE mRNA. In the contralateral striatum, administration of quinpirole decreased PPE mRNA, while administration of SKF 38393 increased PPE mRNA compared to sham lesioned control levels. These data suggest the action of DA at D1 and D2 DA receptors differentially regulates striatal PPE mRNA levels and the apparent inhibition of ENK biosynthesis by DA is mediated via an interaction with D2 DA receptors.     

Modulation of pre- and postsynaptic dopamine D2 receptor function by the selective kappa-opioid receptor agonist U69593

The repeated administration of selective kappa-opioid receptor agonists prevents the locomotor activation produced by acute cocaine administration and the development of cocaine-induced behavioral sensitization. Previous studies have shown that dopamine (DA) D2 autoreceptors modulate the synthesis and release of DA in the striatum. Evidence that kappa agonist treatment downregulates DA D2 receptors in this same brain region has recently been obtained. Accordingly, the present studies were undertaken to examine the influence of repeated kappa-opioid receptor agonist administration on pre- and postsynaptic DA D2 receptor function in the dorsal striatum using pre- and postsynaptic receptor-selective doses of quinpirole. Rats were injected once daily with the selective kappa-opioid receptor agonist U69593 (0.16-0.32 mg/kg s.c.) or vehicle for 3 days. Microdialysis studies assessing basal and quinpirole-evoked (0.05 mg/kg s.c.) DA levels were conducted 2 days later. Basal and quinpirole-stimulated locomotor activity were assessed in a parallel group of animals. The no-net flux method of quantitative microdialysis revealed no effect of U69593 on basal DA dynamics, in that extracellular DA concentration and extraction fraction did not differ in control and U69593-treated animals. Acute administration of quinpirole significantly decreased striatal DA levels in control animals, but in animals treated with U69593, the inhibitory effects of quinpirole were significantly reduced. Quinpirole produced a dose-related increase in locomotor activity in control animals, and this effect was significantly attenuated in U69593-treated animals. These data reveal that prior repeated administration of a selective kappa-opioid receptor agonist attenuates quinpirole-induced alterations in DA neurotransmission and locomotor activity. These results suggest that both pre- and postsynaptic striatal DA D2 receptors may be downregulated following repeated kappa-opioid receptor agonist administration. Synapse 39:343-350, 2001. Published 2001 Wiley-Liss, Inc.     

Effects of low,autoreceptor selective doses of dopamine agonists on the discriminative cue and locomotor hyperactivity produced by d-amphetamine

Summary The ability of low doses of the dopamine (DA) agonists quinpirole and (+)-3-PPP to reduce the discriminative stimulus properties and locomotor hyperactivity produced by d-amphetamine (0.5 mg/kg) was assessed in two groups of rats. Quinpirole (0.0125–0.05mg/kg) and (+)-3-PPP (1.0–2.0 mg/kg) completely antagonized d-amphetamine-induced locomotor hyperactivity. In contrast, only single doses of quinpirole (0.025 mg/kg) and (+)-3-PPP (2.0 mg/ kg) were effective in the drug discrimination paradigm; the antagonisms were small (18–47%), but significant. The inhibitory effects of quinpirole and (+)-3-PPP in these behavioural models are probably due to their ability to selectively stimulate DA autoreceptors in the nucleus accumbens and reduce the increase in DA release produced by d-amphetamine. It is suggested that the much weaker effects of the drugs in the discrimination paradigm are due to changes produced by the long-term periodic administration of d-amphetamine to these animals, such as a down-regulation in the sensitivity of DA autoreceptors.     

Repeated D1 dopamine receptor agonist administration prevents the development of both D1 and D2 striatal receptor supersensitivity following denervation.

