Selective Serotonin 1A Receptor Agonist Research Articles

PRX-00023, a selective serotonin 1A receptor agonist, reduces ultrasonic vocalizations in infant rats bred for high infantile anxiety

To address the development of early anxiety disorders across the lifespan, the High USV line of rats was bred based on rates of infant ultrasonic vocalization in the 40–50 kHz range of predominant frequencies (USV) to maternal separation at postnatal day (P) 10. In this study, rates of USV in High line infants (pups: Postnatal Day 11 ± 1) were compared to those of randomly-bred controls in response to EPIX compound PRX-00023, a unique serotonin (5-HT) agonist, acting exclusively at the 5-HT1A receptor, or buspirone, a nonspecific 5HT1A agonist. After testing, pups were examined for sedation and other drug-related effects. The results indicated that all doses of buspirone reduced USV rates in isolation, consistent with other reports. PRX-00023 significantly reduced USV rates at the lowest doses (0.01–0.05 mg/kg). None of the PRX-00023 doses produced sedation, whereas all but the lowest dose of buspirone (0.1 mg/kg) produced sedation effects. The results suggest that this compound alleviates infantile anxiety-like behavior with great specificity in rats bred for high anxiety/depressive phenotypes by selectively targeting 5-HT1A receptors, possibly by both pre- and post-synaptic mechanisms.

Attenuation of somatodendritic responses to 8-hydroxy-2-di-npropylamino tetralin following long-term dietary sugar consumption in rats.

To determine changes in response to a selective serotonin-1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) following long-term consumption of sugar as part of meal in rats. Experimental study. The Department of Biochemistry, University of Karachi, from June to August 2005. The study was conducted on 24 male albino Wistar rats. Sugar containing diet was prepared by mixing standard rodent diet and table sugar in the ratio of 3:1 (w/w) and rats were fed freely on this diet. Control rats were fed freely on standard rodent diet. After five weeks of treatment, control and sugar diet treated animals were injected with 8-OH-DPAT, at a dose of 0.5 mg/ml/kg, to monitor the effects of drug on food intake and brain serotonin (5-hydroxytryptamine, 5-HT) metabolism. Dissected neural tissue was analyzed electrochemically and findings were compared by Newman-Keuls test. Administration of 8-OH-DPAT elicited hyperphagia and decreased 5-HT metabolism in normal diet treated rats. The neurochemical and hyperphagic responses to 8-OH-DPAT were smaller in sugar than normal diet treated animals suggesting a downregulation of somatodendritic responses in sugar diet treated animals. A decrease in serotonin metabolism but not an increase in the responsiveness of somatodendritic 5-HT-1A receptors is involved in sugar-rich diet induced hyperphagia.

Effects of PRX-00023, a Novel, Selective Serotonin 1A Receptor Agonist on Measures of Anxiety and Depression in Generalized Anxiety Disorder

PRX-00023, a serotonin 1A receptor agonist, was designed to provide high potency and selectivity for its target. To assess the possible therapeutic utility in anxiety, a randomized, double-blind, placebo-controlled trial was conducted in 311 subjects who met the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, for generalized anxiety disorder. All subjects underwent a 1-week placebo run-in and were randomized to receive once-daily capsules containing either PRX-00023 (80 mg/d) or placebo for an additional 8 weeks. The primary outcome measure was the Hamilton Anxiety Scale (HAM-A). The Montgomery-Asberg Depression Rating Scale was used as a secondary endpoint to measure depressive symptoms. Statistical testing was performed with analysis of covariance, between baseline and week 8, with baseline values as a covariate. The anxiolytic effect of PRX-00023, compared with placebo, showed trends across all anxiolytic measures but failed to reach significance on the primary endpoint (HAM-A total score). Among the components of the HAM-A total score, the anxious mood item was significantly different from placebo in the PRX-00023-treated group (-1.015 vs -0.748; P = 0.02). The scores of the Montgomery-Asberg Depression Rating Scale were significantly improved compared with placebo at week 8 (-4.5 vs -1.6; P = 0.0094 in the last observation carried forward analysis). PRX-00023 was well tolerated; of note, there were no drug-related serious adverse events, and more patients discontinued due to adverse events in the placebo group (2.9%) than in the PRX-00023 group (1.4%). The most common adverse event was headache, observed in 15.7% and 10.9% of PRX-00023- and placebo-treated patients, respectively. Furthermore, there was no evidence of impaired sexual function, as measured by the Massachusetts General Hospital Sexual Function Scale. Collectively, these results support further clinical investigation of higher doses of PRX-00023 in anxiety and depression.

