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PubMed2006

Glucocorticoid receptor-dependent desensitization of 5-HT1A autoreceptors by sleep deprivation: studies in GR-i transgenic mice.

UNLABELLED: Sleep deprivation for one night induces mood improvement in depressed patients, an action that probably involves the serotonergic (5-HT) system. In animals, sleep deprivation and pharmacologic treatment with antidepressants exert similar effects on 5-HT neurotransmission, notably functional desensitization of 5-HT1A autoreceptors located on 5-HT neurons in the dorsal raphe nucleus (DRN). However, in stressful conditions, corticosterone can also induce a desensitization of these autoreceptors. STUDY OBJECTIVES: To investigate the mechanisms of this adaptation during sleep deprivation and the possible involvement of corticosterone, we studied the effects of an 18-hour sleep deprivation, by forced locomotion, on 5-HT1A receptor-mediated firing response of DRN 5-HT neurons in transgenic mice with impaired glucocorticoid-receptor expression (GR-i) and in wild-type animals. We also examined the effects of chronic treatment with the antidepressant drug fluoxetine in the same paradigm. MEASUREMENTS AND RESULTS: In both wild-type and GR-i mice, the 18-hour sleep deprivation or fluoxetine treatment had no effect on the spontaneous firing of 5-HT neurons recorded under anesthesia. However, sleep deprivation decreased the potency of the 5-HT1A agonist 8-OH-DPAT to inhibit 5-HT neuronal firing in wild-type mice, whereas it had no effect in GR-i animals. Conversely, after chronic fluoxetine treatment, the induced reduction of this 5-HT1A autoreceptor-driven response was of larger amplitude in GR-i than in wild-type mice. CONCLUSIONS: These data suggest that glucocorticoid-receptor activation by corticosterone participates in the antidepressant-like adaptive changes in 5-HT1A autoreceptors in sleep-deprived mice. On the other hand, GR-i animals exhibited enhanced 5-HT1A autoreceptor desensitization induced by fluoxetine, in line with data in other animal models of depression.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2000

Functional role of NMDA autoreceptors in olfactory mitral cells.

The output of the olfactory bulb is governed by the interaction of synaptic potentials with the intrinsic conductances of mitral cells. While mitral cells often are considered as simple relay neurons, conveying activity in olfactory receptor cells to the piriform cortex, there is strong physiological and behavioral evidence that local synaptic interactions within the olfactory bulb modulate mitral cell discharges and facilitate odorant discrimination. Understanding the circuitry of the olfactory bulb is complicated by the fact that most dendrites in this region are both pre- and postsynaptic. Feedback inhibition is mediated through reciprocal dendrodendritic synapses between the secondary dendrites of mitral cells and GABAergic granule cells. Here we show that glutamate released from mitral cell dendrites also activates local N-methyl-D-aspartate (NMDA) autoreceptors, generating an inward tail current following depolarizing voltage steps. Autoreceptor-mediated self-excitation is calcium dependent, can be evoked by single action potentials in the presence of magnesium, and is graded with the number of spikes in a train. We find that dendrodendritic inhibition also is evoked by single action potentials but saturates rapidly during repetitive discharges. Self-excitation also underlies the prolonged afterdischarges apparent in mitral cells following potassium channel blockade. Both afterdischarges and autoreceptor-mediated tail currents persist in TTX, suggesting that they are produced by local rather than polysynaptic actions of glutamate. Blockade of NMDA autoreceptors with 2-amino-5-phosphonovaleric acid (APV) reduces the firing frequency within action potential cluster. The rapid kinetics of self-excitation suggests a functional role of NMDA autoreceptors in prolonging periods of phasic firing in mitral cells.

2-Amino-5-phosphonovalerate↗
PubMed2001

Dendritic glutamate autoreceptors modulate signal processing in rat mitral cells.