Following 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopamine (DA) pathway, rat caudate-putamen (CPu) neurons are supersensitive to the inhibitory effects of both D1 and D2 dopamine (DA) receptor selective agonists. In addition, both the necessity of D1 receptor stimulation for D2 agonist-induced inhibition and the synergistic inhibitory effects of D1 and D2 agonists are abolished by denervation. The present study attempted to determine the relative roles of D1 and D2 DA receptors in the development of denervation supersensitivity to DA agonists and the "uncoupling" of functional interactions between the receptors following 6-OHDA lesions of the nigrostriatal DA pathway. Beginning on the day after an intraventricular 6-OHDA (or vehicle) injection, groups of rats received daily injections of either the selective D1 receptor agonist SKF 38393 (8.0 mg/kg, s.c.), the D2 agonist quinpirole (0.5 mg/kg, s.c.), or saline for 7 days. On the day following the last agonist injection, rats were anesthetized and prepared for extracellular single cell recording with iontophoretic drug administration. Daily administration of quinpirole selectively prevented the development of D2 receptor supersensitivity, whereas daily administration of SKF 38393 prevented the development of both D1 and D2 receptor supersensitivity. In addition, D1, but not D2, agonist treatment prevented the loss of synergistic inhibitory responses typically produced by 6-OHDA lesions. Behavioral observations revealed similar effects; daily injections of SKF 38393, but not quinpirole, prevented contralateral rotational responses to the mixed D1/D2 agonist apomorphine (1.0 mg/kg, s.c.) in rats with unilateral 6-OHDA lesions of the nigrostriatal pathway. After a 4-week withdrawal from repeated D1 agonist treatment, both supersensitive inhibitory responses of CPu neurons and contralateral rotations to apomorphine were evident, indicating that the preventative effects on DA receptor supersensitivity were not permanent. These findings indicate that continued agonist occupation of striatal D1 DA receptors following DA denervation not only prevents the development of D1 DA receptor supersensitivity but also exerts a similar regulation of D2 receptor sensitivity.     

The influence of repeated treatment with imipramine, (+)- and (−)-oxaprotiline on behavioural effects of dopamine D-1 and D-2 agonists

Summary The paper examined the action of imipramine, (+)- and (–)-oxaprotiline, administered repeatedly to rats, on the behavioural effects of the dopamine D-1 and D-2 agonists, SKF 38393 and quinpirole, respectively. The three antidepressants studied, given in the single dose or repeatedly, attenuate the enhanced grooming evoked by SKF 38393. The locomotor hyperactivity, evoked by quinpirole administered s.c., is increased by repeated but not single-dose treatment with imipramine and (+)-oxaprotiline [but not with (–)-oxaprotiline]. Quinpirole at a low dose produces the locomotor hypoactivity which is attenuated by repeated, but not single-dose, treatment with the antidepressants studied here. Repeated imipramine and (+)-oxaprotiline [but not (–)-oxaprotiline] increase the locomotor activity effect of quinpirole injected into the nucleus accumbens.The results indicate that the enhanced responsiveness of the dopamine system, observed previously after repeated treatment with antidepressants, may be mediated by the dopamine D-2 receptors.     

Striatal c-fos levels do not correlate with haloperidol-induced behavioral supersensitivity

Striatal c-fos levels and stereotyped behavior have been evaluated in chronically haloperidol-treated rats which received subsequent subacute dopamine (DA) agonist treatment to investigate the possible relationship between striatal c-fos and behavioral supersensitivity. Haloperidol treatment (1 mg/kg/day for 21 days) increased apomorphine-induced stereotypies but did not modify striatal c-fos levels. The subacute administration of the DA D-1 agonist SKF38393 (10 mg/kg/day for 5 days) and the combination of the D-1 agonist with the D-2 agonist quinpirole (1 mg/kg/day for 5 days) attenuated apomorphine-induced stereotypies after haloperidol pretreatment. The administration of quinpirole alone, however, did not modify the response to haloperidol. All DA agonists significantly increased c-fos levels after apomorphine injection. The dissociation between haloperidol-induced behavioral supersensitivity and striatal c-fos levels observed in this study suggests that mechanisms different from striatal c-fos induction might be involved, and that striatal c-fos levels are not a good marker of behavioral supersensitivity expression. © 1996 Wiley-Liss, Inc.     