Monoamine oxidase inhibitors reduce conditioned fear stress-induced freezing behavior in rats

The present study examined the acute anxiolytic effects of monoamine oxidase inhibitors on freezing behavior, a putative index of anxiety induced by conditioned fear stress. The selective serotonin 1A receptor agonist tandospirone (0.1–10 mg/kg) inhibited freezing dose dependently. The irreversible, non-selective monoamine oxidase inhibitors tranylcypromine (3 and 15 mg/kg) and phenelzine (30 and 80 mg/kg) reduced freezing significantly. Clorgyline (10 mg/kg, irreversible selective monoamine oxidase A inhibitor), N-(2-aminoethyl)-5-( m-fluorophenyl)-4-thiazole carboxamide (Ro 41-1049) (30 mg/kg, reversible selective monoamine oxidase A inhibitor), selegiline (3 mg/kg, irreversible selective monoamine oxidase B inhibitor) and lazabemide (10 mg/kg, reversible selective monoamine oxidase B inhibitor) had no effect on freezing behavior. However, combined administration of clorgyline (10 mg/kg) and selegiline (3 mg/kg) reduced freezing significantly, as well as combined administration of clorgyline (10 mg/kg) and lazabemide (10 mg/kg), Ro 41-1049 (30 mg/kg) and selegiline (3 mg/kg), or Ro 41-1049 (30 mg/kg) and lazabemide (10 mg/kg). These effects of monoamine oxidase inhibitors on freezing were not due to non-specific motor effects. These results suggest that acute inhibition of both monoamine oxidase A and B reduced anxiety or fear, while inhibition of monoamine oxidase A or B alone failed to reduce anxiety or fear.

Simultaneous quantification of serotonin, dopamine and noradrenaline levels in single frontal cortex dialysates of freely-moving rats reveals a complex pattern of reciprocal auto- and heteroreceptor-mediated control of release

In the present study, a novel and exceptionally sensitive method of high-performance liquid chromatography coupled to coulometric detection, together with concentric dialysis probes, was exploited for an examination of the role of autoreceptors and heteroceptors in the modulation of dopamine, noradrenaline and serotonin levels in single samples of the frontal cortex of freely-moving rats. The selective D 3/D 2 receptor agonist, CGS 15855A [(±)- trans-1,3,4,4a,5,10b-hexahydro-4-propyl-2H-[1]benzopyrano[3,4-b]-pyridin-9-ol], and antagonist, raclopride, respectively decreased (−50%) and increased (+60%) levels of dopamine without significantly modifying those of serotonin and noradrenaline. The selective α 2-adrenergic receptor agonist, dexmedetomidine, markedly decreased noradrenaline levels (−100%) and likewise suppressed those of serotonin and dopamine by −55 and −45%, respectively. This effect was mimicked by the preferential α 2A-adrenergic receptor agonist, guanabenz (−100%, −60% and −50%). Furthermore, the α 2-adrenergic receptor antagonist, RX 821,002 [2(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline], and the preferential α 2A-adrenergic receptor antagonist, BRL 44408 [2-(2H-(1-methyl-1,3-dihydroisoindole)methyl)-4,5-dihydroimidazole], both evoked a pronounced elevation in levels of noradrenaline (+212%, +109%) and dopamine (+73%, +85%). In contrast, the preferential α 2B/2C-adrenergic receptor antagonist, prazosin, did not modify noradrenaline and dopamine levels. RX 821,002 and BRL 44408 did not significantly modify levels of serotonin, whereas prazosin decreased these levels markedly (−55%), likely due to its α 1-adrenergic receptor antagonist properties. The selective serotonin-1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), reduced serotonin levels (−65%) and increased those of dopamine and noradrenaline by +100% and +175%, respectively. The selective serotonin-1A antagonist, WAY 100,635 [ N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}- N-(2-pyridinyl)cyclo-hexanecarboxamide], which had little affect on monoamine levels alone, abolished the influence of 8-OH-DPAT upon serotonin and dopamine levels and significantly attenuated its influence upon noradrenaline levels. Finally, the selective serotonin-1B agonist, GR 46611 [3-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]- N-(4-methoxybenzyl)acrylamide], decreased serotonin levels (−49%) and the serotonin-1B antagonist, GR 127,935 [ N-[4-methoxy- 3-(4-methylpiperazin-1-yl)phenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)-biphenyl-4-carboxamide], which did not significantly modify serotonin levels alone, abolished this action of GR 46611. Levels of dopamine and noradrenaline were not affected by GR 46611 or GR 127,935. In conclusion, there is a complex pattern of reciprocal autoreceptor and heteroceptor control of monoamine release in the frontal cortex. Most notably, activation of α 2-adrenergic receptors inhibits the release of noradrenaline, dopamine and serotonin in each case, while stimulation of serotonin-1A receptors suppresses serotonin, yet facilitates noradrenaline and dopamine release. In addition, dopamine D 2/D 3 autoreceptors restrain dopamine release while (terminal-localized) serotonin-1B receptors reduce serotonin release. Control of serotonin release is expressed phasically and that of noradrenaline and dopamine release tonically.