It has been shown recently that in mitral cells of the rat olfactory bulb, N-methyl-D-aspartate (NMDA) autoreceptors are activated during mitral cell firing. Here we consider in more details the mechanisms of mitral cell self-excitation and its physiological relevance. We show that both ionotropic NMDA and non-NMDA autoreceptors are activated by glutamate released from primary and secondary dendrites. In contrast to non-NMDA autoreceptors, NMDA autoreceptors are almost exclusively located on secondary dendrites and their activation generates a large and sustained self-excitation. Both intracellularly evoked and miniature NMDA-R mediated synaptic potentials are blocked by intracellular bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA) and result from a calcium-dependent release of glutamate. Self-excitation can be produced by a single spike, and trains of spikes result in frequency facilitation. Thus activation of excitatory autoreceptors is a major function of action potentials backpropagating in mitral cell dendrites, which results in an immediate positive feedback counteracting recurrent inhibition and increasing the signal-to-noise ratio of olfactory inputs.

Action Potentials↗
PubMed1994

Direct observation of the effect of autoreceptors on stimulated release of catecholamines from adrenal cells.

The direct effect of alpha 2-autoreceptors was studied by measuring the effects of piperoxan, an alpha 2-autoreceptor antagonist, and clonidine, an agonist on catecholamine exocytosis, from single bovine chromaffin cells in culture. Catecholamine release was elicited by stimulation with 100 microM nicotine and was monitored electrochemically with a carbon-fiber microelectrode placed adjacent to the cell. These electrodes allowed the number of exocytotic release events to be monitored and reported as total charge for release following a specific stimulus. Repeated stimulation with 100 microM nicotine showed that total release caused by the second exposure to nicotine was 32% of the first, and release caused by the third exposure to nicotine was 80% of the second. Total release of catecholamine increased significantly after application of 20 microM piperoxan relative to a control application of balanced salt solution. Application of 20 microM piperoxan alone did not cause release. After the cells were incubated in culture medium containing 20 microM clonidine, a significant decrease in nicotine-stimulated catecholamine release was observed. These results confirm that there are autoreceptors on chromaffin cells and, when relatively high levels of catecholamine are released, the catecholamine stimulates the alpha 2-autoreceptors, which inhibits subsequent release through a negative feedback mechanism. In addition to piperoxan, the sympathomimetic drug amphetamine also increases quantal release after application of nicotine. Amphetamine increases the extracellular concentration of catecholamine, and these data appear to indicate that at least part of the pharmacology of amphetamine might involve blocking catecholamine autoreceptors.

Adrenal Medulla↗
PubMed1996

The presynaptic alpha-2 autoreceptors in pig brain cortex are alpha-2A.

The presynaptic alpha-2 autoreceptors in pig brain cortex were subclassified in terms of alpha-2A, alpha-2B, alpha-2C and alpha-2D to test the hypothesis that alpha-2 autoreceptors belong predominantly to the alpha-2A/D pair of orthologous alpha-2 adrenoceptors. Slices of brain cortex were preincubated with [3H]norepinephrine and then superfused and stimulated electrically. pKd values of 13 alpha-2 adrenoceptor antagonists (including the partial agonist oxymetazoline) against the alpha-2 agoinst 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline (UK 14,304) were determined. The stimulation periods used (six pulses at 100 Hz) did not lead to alpha-2 autoinhibition, as shown by the failure of all but one of the alpha-2 antagonists to increase the stimulation-evoked overflow of tritium. UK 14,304 caused a concentration-dependent decrease of the evoked overflow of tritium, with an EC50 value of 0.90 nM and a maximal inhibition of 95.2%. All antagonists shifted the concentration-inhibition curve of UK 14,304 to the right in a parallel manner. Antagonist pKd values were calculated from the shifts. The pKd values at the presynaptic alpha-2 autoreceptors in pig brain cortex correlated excellently with pKd values at previously subclassified alpha-2A sites but did not correlate significantly or correlated much less well with pKd values at alpha-2B, alpha-2C and alpha-2D sites. Also, ratios of Kd values of the antagonists at the presynaptic alpha-2 autoreceptors in pig brain cortex agreed well with ratios at previously subclassified alpha-2A sites but not with those at previously subclassified alpha-2B-D sites. It is concluded that the alpha-2 autoreceptors in pig brain cortex are alpha-2A, in accordance with the hypothesis mentioned.

