Nerve Terminal Autoreceptors Research Articles

Inhibition of hippocampal 5-HT synthesis by fluoxetine and paroxetine: evidence for the involvement of both 5-HT1A and 5-HT1B/D autoreceptors.

Hippocampal serotonin (5-hydroxytryptamine, 5-HT) synthesis, as determined by the accumulation of 5-hydroxytryptophan (5-HTP) following inhibition of L-aromatic amino acid decarboxylase with NSD 1015, was inhibited by systemic administration of the selective serotonin reuptake inhibitors fluoxetine (10 mg/kg i.p.) and paroxetine (3 mg/kg i.p.). Pretreatment of rats with the selective 5-HT1A receptor antagonist WAY 100635 for a period of 7 days using subcutaneously implanted osmotic minipumps (1 mg/kg/day) was sufficient to block the inhibition of 5-HT synthesis following the 5-HT 1A receptor agonist 8-OH-DPAT (0.3 mg/kg s.c.), but failed to inhibit the decrease of hippocampal 5-HT synthesis by fluoxetine (10 mg/kg i.p.) or paroxetine (3 mg/kg i.p.). Similarly, pretreatment of rats with GR 127935 (5 mg/kg i.p.), an antagonist with high affinity for 5-HT1B/D receptors, blocked the reduction of hippocampal 5-HT synthesis following the 5-HT receptor agonist TFMPP (3 mg/kg s.c.) without affecting the reduction of hippocampal 5-HT synthesis by either fluoxetine or paroxetine. In contrast, pretreatment with WAY 100635 (1 mg/kg/day, for 7 days s.c. in osmotic minipumps) in combination with GR 127935 (5 mg/kg i.p.) significantly attenuated the decrease of hippocampal 5-HT synthesis by both fluoxetine and paroxetine. These results indicate that both 5-HT1A and 5-HT1B/1D receptors, which function in the rat as inhibitory somatodendritic and nerve terminal autoreceptors, independently regulate hippocampal 5-HT synthesis and must be simultaneously blocked to prevent the inhibition of 5-HT synthesis by selective serotonin reuptake inhibitors which increase 5-HT availability at both nerve terminals in hippocampus and 5-HT cell bodies in the raphe nuclei.

Antagonism of the effects of (+)-PD 128907 on midbrain dopamine neurones in rat brain slices by a selective D2 receptor antagonist L-741,626.

1. The ability of PD 128907 to activate dopamine receptors in the ventral tegmental area, substantia nigra pars compacta, and striatum was investigated by use of in vitro electrophysiological recording and fast cyclic voltammetry. The affinity of a novel D2 selective antagonist L-741,626 for receptors activated by this agonist was measured to determine if its effects were mediated by D2 or D3 receptors. 2. The active (+) enantiomer of PD 128907 bound with high affinity and selectivity to rat D3 dopamine receptors. The Ki values for (+)-PD 128907 were 620 nM at D2, 1 nM at D3 and 720 nM at D4 receptors. 3. (+)-PD 128907 inhibited cell firing in both the ventral tegmental area and substantia nigra pars compacta with EC50 values of 33 nM (pEC50 = 7.48 +/- 0.10, n = 10) and 38 nM (pEC50 = 7.42 +/- 0.15, n = 5), respectively. No effects of (+)-PD 128907 (100 nM) were observed on glutamate or GABA-mediated synaptic potentials elicited by focal bipolar stimulation. 4. L-741,626 antagonized these effects of (+)-PD 128907 in a concentration-dependent and surmountable manner with an affinity, determined from Schild analysis, of 20 nM (pKB = 7.71 +/- 0.14) in the ventral tegmental area and 11 nM (pKB = 7.95 +/- 0.18) in the substantia nigra pars compacta. 5. (+)-PD 128907 also inhibited dopamine release in the caudate-putamen with an EC50 of 66 nM (n = 5). The affinity of L-741,626 for these nerve terminal autoreceptors (pKB = 7.71 +/- 0.06; = 20 nM) was identical to that observed on midbrain dopamine neurones. 6. These data demonstrate that the D3 receptor ligand (+)-PD 128907 is a potent agonist on rat midbrain dopamine neurones. However, its lack of regional selectivity, and the high affinity of the selective D2 receptor antagonist L-741,626 for receptors activated by (+)-PD 128907, was more consistent with an action on D2 autoreceptors rather than upon a D3 dopamine receptor subtype.

Antagonism of cocaine's stimulant effects on local cerebral glucose utilization by the preferential autoreceptor antagonist (+)-AJ 76.