Effects of amantadine and budipine on antidepressant drug-evoked changes in extracellular dopamine in the frontal cortex of freely moving rats

NMDA receptors play a role in the aetiology of depression with non-competitive NMDA receptor antagonists such as amantadine showing synergy with conventional antidepressants. To advance a neurochemical rational for these findings, we have studied the effects of administration of amantadine and budipine with the antidepressants reboxetine (REB), paroxetine (PAROX) and clomipramine (CLOM) on extracellular DA in rats using microdialysis. Acutely, amantadine (40 mg/kg) or budipine (10 mg/kg) did not significantly alter extracellular DA. REB (10 mg/kg), PAROX (10 mg/kg) both increased cortical DA while CLOM (10 mg/kg) produced a decrease. When amantadine or budipine was administered 30 min before the antidepressants, DA increases were markedly greater than following the antidepressants alone. Chronically drug effects were studied at 4, 7, 14 and 21 days. Amantadine and budipine did not significantly alter extracellular DA at any time. The three antidepressants elicited a gradual increase in DA which became significant after 7 days and tended to plateau thereafter. When amantadine (20 mg/kg) or budipine (5 mg/kg) was co-administered with the three antidepressants, two differences were seen compared with the antidepressants alone. Firstly, the time required for significant increases in cortical DA was reduced with elevated levels now being observed by 4 days. Secondly, the increase in extracellular DA was greater in these rats throughout the experiment. If increased extracellular DA represents a step in the mechanism of action of antidepressants, these data suggest that combined treatment with clinically tolerated NMDA antagonists such as amantadine could reduce the delay in therapeutic onset of antidepressants and possibly enhance their efficacy.     

Effect of long-term haloperidol treatment on striatal neuropeptides: Relation to stereotyped behavior

Behavioral and biochemical responses to D₁ and D₂ dopamine (DA) agonists were used to evaluate the participation of striatal peptidergic mechanisms in the motor function alterations that attend chronic neuroleptic treatment. Rats, given haloperidol (1 mg/kg, s.c.) for 21 consecutive days, were randomly allocated to one of the following treatments: the D₁ agonist SKF 38393, the D₂ agonist quinpirole, their combination or saline. Stereotyped behavior and neuropeptide levels were evaluated after 5 days treatment and 4 days washout. Haloperidol increased most oral behaviors including licking, chewing and biting as well as striatal enkephalin and somatostatin levels. Subsequent treatment with SKF 38393 diminished the haloperidol-induced increase in licking and chewing; quinpirole reduced chewing behavior. The administration of both agonists together decreased chewing and biting. Neither DA agonist alone, nor their combination, reduced the haloperidol-induced increase in enkephalin levels. Both SKF 38393 and quinpirole, when given alone, tended to decrease the haloperidol-induced increase in somatostatin levels; when both the D₁ and D₂ agonists were administered together, somatostatin levels declined significantly. These results suggest that somatostatin- but not enkephalin-containing striatal neurons contribute to the expression of haloperidol-induced stereotypies.     

Effect of repeated administration of dopamine agonists on striatal neuropeptide mRNA expression in rats with a unilateral nigral 6-hydroxydopamine lesion

Summary Striatal mRNA expression for preproenkephalin (PPE) and preprotachykinin (PPT) was studied in unilateral 6-OHDA lesioned rats treated subchronically with a range of selective and non-selective D-1 or D-2 dopamine (DA) agonists. Apomorphine (5mg/kg sc), pergolide (0.5mg/kg sc), SKF 38393 (5mg/kg sc), SKF 80723 (1.5mg/kg sc), and quinpirole (5mg/ kg sc), or 0.9% saline (150l sc) were all given twice daily (except pergolide: once daily) for 7 days. The abundance of PPE mRNA was not altered by any of these DA agonists in the intact striatum contralateral to the 6-OHDA lesion. Only apomorphine and quinpirole increased the abundance of PPT mRNA in the intact striatum. In saline treated 6-OHDA lesioned animals PPE mRNA was elevated (+160%, p < 0.005) and PPT mRNA decreased (–36%, p < 0.005) in the denervated striatum. The up-regulation of striatal PPE mRNA in the lesioned striatum was reversed only by pergolide. The downregulation of striatal PPT mRNA in the lesioned striatum was reversed only by apomorphine. The differential sensitivity of the striatal PPE message to the long-acting DA agonist pergolide, and of the striatal PPT message to the mixed D-1/D-2 DA agonist apomorphine suggests that the striatopallidal enkephalinergic pathways are mainly regulated by prolonged DA receptor stimulation, whereas the striatonigral substance P pathways are mainly regulated by mixed D-1/D-2 DA receptor stimulation.     