Adrenergic alpha-Agonists↗
PubMed1998

Alterations in dopamine release but not dopamine autoreceptor function in dopamine D3 receptor mutant mice.

Dopamine (DA) autoreceptors expressed along the somatodendritic extent of midbrain DA neurons modulate impulse activity, whereas those expressed at DA nerve terminals regulate both DA synthesis and release. Considerable evidence has indicated that these DA autoreceptors are of the D2 subtype of DA receptors. However, many pharmacological studies have suggested an autoreceptor role for the DA D3 receptor. This possibility was tested with mice lacking the D3 receptor as a result of gene targeting. The basal firing rates of DA neurons within both the substantia nigra and ventral tegmental area were not different in D3 receptor mutant and wild-type mice. The putative D3 receptor-selective agonist R(+)-trans-3,4,4a, 10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin+ ++-9-ol (PD 128907) was equipotent at inhibiting the activity of both populations of midbrain DA neurons in the two groups of mice. In the gamma-butyrolactone (GBL) model of DA autoreceptor function, mutant and wild-type mice were identical with respect to striatal DA synthesis and its suppression by PD 128907. In vivo microdialysis studies of DA release in ventral striatum revealed higher basal levels of extracellular DA in mutant mice but similar inhibitory effects of PD 128907 in mutant and wild-type mice. These results suggest that the effects of PD 128907 on dopamine cell function reflect stimulation of D2 as opposed to D3 receptors. Although D3 receptors do not seem to be significantly involved in DA autoreceptor function, they may participate in postsynaptically activated short-loop feedback modulation of DA release.

Animals↗
PubMed1987

Short-term lithium treatment enhances responsiveness of postsynaptic 5-HT1A receptors without altering 5-HT autoreceptor sensitivity: an electrophysiological study in the rat brain.

Short-term lithium administration to rats has previously been shown to enhance 5-HT neurotransmission through a modification of 5-HT neuron properties. In the first part of the present study, the effect of lithium on the function of terminal 5-HT autoreceptors was assessed by comparing in controls and lithium-treated rats the differential effect of two frequencies of stimulation (0.8 and 5 Hz) and that of methiothepin, a terminal 5-HT autoreceptor antagonist, on the effectiveness of the electrical activation of the ascending 5-HT pathway in suppressing dorsal hippocampus pyramidal neuron firing activity. Both procedures produced similar effects in controls and lithium-treated rats. In the second part of the study, the function of somatodendritic 5-HT autoreceptors was studied. The effect of intravenous LSD, an agonist of the somatodendritic 5-HT autoreceptor, on the firing activity of 5-HT neurons was not modified by the lithium treatment, whereas that of intravenous 8-OH-DPAT, a 5-HT1A receptor agonist, was increased two-fold. However, lithium did not alter the responsiveness of 5-HT neurons to direct microiontophoretic applications of 8-OH-DPAT as well as of LSD and 5-HT. It is concluded that short-term lithium treatment does not alter the function of terminal and somatodendritic 5-HT autoreceptors and that it enhances the sensitivity of a subset of postsynaptic 5-HT1A receptors involved in controlling 5-HT neuron firing activity, presumably through a feedback loop.

Acetylcholine↗
PubMed1989

Phorbol-12,13-dibutyrate antagonizes while forskolin potentiates the presynaptic autoreceptor-mediated inhibition of [3H]-5-hydroxytryptamine release in rat hypothalamic slices.