(+)-AJ 76 is a stimulant dopamine (DA) antagonist, which has a putative preferential action at DA nerve terminal autoreceptors. Because it is both a mild stimulant and a DA antagonist, it has previously been suggested that (+)-AJ 76 might antagonize both the euphoria and craving associated with cocaine abuse and withdrawal, respectively. To evaluate this hypothesis further, (+)-AJ 76 was evaluated for its ability to affect cocaine-induced changes in regional brain energy metabolism. Using Sokoloff's 2-deoxyglucose autoradiographic technique, (+)-AJ 76 antagonized the stimulant effect of cocaine. Although classical DA antagonists are known to depress regional brain energy metabolism, (+)-AJ 76 by itself had no effect. It is concluded that the results are consistent with the previously stated hypothesis that (+)-AJ 76 might be useful as a pharmacotherapy for treatment of cocaine abuse.

5-HT 3 receptors are not involved in the modulation of the K +-evoked release of [ 3H]5-HT from spinal cord synaptosomes of rat

The ability of 5-HT 3 receptor agonists to modulate the resting efflux or K +-evoked release of [ 3H]-HT from superfused synaptosomes from the spinal cord of the rat was investigated. Phenylbiguanide did not alter the resting efflux of [ 3H]-HIAA or [ 3H]5-HT or modify the K +-evoked release of [ 3H]-HT. 2-Methyl-5-HT (10μM) caused an increase in resting efflux of [ 3H]-HIAA, an effect that was blocked by the inhibitor of the uptake of 5-HT fluoxetine. No effect on K +-evoked release of tritium was observed. Bufotenine (100–1000 nM) increased the resting efflux of [ 3H]-HT and [ 3H]-HIAA. These effects were not antagonized by the 5-HT 3 antagonist ICS 205–930 but were antagonized by fluoxetine. The drug ICS 205–930 (1 μM) did not alter resting efflux or block the ability ofserotonin (30 and 100 nM) to decrease K +-evoked release of tritium. Quipazine, a potent antagonist of peripheral 5-HT 3 receptors (subnanomolar concentrations), was also unable to alter resting or K +-evoked release of [ 3H]-HT. It did, however, attenuate the inhibitory effect 5-HT on K +-evoked release. The concentrations required were in the micromolar range, consistent with the ability of the drug to antagonize the 5-HT 1B autoreceptor. These results support the idea that 5-HT 3 receptors do not act as nerve terminal autoreceptors in the spinal cord of the rat.

Electrophysiological effects of dopamine autoreceptor antagonists, (+)-AJ 76 and (+)-UH 232

The weak aminotetralin stimulants, (+)-AJ 76, cis-(+)-5-methoxy-1-methyl-2-(n-propylamino)tetralin and (+)-UH 232, cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin, were tested for their effects on firing rates of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNPC). (+)-AJ 76 and (+)-UH 232 antagonized the depression of DA neuron firing rates following autoreceptor stimulation by apomorphine. Thus, just as they antagonize DA autoreceptors on presynaptic terminals, these aminotetralins also antagonize the somatodendritic DA autoreceptor. However, in contrast to terminal autoreceptors where (+)-AJ 76 is the most potent antagonist, (+)-UH 232 is the most potent on cell body autoreceptors. (+)-AJ 76 and (+)-UH 232 also reversed the depression of DA neurons arising from activation of negative feedback pathways by amphetamine-induced DA release in postsynaptic areas. Based on potencies to reverse amphetamine and apomorphine, respectively, the postsynaptic/presynaptic potency ratios for (+)-AJ 76, (+)-UH 232, and haloperidol were all near unity. It is concluded that (+)-AJ 76 and (+)-UH 232 antagonize both postsynaptic and somatodendritic sites with equal potencies, and that their weak stimulant properties may be due to a preferential antagonism of nerve terminal autoreceptors.

The Biochemistry and Pharmacology of Mesoamygdaloid Dopamine Neuronsa

Populations of DA neurons innervating the component nuclei of the amygdaloid complex differ in their inferred density of innervation, estimated rate of impulse activity, and adaptive response to the prolonged administration of antipsychotic drugs. Mesoamygdaloid DA neurons have in common the absence of tonically inhibitory, nerve terminal autoreceptors regulating DA synthesis, the nonassociation with a DA-stimulated adenylate cyclase, and the regulation of DA synthesis by receptor-mediated neuronal feedback mechanisms and end-product inhibition. The output of the amygdaloid complex appears to be organized into distinct functions subserved by component nuclei. The present findings suggest a differing role for DA afferents in modulating the functional output of discrete nuclei. The significance of this focal influence will be speculative pending a more complete understanding of the physiology of DA neurotransmission in the amygdaloid complex. Populations of DA neurons innervating discrete amygdaloid nuclei exhibit a composite of mechanisms of regulation and signal transduction and pharmacology that differ from that of other mesotelencephalic DA systems. These comparisons highlight the fact that the nucleus accumbens and olfactory tubercle do not represent or reflect DA neurotransmission in the limbic system. The study of the physiology, pharmacology, and pathology of mesolimbic DA neurons can and should extend beyond the nucleus accumbens and olfactory tubercle to the amygdala and other brain structures central to the organization of the limbic system. It is our opinion that the term "mesolimbic" DA system has purely anatomical connotations and that a more specific terminology (e.g., meso-central amygdaloid nuclear) would express the functional organization of this system more accurately.