Dopaminergic mechanism of imipramine action in an animal model of depression

Rats, subjected chronically (10-12 weeks) to a variety of mild, unpredictable stressors, showed a decrease in their consumption of weak sucrose solutions; normal behavior was restored by chronic (5-9 weeks) treatment with the tricyclic antidepressant imipramine. Acute administration of the dopamine receptor antagonist pimozide or the specific dopamine D2 receptor antagonist raclopride had no effect in nonstressed animals and in vehicle-treated stressed animals, but both drugs selectively reversed the improvement of performance in imipramine-treated stressed animals. The 5HT antagonist metergoline increased sucrose consumption in all groups. The data suggest that the mechanism of action of imipramine in this model is an increase in functional activity at dopamine (DA) synapses.     

Nigral D1 and striatal D2 receptors mediate the behavioral effects of dopamine agonists

The mediation of behavior by nigral and striatal dopamine (DA) D1 and D2 receptors was investigated in rats that had sustained extensive unilateral 6-hydroxydopamine-induced injury to ascending DA neurons. Selective D1 and D2 agonists and antagonists were injected directly into the DA-denervated substantia nigra pars reticula or the caudate-putamen via a chronically indwelling cannula. Contralateral rotation resulting from unilateral stimulation of supersensitive DA receptors was quantified over 46 min. Intrastriatal apomorphine (5 micrograms) or the selective D2 agonist quinpirole (5 micrograms), but not the selective D1 agonist (+/-)-SKF 38393 (15 micrograms), induced vigorous rotation. The rotation induced by intrastriatal quinpirole was greatly diminished by systemic administration of the selective D2 antagonist eticlopride (0.5 mg/kg, i.p.) and could not be enhanced by additional injection of intrastriatal (+/-)-SKF 38393. Intranigral administration of apomorphine or (+/-)-SKF 38393, but not quinpirole (same doses as above), elicited vigorous rotation. However, the rotation induced by intranigral (+/-)-SKF 38393 could not be blocked by systemic administration of the selective D1 antagonist SCH 23390 (0.5 mg/kg, s.c.), and was mimicked by intranigral (-)-SKF 38393 (15 micrograms), which exhibits 100-fold less activity than the dextrorotatory enantiomer at the D1 receptor. In order to circumvent the problem of this drug's apparent non-D1-mediated action when injected intranigrally, rotation was induced by systemic (+/-)-SKF 38393 (2.0 mg/kg, i.p.) 10 min after intranigral administration of selective antagonists. Intranigral SCH 23390 (10 micrograms), but not eticlopride (10 micrograms), powerfully antagonized the rotation induced by systemic (+/-)-SKF 38393. Conversely, rotation induced by systemic quinpirole (0.5 mg/kg, i.p.) was potently blocked by intrastriatal eticlopride but not SCH 23390. Rotation induced by systemic apomorphine (0.25 mg/kg, i.p.) was not attenuated by either antagonist alone, regardless of intracerebral injection site. The results indicate that both nigral D1 and striatal D2 receptors mediate the behavioral effects of DA agonists. These data may be useful in elucidating the mechanism(s) underlying the D1/D2 synergism observed in neurologically intact animals, as well as in understanding the action of drugs used in the treatment of Parkinson's disease.     

Dopamine agonists at repeated "autoreceptor-selective" doses: effects upon the sensitivity of A10 dopamine autoreceptors