In superfused rat hypothalamic slices prelabeled with [3H]-5-hydroxytryptamine [( 3H]-5-HT), the 5-HT autoreceptor agonists 5-methoxytryptamine and RU 24969 inhibited in a concentration-dependent manner the electrically evoked release of [3H]-5-HT. Exposure to phorbol-12,13-dibutyrate increased in a concentration-dependent manner the stimulation-evoked overflow of [3H]-5-HT and shifted to the right the 5-methoxytryptamine inhibition curve. Exposure to forskolin, a potent activator of adenylate cyclase, increased the stimulation-evoked [3H]-5-HT overflow and shifted to the left the 5-methoxytryptamine or RU 24969 inhibitory curves on transmitter release. A similar interaction was observed in the presence of 1-isobutyl,3-methylxanthine (IBMX), a phosphodiesterase inhibitor, or 8-bromo-cyclic AMP and the serotonin autoreceptor agonist 5-methoxytryptamine. In the presence of phorbol-12,13-dibutyrate or forskolin, the enhancing effect of the 5-HT autoreceptor antagonist methiothepin on the stimulation-evoked [3H]-5-HT overflow was significantly less pronounced than in the absence of these compounds. These results indicate that the presynaptic 5-HT autoreceptors that modulate the release of [3H]-5-HT in rat hypothalamic slices may be coupled to the phosphoinositide cycle and protein kinase C-dependent mechanisms. In addition, the increase in intracellular level of cyclic AMP by forskolin, IBMX, and 8-bromo-cyclic AMP potentiates the inhibitory effects of the autoreceptor agonist 5-methoxytryptamine on [3H]-5-HT release, although the mechanism of the interaction remains to be elucidated.

1-Methyl-3-isobutylxanthine↗
PubMed1989

D1 dopamine receptor stimulation enables the postsynaptic, but not autoreceptor, effects of D2 dopamine agonists in nigrostriatal and mesoaccumbens dopamine systems.

Possible functional interactions between D1 and D2 dopamine (DA) receptors were examined using extracellular single-cell recording with microiontophoretic application of selective D1 and D2 receptor agonists both postsynaptically, in the rat nucleus accumbens (NAc) and caudate-putamen (CPu), and presynaptically, at impulse-regulating somatodendritic DA autoreceptors in the ventral tegmental area (A10) and substantia nigra pars compacta (A9). In addition, synthesis-modulating nerve terminal DA autoreceptors were studied in both the CPu and NAc using the gamma-butyrolactone (GBL) neurochemical model of isolated nerve terminal autoreceptor function in vivo. In both the NAc and CPu, the inhibition of neurons produced by iontophoresis of the D2 receptor agonists quinpirole or RU-24213 was attenuated by acute DA depletion via the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT). However, during iontophoresis of the selective D1 DA receptor agonist SKF 38393, the inhibitory effects of the D2 agonists were again evident, suggesting that the attenuation of D2 agonist-induced inhibition was due to decreased D1 receptor activation. In contrast, the inhibitory effects produced by the non-selective D1/D2 agonist apomorphine or by SKF 38393 were unaffected by AMPT pretreatment. Thus, D1 receptor activation appears necessary for D2 receptor-mediated inhibition of NAc and CPu neurons, whereas D2 receptor activation is not required for the inhibition produced by D1 receptor stimulation. In contrast to postsynaptic D2 receptors, the ability of DA agonists to stimulate D2 DA autoreceptors was not altered by manipulations of D1 receptor occupation. Enhancing D1 receptor stimulation with SKF 38393 or reducing D1 receptor occupation with either the selective D1 receptor antagonist SCH 23390 or AMPT failed to alter the rate-inhibitory effect of i.v. quinpirole on A9 or A10 DA neurons. Similarly, iontophoresis of SKF 38393 failed to alter the inhibitory effects of iontophoretic quinpirole. SKF 38393 also failed to affect the inhibition of GBL-induced increases in DOPA accumulation (tyrosine hydroxylase activity) produced by quinpirole in either the NAc or CPu. Furthermore, reversal of GBL-induced increases in DOPA accumulation by apomorphine or quinpirole was unaffected by pretreatment with SCH 23390. Therefore, D1 receptor occupation appears to be necessary for the expression of the functional effects of postsynaptic D2 receptor stimulation but not presynaptic D2 DA autoreceptor stimulation.