Effects of serotonin through serotonin 1A and serotonin 4 receptors on inhibition in the guinea-pig dentate gyrus in vitro

The role of serotonin 1A and serotonin 4 receptors in the modulation of synaptic inhibition in the dentate gyrus of guinea-pig hippocampal slices was studied. The effects of serotonin (5-hydroxytryptamine) on hilar neurons and on inhibitory postsynaptic potentials in granule cells were compared using intracellular recording in the presence of glutamatergic receptor antagonists. On the basis of electrophysiological properties hilar neurons were classified as type I neurons (presumably inhibitory) and type II neurons (presumably excitatory). Serotonin hyperpolarized a proportion of type I hilar neurons (60%) and decreased their input resistance through activation of a K +-conductance. This effect was mediated by serotonin 1A receptors since it was mimicked by the selective serotonin 1A receptor agonist (±)-8-hydroxy-dipropylaminotetralin hydrobromide and blocked by the selective serotonin 1A receptor antagonist (+) WAY 100135. In some type I hilar neurons (40%) neither serotonin nor (±)-8-hydroxy-dipropylaminotetralin hydrobromide induced a membrane hyperpolarization. Instead, serotonin induced an excitatory response, depolarizing the cells and blocking the slow afterhyperpolarization. Similar effects were seen in all hilar neurons after blockade of serotonin 1A receptors. They were mimicked by the serotonin 4 receptor agonist zacopride. Serotonin induced either decreases or increases in the frequency of spontaneous GABA A receptor-mediated inhibitory postsynaptic potentials in granule cells via activation of serotonin 1A and of serotonin 4 receptors, respectively. 4-aminopyridine-evoked GABA B receptor-mediated inhibitory postsynaptic potentials were inhibited by serotonin via activation of serotonin 1A receptors. However, after blockade of serotonin 1A receptors, serotonin increased the frequency of GABA B-inhibitory postsynaptic potentials through the activation of serotonin 4 receptors. We conclude that a proportion of inhibitory neurons in the dentate area does not express serotonin 1A receptors and is excited by serotonin. Other inhibitory neurons express serotonin 1A receptors and are inhibited by serotonin.

Effects of acute, chronic ethanol and withdrawal on dorsal raphe neurons: electrophysiological studies

The effect of a single intravenous administration of ethanol (0.25–1.0 g/kg) on the spontaneous activity of putative serotonin neurons of the dorsal raphe nucleus was studied in unanesthetized rats. Ethanol produced a slight but progressive decline in neuronal activity in 67% (six of nine) of all neurons tested. The remaining 33% (three of nine) were unresponsive. Upon withdrawal of chronic ethanol treatment (1–5 g/kg every 6 h for six consecutive days, 12 h from last ethanol administration), the mean firing rate of dorsal raphe neurons was found to be significantly reduced, by about 30% ( n=71), as compared with the control group ( n=83), whereas the cells/track index was unaltered. Under these conditions, ethanol administration further reduced firing rate in 67% (four of six) of all the neurons tested. In the remaining 33% (two of six), no response was observed. At 72 h after the last ethanol administration, the mean firing rate of dorsal raphe neurons was found to be within control values ( n=90). Further, to evaluate the functional status of the autoreceptors under control conditions and after withdrawal from chronic ethanol, the selective serotonin-1A receptor agonist 8-hydroxy-(2-di-n-propylamino)tetralin was administered intravenously in cumulative doses (1–16 μg/kg) and dose–response curves were generated for both groups. Autoreceptor sensitivity of dorsal raphe neurons was found to be not statistically different in control and ethanol withdrawn rats ( n=6 for both groups) as indexed by a similar potency displayed by 8-hydroxy-(2-di-n-propylamino)tetralin in reducing the spontaneous activity of dorsal raphe neurons. The results indicate that, in spite of the widespread use of serotonin transmission potentiating agents in the treatment of alcoholism, neither acute nor withdrawal from chronic ethanol administration produces drastic effects on dorsal raphe neurons. However, the inhibition of dorsal raphe neuronal activity after acute ethanol may be due to the reported ability of ethanol to increase serotonin release from terminal areas. This increased serotonin tone could, at the level of recurrent axon collaterals in the dorsal raphe nucleus, reduce the spontaneous activity of the cells. On the other hand, a similar reduction in spontaneous activity after withdrawal from ethanol correlates well with the reduction in serotonin levels observed under these conditions in microdialysis studies.