Previous reports have established the ability of dopamine (DA) agonists to stimulate inhibitory DA autoreceptors at doses which minimally stimulate postsynaptic DA receptors, suggesting that hyperactive DA transmission may be controlled clinically by treatment with DA agonists. Little is known, however, about the possible loss of autoreceptor sensitivity that may occur after repeated treatment with low doses of DA agonists. Extracellular single cell recording and microiontophoretic techniques were used to measure the sensitivity of impulse-regulating DA autoreceptors on A10 DA cells in the ventral tegmental area (VTA) of chloral hydrate-anesthetized rats pretreated for seven days with repeated subcutaneous (s.c.) doses of the DA agonist apomorphine (APO). The ability of intravenous (i.v.) administration of the potent D2 DA agonist quinpirole (QUIN) to inhibit the firing of A10 cells was not attenuated in rats pretreated with repeated low doses (2 x 50 micrograms/kg/day, s.c.) of APO for 7 days, although higher doses (2 x 250 or 500 micrograms/kg/day) did cause subsensitive responses to QUIN. In rats pretreated with repeated low doses of APO, microiontophoretic application of DA on A10 cells revealed somewhat subsensitive responses. However, ibotenic acid lesions of postsynaptic cells in the nucleus accumbens (NAc) prior to initiation of APO treatment (2 x 50 micrograms/kg/day) did not alter the response of A10 cells to systemic QUIN, contradicting the possibility that the feedback projection from the NAc to the VTA was compensating for autoreceptor down-regulation during systemic challenge with QUIN. In contrast, administration of the irreversible DA antagonist EEDQ (2 mg/kg, i.p.) to control and APO-treated rats (2 x 50 micrograms/kg/day) 24 hr prior to recording did reveal a difference in A10 cell sensitivity to systemic QUIN and to microiontophoretic DA between the two groups, suggesting that "spare" DA autoreceptors may have concealed the down-regulation of autoreceptors induced by repeated low doses of APO. Challenge of A10 DA cells with the partial DA autoreceptor agonist (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(-)3-PPP], for which an autoreceptor reserve should not exist, produced slightly attenuated responses in APO-treated rats (2 x 50 micrograms/kg/day). These findings provide evidence for the existence of spare somatodendritic DA autoreceptors on A10 DA cells with respect to potent DA agonists, suggesting that repeated administration of "autoreceptor-selective" doses of DA agonists may not result in a diminished inhibition of DA neuronal activity.     

Evidence for an increased catecholamine synthesis in rat adrenal glands following stimulation of peripheral dopamine receptors

Summary In studies on peripheral dopamine (DA) turnover in our department evidence has accumulated that changes in adrenal DA levels induced by varying degrees of neurogenic stimulation roughly reflect changes in the catecholamine (CA) synthesis rate. The question arises if changes in DA levels in rat adrenals induced by different DA D-2 receptor agonists and previously reported from our laboratory, also indicate changes in CA synthesis. After various periods of drug administration rats were killed by decapitation and tissue CA levels in adrenals and forebrain were determined by HPLC-EC. The potent inhibitor of DA--hydroxylase FLA 63 (40 mg/kg i.p.) increased adrenal DA by 186% after 1 h and by 423% after 3 h. The DA D-2 agonist quinpirole (0.2 mg/kg s.c, 30 min) itself increased adrenal DA by 55–60% compared to control. In FLA 63 pretreated rats quinpirole increased adrenal DA levels by further 127% (FLA 63 — 1 h), resp. 122% (FLA 63 — 3h) than did FLA 63 itself. The DA D-2 receptor antagonist domperidone (3 mg/kg s.c, 150 min) blocked the quinpirole effect both in saline and FLA 63 (3 h) pretreated rats. Adrenal DOP AC was changed in similar manner as adrenal DA in FLA 63 pretreated rats. No significant changes either in adrenal NA or A were observed after FLA 63 pretreatment.Under the present experimental conditions adreanal DA may thus mainly be looked upon as an intermediate in the synthesis of NA and A, and the elevation of DA induced by DA D-2 receptor stimulation as a consequence of increased catecholamine synthesis.     

alpha2-Adrenergic agonists antagonise the anxiolytic-like effect of antidepressants in the four-plate test in mice

Selective serotonin reuptake inhibitors (SSRIs) and serotonin/noradrenaline reuptake inhibitors (SNRIs) has been reported to be efficient in anxiety disorders. Some animal models have demonstrated an anxiolytic-like effect following acute administration, however, it is not yet known how noradrenergic receptors are implicated in the therapeutic effects of antidepressants (ADs) in anxiety. The effects of two alpha(2)-adrenoceptor agonists (clonidine, guanabenz) on anxiolytic-like effect of two SSRIs (paroxetine and citalopram) and two SNRIs (venlafaxine and milnacipran) were evaluated in the four-plate test (FPT) in mice. Paroxetine (4 mg/kg), citalopram (8 mg/kg), venlafaxine (8 mg/kg), and milnacipran (8 mg/kg) administered intraperitoneally (i.p.) increased the number of punishments accepted by mice in the FPT. Clonidine (0.0039-0.5 mg/kg) and guanabenz (0.03-0.5mg/kg) had no effect on the number of punishments accepted by mice. Clonidine (0.03 and 0.06 mg/kg) and guanabenz (0.125 and 0.5 mg/kg) (i.p. -45 min) reversed the anti-punishment effect of paroxetine, citalopram, venlafaxine and milnacipran (i.p. -30 min). But if the antidepressants are administered 45 min before the test and alpha(2)-adrenoceptor agonists 30 min before the test, alpha(2)-adrenoceptor agonists failed to alter the anti-punishment effect of antidepressants. The results of this present study indicate that alpha(2)-adrenoceptor agonists antagonise the anxiolytic-like effect of antidepressants in mice when they are administered 15 min before the administration of antidepressant suggesting a close inter-regulation between noradrenergic and serotoninergic system in the mechanism of SSRIs and SNRIs in anxiety-like behaviour.     