Animals↗
PubMed1993

Autoreceptor-mediated regulation of GABA release: role of uptake inhibition and effects of novel GABAB antagonists.

While the role of GABAB autoreceptors in the regulation of GABA release in synaptosomes and brain slices is well established, little is known about their role in vivo. Doubts have arisen because there is an apparent discrepancy between the frequencies at which GABA neurons fire and the frequency range within which autoreceptor regulation is observed in vitro. To see whether this apparent mismatch could be due to the use of a GABA uptake inhibitor in the release experiments in slices, we have compared the frequency dependencies of GABA release in the presence and absence of uptake inhibition. Before-hand, the previously incomplete frequency curve in the presence of uptake inhibition was extended at the lower end. To achieve this, stimulation was performed by means of groups of 4 pseudo-one-pulses (POP's) at inter-POP intervals corresponding to frequencies of 0.015625-0.5 Hz. It could be shown that activation of the GABAB autoreceptor by endogenously released GABA begins at a stimulation frequency as low as 0.0625 Hz. Experiments with the antagonist, CGP 35348, at inter-POP intervals of 1 min, at which the preceding POP has no longer an effect on GABA release during the next one, showed that basal release alone already substantially activated the autoreceptor. The frequency dependence in the absence as compared to the presence of uptake inhibition was shifted towards higher frequencies by a factor of 4. We do not consider this enough to remove our doubts about the in vivo operativity of GABAB autoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Terminal serotonin autoreceptor function in the rat hippocampus is not modified by pertussis and cholera toxins.

The possibility that the terminal serotonin (5-HT) autoreceptor in the rat hippocampus is coupled to Gi, Go or Gs regulatory proteins was investigated using the electrically evoked overflow of [3H]5-HT from preloaded slices. Pertussis toxin, which inactivates Gi/o or cholera toxin, which stimulates Gs, was injected directly in the hippocampus 3 to 11 days prior to the experiments. Hippocampus slices were prepared, loaded with [3H]5-HT, superfused continuously, and stimulated electrically 72 min (S1) and 116 min (S2) after the beginning of superfusion. In the absence of any drug, the evoked overflow of [3H]5-HT in S1 was not altered by either toxin. The enhancing effect of the 5-HT reuptake blocker paroxetine (1 mumol/l) on the evoked [3H]5-HT overflow was also unaltered by these toxins. 5-Carboxyamidotryptamine, a 5-HT autoreceptor agonist, inhibited in a concentration-dependent manner the stimulation-evoked release of [3H]5-HT. The concentration-effect curve (0.001-0.1 mumol/l) for this drug was not altered by pretreatment with either pertussis or cholera toxin. Similarly, the effect of another 5-HT autoreceptor agonist, 5-methoxytryptamine (0.1 and 1 mumol/l), was not altered in the pretreated rats. In addition, the reduction of [3H]5-HT overflow obtained by increasing the stimulation frequency from 1 Hz to 5 Hz, which is due to an increase in terminal 5-HT autoreceptor activation at the higher frequency, was not altered by either toxin. The enhancing effect of the 5-HT autoreceptor antagonist methiothepin (1 mumol/l) on stimulation-evoked [3H]5-HT overflow was not changed by either pretreatment. N-Ethylmaleimide inactivates Gi/o proteins by alkylation.(ABSTRACT TRUNCATED AT 250 WORDS)

5-Methoxytryptamine↗
PubMed1991

Species differences in presynaptic serotonin autoreceptors: mainly 5-HT1B but possibly in addition 5-HT1D in the rat, 5-HT1D in the rabbit and guinea-pig brain cortex.