Dopamine neurons projecting to the medial prefrontal cortex possess release-modulating autoreceptors

The ability of dopamine (DA) agonists and antagonists to modulate the K +-evoked overflow of radioactivity from superfused slices of prefrontal cortex of the rat, preincubated with [ 3H]DA in the presence of 1 μM desipramine, was examined. Apomorphine and the putative autoreceptor-selective DA agonist EMD 23 448 inhibited the K +-evoked overflow of radioactivity, while the DA antagonist sulpiride enhanced the evoked overflow in a dose-dependent and stereoselective manner. The latter effect was partially reversed by EMD 23 448. More than 95% of the radioactivity retained by the slices chromatographed with DA, while deaminated metabolites represented the majority of both the basal efflux (84% metabolites, 4–5% DA) and evoked overflow (84% metabolites, 14% DA) of radioactivity. These findings indicate that mesoprefrontal DA neurons possess release-modulating nerve terminal autoreceptors. Previous studies have shown that these neurons lack synthesis-modulating autoreceptors. Thus, autoreceptors on prefrontal DA terminals appear to be coupled to regulation of the release but not the synthesis of DA.

Brain dopamine autoreceptors in aging rats

The function of dopamine (DA) autoreceptors is evaluated in vivo in striatum and mesolimbic regions of young adult (4 months), mature (14 months) and old (26 months) male Wistar rats. γ-Butyrolactone (GBL)-induced dihydroxyphenylalanine (DOPA) accumulation in rats also treated with an inhibitor of aromatic L-aminoacid decarboxylase was used to determine the presence of synthesis-modulating nerve terminal autoreceptors while its reversal with apomorphine served as an index of autoreceptor stimulation. GBL-induced DOPA accumulation in striatum is very high at all three ages (130–150% increase in comparison with controls) as is its reversal by apomorphine (65–80% decrease in comparison with GBL alone). In mesolimbic regions, GBL has much less effect than in striatum (31% rise at 4 and 26 months, 12% rise at 14 months), but apomorphine's effect is of the same order of magnitude (down 60–80%). The conclusion can be drawn that aging does not significantly affect DA autoreceptor function in striatum and mesolimbic area.

Unique response to antipsychotic drugs is due to absence of terminal autoreceptors in mesocortical dopamine neurones.

A projection of dopamine (DA) neurones has been identified which runs from the rat midbrain ventral tegmental area to the cerebral cortex1. Relative to other cortical areas, the prefrontal cortex is enriched in DA2,3, tyrosine hydroxylase3, DA uptake2,3, DA-sensitive adenylate cyclase2 and DA-responsive neurones4. Lesions of the prefrontal cortex or selective lesions of the prefrontal cortical DA innervation induce functional deficits, including detrimental effects on delayed response tasks, a difficulty in suppressing attention to irrelevant stimuli and a diminution in affective and social behaviour (for a review, see ref. 5). Recent studies have shown that this mesocortical DA system differs from other DA systems (such as the nigrostriatal and mesolimbic DA systems) in terms of drug responsiveness. For example, the acute administration of antipsychotic drugs (for example, haloperidol) greatly accelerates DA turnover in the nigrostriatal and mesolimbic DA systems through multiple sites of action, but only modestly accelerates mesocortical DA turnover. Following the chronic administration of moderate doses of antipsychotic drugs, tolerance to the effects of a haloperidol challenge dose is generally seen in the striatum and olfactory tubercle but not in the frontal cortex6–8. Similar results obtained in experiments involving primates have led to the suggestion that the frontal cortex may be the site of therapeutic action of the antipsychotic agents9,10. In light of the recent finding that rat mesocortical DA neurones lack terminal autoreceptors11, we have investigated the possible role of nerve terminal DA autoreceptors in mediating the varied responses seen in different brain regions following acute and chronic antipsychotic drug treatment. The results, reported here, suggest that both the relatively small activation of the mesocortical DA system in response to a haloperidol challenge, and the lack of tolerance to haloperidol following chronic treatment, may be related to the absence of nerve terminal autoreceptors.