The NK1-receptor antagonist NKP608 has an antidepressant-like effect in the chronic mild stress model of depression in rats

The chronic mild stress (CMS) model of depression was used to study the potential antidepressant-like activity of NKP608, a non-peptidic, specific, potent and orally active NK1 receptor antagonist. In this model, a substantial decrease in consumption of a 1% sucrose solution is observed in rats continously subjected to a variety of mild stressors. This effect can be reversed by chronic administration of various classes of antidepressant drugs. Chronic, oral treatment with NKP608 (once daily for 5 weeks) gradually reversed CMS-induced reductions in sucrose consumption and, the magnitude of this effect was comparable to that observed following administration of imipramine (10 mg/kg). The time-course of action of NKP608 in the CMS model was dose-dependent. At the dose of 0.03 mg/kg, NKP608 caused a full reversal of the CMS-induced deficit in sucrose consumption after 4 weeks of treatment (comparable to 5 weeks required for imipramine), while only 1 week of treatment was required in the group receiving the dose of 0.1 mg/kg NKP608. Lower (0.003 mg/kg) and higher (1.0 mg/kg) doses of the compound were ineffective. These results suggest that NKP608 has antidepressant-like properties in the CMS model in rats; the effect was comparable to conventional drugs, but the onset of action was faster than with the representative tricyclic antidepressant imipramine.     

Repeated administration of the selective kappa-opioid receptor agonist U-69593 increases stimulated dopamine extracellular levels in the rat nucleus accumbens

Reinforcing properties of drugs of abuse are reduced by the coadministration of kappa opioid receptor (KOR) agonists. This effect is related to the inhibition of dopamine (DA) release in the nucleus accumbens (NAc) produced by the acute administration of KOR agonists. The present study was undertaken to investigate the in vivo effect of the repeated administration of KOR agonist on extracellular DA levels in the NAc. Rats were injected once daily with the selective KOR agonist U-69593 (0.16-0.32 mg/kg) or vehicle for 4 days. Microdialysis studies assessing extracellular concentration of DA in the NAc under basal and K(+)-stimulatory conditions were conducted 1 day later. The microdialysis studies revealed that preexposure to U-69593 had no effect on basal extracellular DA levels but significantly augmented the amount of extracellular DA induced by high K(+) compared with vehicle pretreated rats. The D2 receptor agonist quinpirole perfused through the dialysis probe in the NAc, although it produced a significant decrease on basal and K(+)-stimulated DA levels in control rats, it did not decrease significantly either basal or K(+)-stimulated DA levels in U-69593 preexposed rats. Preexposure to U-69593 did not alter the expression of tyrosine hydroxylase or dopamine transporter in the ventral tegmental area. These results show that repeated administration of U-696593 increases the amount of extracellular DA induced by high K in the NAc, an effect that may be related to decreased D2 autoreceptor function. It is suggested that repeated activation of KOR changes the response status of dopaminergic neurons in the NAc.     

Effects of dopamine on neurons of the lateral geniculate nucleus: An iontophoretic study