The pharmacological properties of presynaptic serotonin autoreceptors were compared in slices of rat, rabbit, and guinea-pig brain cortex. The slices were preincubated with 3H-serotonin and then superfused with medium containing fluvoxamine 3 mumol/l and stimulated four times by trains of four pulses delivered at 100 Hz. Cumulative concentration-response curves were determined and used for the calculation of agonist EC50 values and maximal effects and antagonist KB values. Unlabelled serotonin itself and the serotonin receptor agonists 5-carboxamidotryptamine (5-CT), 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU 24969) and (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) reduced the stimulation-evoked overflow of tritium with a rank order of potency 5-CT = RU 24969 greater than serotonin greater than 8-OH-DPAT in the rat and 5-CT greater than serotonin greater than RU 24969 greater than 8-OH-DPAT in the rabbit and guinea-pig. Ipsapirone caused no change. Metitepine and metergoline antagonized the effect of 5-CT; the KB values were lower in the rabbit and guinea-pig than in the rat. Yohimbine at up to 1 mumol/l did not reduce the evoked overflow of tritium and did not antagonize the inhibitory effect of 5-CT in the rat but reduced the evoked overflow in the rabbit and counteracted the effect of 5-CT in the guinea-pig. (-)-Propranolol, conversely, reduced the evoked overflow of tritium in the rat but neither reduced the evoked overflow nor antagonized the effect of 5-CT in the rabbit and guinea-pig. Isamoltane did not significantly change the effect of 5-CT in any species. In the rat, it also failed to antagonize the inhibitory effect of 8-OH-DPAT but did antagonize the effect of RU 24969. The inhibition caused by 8-OH-DPAT persisted in the presence of idazoxan but was attenuated by metitepine in all species. The experimental conditions used permit the determination of the constants of agonist and antagonist action undistorted by autoinhibition. The results confirm the view that the serotonin axons of rat brain possess 5-HT1B autoreceptors. They show by direct comparison under identical conditions that the autoreceptors in rabbit and guinea-pig are very similar to each other but differ markedly from those in the rat. The results give additional credence to previous suggestions that, in the rabbit and guinea-pig, the autoreceptors are 5-HT1D. The serotonin axons of rat brain cortex may possess 5-HT1D in addition to 5-HT1B autoreceptors.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Dopamine D2 autoreceptors in rats are behaviorally functional at 21 but not 10 days of age.

Previous studies used either racemic 3-(3-hydroxyphenyl)-N-n-propylpiperidine [(+/-)-3-PPP] or lower doses of the mixed dopamine (DA) D1/D2 agonist apomorphine (APO) to conclude that brain DA D2 autoreceptors are not behaviorally functional until 28 days of age. The purpose of this study was to provide behavioral evidence for functional D2 autoreceptors before 28 days of age using DA agonists with greater selectivity for D2 autoreceptors. The locomotor activity of 10-, 21-, 35-day-old and adult rats was monitored after injection of a D2 autoreceptor agonist. There were significant decreases in the locomotor activity of 21-, 35-day-old, and adult rats injected with (-)-3-PPP, SND 919, or PD 128483. Lower doses of APO significantly decreased the activity of adult and 35-day-old rats but not younger rats. The only significant effect on the locomotor activity of 10-day-old rats was an increase in activity after injection of APO, 0.01 mg/kg or higher, or B-HT 920, 0.01 mg/kg. The results suggest that brain DA D2 autoreceptors are behaviorally functional at 21, but not 10, days of age.

Aging↗
PubMed1981

Pharmacological profiles of the putative dopamine autoreceptor agonists 3-PPP and TL-99.