In urethane anesthetized rats, the iontophoretic administration of dopamine (DA) induced an inhibition of flash-evoked activity in the majority of geniculate cells investigated. Excitatory effects of DA also were found in some neurons of the dorsal lateral geniculate nucleus. The observed excitatory effects of DA were blocked selectively by D2 receptor antagonists, and the majority of inhibitory effects could be blocked by D1 receptor antagonists. In some neurons, the D2 receptor antagonist also blocked the DA-induced inhibition. Nine of 33 neurons tested responded differently to DA according to the amount ejected: with lower iontophoretic currents they increased their rates of discharge, whereas higher DA ejecting currents resulted in a suppression of their activity. Iontophoretic administration of a D1 agonist (SKF 38393) for the most part induced a decrease in baseline activity, whereas the D2 agonist (quinpirole) frequently induced an increase. These effects of agonists were dose-dependent and reproducible. Effects of the D1 and D2 agonists could be reversed by the receptor-specific dopamine antagonists. Presumed local circuit interneurons appeared to be involved in mediation of some inhibitory effects of DA, since the D2-induced inhibitions could be abolished by the GABA_A antagonist, bicuculline. The majority of cells also was affected by DA antagonists given alone; these cells' responses to light usually were of an inhibitory nature. The results show that like other monoamines, DA also is involved in certain aspects of visual processing at the level of the thalamus. © 1996 Wiley-Liss, Inc.     

Altered responsiveness of regional brain dopamine and DOPAC levels to systemic administration of quinpirole, a dopamine D2 agonist, in DOCA/NaCl-hypertensive rats

Our previous studies have demonstrated that administration of quinpirole (LY171555), a potent and highly selective dopamine (DA) D2 receptor agonist, to conscious Sprague-Dawley rats produces increases in arterial pressure through the activation of sympathetic outflow and vasopressinergic activity. To test the hypotheses that quinpirole inhibits in vivo release of DA from central dopaminergic neurons by activation of DA receptors in the central nervous system (CNS) and that this mechanism may be altered in the desoxycorticosterone acetate (DOCA)/NaCl model of hypertension, we examined the effects of quinpirole on stores of DA and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in brain regions of 4-week DOCA/NaCl-hypertensive rats and their normotensive controls. Levels of DA and DOPAC were measured in brain regions by HPLC 15 min after the i.v. administration of quinpirole (1 mg/kg). Quinpirole resulted in a significant increase in DA stores and decrease in DOPAC stores in most brain regions examined in both DOCA/NaCl-hypertensive rats and normotensive controls, presumably by inhibiting DA release through a presynaptic mechanism. In the vehicle-treated groups, DA stores in the anterior hypothalamus and DOPAC stores in the nucleus accumbens were lower in DOCA/NaCl-hypertensive rats than in H2O controls. Following quinpirole administration, DA stores in the anterior hypothalamus increased significantly in DOCA/NaCl-treated rats but not in H2O controls and DOPAC stores in the nucleus accumbens decreased significantly in H2O control rats but not in DOCA/NaCl-treated rats. These observations provide further evidence for the presence of inhibitory DA D2 receptors which modulate the activity of dopaminergic neurons in the CNS.(ABSTRACT TRUNCATED AT 250 WORDS)     

Low doses of apomorphine elicit two opposing influences on dopamine cell electrophysiology

Dopamine (DA) cells are known to be very sensitive to direct acting DA agonists, and inhibition of DA cell firing by low doses of DA agonists is generally considered to be an action of these agonists on DA cell autoreceptors. During intracellular recording from spontaneously discharging DA cells in vivo, intravenous administration of apomorphine (20 micrograms/kg i.v.) elicited a hyperpolarization and an increase in input resistance. The calculated reversal potential of the apomorphine effect was approximately -40 mV. However, in non-firing DA cells the reversal potential of these effects was significantly different (P less than 0.01), being close to the reversal potential of responses induced by stimulation of striatonigral pathways (i.e. -67 mV). In addition, haloperidol (0.01 mg/kg i.v.) reversed the hyperpolarization produced by apomorphine but not the increase in input resistance. Transection of striatonigral pathways eliminated most of the increase in input resistance accompanying apomorphine administration, and shifted the apomorphine reversal potential to a value positive to 0 mV. Low doses of apomorphine were also found to affect a class of zona reticulata (ZR) interneurons. Apomorphine caused decreases in ZR cell firing rate, which were abolished by striatonigral pathway transection. Thus, the following mechanism is proposed for the electrophysiological actions of autoreceptor-selective doses of apomorphine on DA cells: (1) apomorphine directly inhibits spontaneous DA cell discharge by inhibiting the slow depolarization preceding action potentials and thereby hyperpolarizes the DA cell, (2) decreased DA cell firing disinhibits GABAergic striatal cells, whose increased firing preferentially (3) inhibits GABAergic ZR interneurons, and thus (4) removes an inhibitory input to DA cells, resulting in an increase in input resistance.