The putative dopamine (DA) autoreceptor agonists, N-n-propyl-3-(3-hydroxyphenyl)-piperidine (3-PPP) and 6, 7-dihydroxy-2-dimethylaminotetralin (TL-99) were compared with apomorphine in a series of tests indicative of DA receptor activation. All three agents displaced [3H] apomorphine and [3H] spiroperidol from DA recognition sites in rat brain and caused contralateral turning in the 6-hydroxydopamine lesioned rat. Apomorphine and TL-99 were generally more potent than 3-PPP. All three agents were also active at the DA autoreceptor that controls the synthesis of dopamine as indicated in vivo using the gamma-butyrolactone (GBL) procedure and in vitro using a synaptosomal preparation. In addition, all agents produced emesis in beagles. clear differences in the drugs' actions were observed in other test procedures. In the rat, apomorphine was the only compound which caused stereotypy or rotation following a reversible KCI-induced lesion of the striatum. Conversely, TL-99 and 3-PPP lacked activity in these procedures. Presumably, activity in these two tests indicates postsynaptic DA receptor activation. Each of the putative autoreceptor agonists produced a monotonic dose-related decrease in the mouse locomotor activity as opposed to the biphasic effect exerted by apomorphine. This action on the mouse locomotor activity, coupled with the results for the GBL test, provides an index of autoreceptor activation. In contrast to 3-PPP, both apomorphine and TL-99 increased locomotor activity in animals pretreated with reserpine and alpha-methyl-p-tyrosine and caused rotation in unilaterally caudectomized mice. In these test procedures thought to reflect activity at the postsynaptic DA receptor, TL-99 differed in its action from 3-PPP in a manner which suggests 3-PPP may be a more selective DA autoreceptor agonist.

4-Butyrolactone↗
PubMed1991

Enantiomers of monohydroxy-2-aminotetralin derivatives and their activity at dopamine autoreceptors as studied by brain dialysis.

The enantiomers of a series of dopamine (DA) agonists, monohydroxy-2-aminotetralin derivatives, were investigated using brain microdialysis. We used a 5-OH-substituted derivative, N-0437 (2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin), and three 7-OH-substituted derivatives, N-0438 (2-(N-propyl-N-2-thienylethylamino)-7-hydroxytetralin), 7-OH-DPAT (7-hydroxy-2-(N,N-di-n-propylamino)tetralin) and PHNO (4-propyl-9-hydroxynaphthoxazine; position 9 of the naphtoxazines corresponds to position 7 of the aminotetralins). We studied the activity of the enantiomers at autoreceptors regulating the release of DA following their local infusion into the striatum of the rat. We were particularly interested in the activity of R(+)-N-0437, S(-)-N-0438, S(-)-7-OH-DPAT and S(-)-PHNO, which are enantiomers that have been classified as less potent or inactive in previous studies. S(-)-N-0437, R(+)-N-0438, R(+)-7-OH-DPAT and R(+)-PHNO decreased DA release by 45-60%. Thus, these enantiomers are potent agonists at autoreceptors regulating the release of DA. The R(+) enantiomer of the 5-OH-substituted derivative N-0437 possessed antagonistic activity at autoreceptors controlling DA release, increasing DA release by 100%. This finding is consistent with reports showing that one enantiomer of other 5-OH DA agonists displays agonistic activity, while the other has antagonistic properties at DA autoreceptors. The less potent enantiomers of the 7-OH-substituted derivatives S(-)-N-0438, S(-)-7-OH-DPAT and S(-)-PHNO, however, all showed weak agonistic activity at DA autoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

The regulation of dopamine release from nigrostriatal neurons in conscious rats: the role of somatodendritic autoreceptors.

Drugs were infused into the substantia nigra of the rat brain via a microdialysis probe, and the extracellular concentration of dopamine (DA) and 3,4-dihydroxyphenylacetic acid was recorded from a second dialysis probe implanted in the ipsilateral striatum. This approach allowed the evaluation of the sensitivity of nigral autoreceptors to various D1 and D2 agonists and antagonists in conscious animals. Intranigral administration of the specific D2 agonists, quinpirole (LY 171555; 1, 10 and 50 mumol/l) and (-)-N-0437 (10 mumol/l), decreased the output of striatal dopamine, whereas the specific D2 antagonist, (-)-sulpiride (10 and 50 mumol/l), stimulated slightly the release of dopamine from the ipsilateral corpus striatum. Intranigral administration of the D1 agonist, SKF 38393 (100 mumol/l), and the D1 antagonist, SCH 23390 (100 mumol/l), was without effect on the release of striatal dopamine. The results indicate that release-controlling autoreceptors on nerve terminals and autoreceptors controlling impulse flow in the nigra contribute equally to the decrease of striatal DA release caused by a high systemic dose of D2 agonists. The stimulating effect of D2 antagonists on the release of DA is mainly caused by release-controlling autoreceptors localized on nerve terminals. The autoreceptors in the nigra controlling impulse flow contributed somewhat less (about 20%) to this effect. Advantages and disadvantages of the use of a microdialysis probe to deliver drugs to restricted brain areas are discussed.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

D-2 dopamine autoreceptor selective drugs: do they really exist?

The catecholamine dopamine plays an important role as a neurotransmitter or neurohormone in the brain and pituitary gland. Dopamine exerts its effects through activation of two types of receptors called D-1 and D-2. These receptors are distinguished by their different pharmacological characteristics and signal transduction mechanism(s). Release of dopamine inhibits the activity of dopaminergic neurons through activation of so-called dopamine autoreceptors which are of the D-2 type. In general, these receptors occur both in the soma-dendritic region of the dopaminergic neuron, where they are involved in the inhibition of the firing rate and on the dopaminergic terminals where they mediate the inhibition of dopamine synthesis and release. D-2 receptors occur also on the target cells of dopaminergic neurons both in the brain (postsynaptic D-2 receptors) and pituitary gland. On the basis of data gathered from in vivo (behavioral- as well as electrophysiological) studies it has been concluded that D-2 agonists are much more potent at dopamine autoreceptors as compared to postsynaptic D-2 receptors, indicating the possibility of a pharmacological distinction between these differentially located D-2 receptors. This concept led to the introduction of a whole group of drugs allegedly displaying a selective agonist profile at the dopamine autoreceptor. In contrast, biochemical (in vitro) studies with brain tissue as well as the pituitary gland, did not reveal any significant difference between the pharmacological profiles of autoreceptors and postsynaptic D-2 receptors. In the present minireview a balanced discussion is presented of these in vivo and in vitro findings and it is concluded that both autoreceptors as well as postsynaptic D-2 receptors are similar if not identical entities.

Animals↗
PubMed1994

The D2 autoreceptor agonists SND 919 and PD 128483 decrease stereotypy in developing rats.

Although stereotyped behavior in adult rats is partly regulated by dopamine (DA) D2 autoreceptors, previous attempts to demonstrate D2 autoreceptor regulation of stereotypy in developing rats have been unsuccessful. In the present study, two highly selective D2 autoreceptor agonists were used to demonstrate D2 autoreceptor regulation of spontaneous stereotyped behavior in developing rats. Both SND 919 and PD 128483 produced significant dose-dependent decreases in the stereotypy counts of 21-day-old, 35-day-old, and adult rats. There was a 51% decrease in the stereotypy counts of 21-day-old rats injected with SND 919, 0.05 mg/kg, compared to a 36% decrease in the counts of rats pretreated with haloperidol. Similarly, PD 128483 significantly decreased the stereotypy counts of 21-, 35-day-old, and adult rats in a dose-dependent fashion. There was a 58% decrease in the stereotypy counts of 21-day-old rats injected with PD 128483, 0.1 mg/kg, compared to a 17% decrease in counts when the rats were first treated with haloperidol. The effect of haloperidol plus PD 128483 was significantly different from the effect of PD 128483 alone. Injection of SND 919 or PD 128483 had no significant effects on the stereotypy counts of 10-day-old rats. The results suggest that DA D2 autoreceptor-mediated regulation of spontaneous stereotyped behavior is functional at 21, but not 10, days of age.

Aging↗