Is fatigue associated with cholestasis mediated by altered central neurotransmission?

Is fatigue associated with cholestasis mediated by altered central neurotransmission?

Electrophysiological and histochemical properties of postnatal rat serotonergic neurons in dissociated cell culture

Serotonin modulates a variety of neural processes, and is present in a subpopulation of neurons in the raphe nuclei. To study their electrophysiological properties, cells from the mesopontine raphe nuclei of the neonatal rat were dissociated and grown for up to 10 weeks in microcultures. Approximately one third of the neurons were identified as serotonergic based on the presence of serotonin immunoreactivity, tryptophan hydroxylase immunoreactivity, or a high affinity monoamine transporter. About 5% of cultured raphe neurons contained tyrosine hydroxylase immunoreactivity, while 25% contained GABA immunoreactivity. However, no neurons contained both serotonin and tyrosine hydroxylase staining, and less than 1% displayed both serotonin and GABA immunoreactivities. Cultured serotonergic neurons did not exhibit pacemaker firing in the presence ofα 1 adrenergic receptor agonists such as phenylephrine or norepinephrine. Approximately one third were hyperpolarized by serotonin or the selective serotonin 1A receptor agonist,(±)-8-hydroxy-2-(di- N-propylamino)tetralin. Virtually all serotonergic neurons responded to application of glutamate, kainate, N-methyl- d-aspartate, GABA, and glycine. Depolarizing and hyperpolarizing synaptic potentials blocked by glutamate or GABA A receptor antagonists were frequently observed in both serotonergic and non-serotonergic raphe neurons. Slow inhibitory postsynaptic potentials were evoked by activating single presynaptic serotonergic neurons with a brief intracellular current pulse. The slow inhibitory synaptic potential had a mean latency to onset of35 ± 5 ms, a duration of 0.8–2.6 s, and was inhibited by the serotonin 1A autoreceptor antagonists, (−)propranolol and spiperone. The rising and falling phases of the inhibitory potential could be fit by single exponential functions with mean time constants of53 ± 8ms and504 ± 78ms, respectively. Serotonin 1A receptor-mediated autoinhibition was observed in microcultures containing a solitary serotonergic neuron, and thus constituted synaptic serotonin release, responsiveness, and re-uptake by a single vertebrate neuron. In summary, histochemical and electrophysiological evidence was obtained for catecholaminergic, GABAergic, and glutamatergic non-serotonergic raphe neurons in culture, many of which formed functional synaptic connections with neighboring cells. Additionally, cultured mesopontine serotonergic neurons expressed many of the cytochemical markers, neurotransmitter receptors, and synaptic functions observed in such cells in vivo, but the proportion of neurons sensitive to serotonergic and adrenergic agonists was significantly less than that reported in vivo. For the first time, the kinetics and pharmacology of serotonergic synaptic transmission by a single vertebrate serotonergic raphe neuron were determined, and were found to resemble those observed after extracellular stimulation of populations of raphe neurons in slices and in vivo.

8-Hydroxy-2-(di-n-propylamino)tetralin, a selective serotonin 1A receptor agonist, reduces the immobility of rats in the forced swimming test by acting on the nucleus raphe dorsalis

8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective serotonin 1A (5-HT 1A) receptor agonist, was studied for its anti-immobility activity in the forced swimming test when administered into the raphe nuclei medianus and dorsalis of rats. At concentrations ranging from 0.5 to 5 μg, 8-OH-DPAT siginificantly reduced the immobility of rats when administered into the nucleus raphe dorsalis, but only 5 μg was effective when administered into the nucleus medianus. The activity of rats in an open-field under conditions identical to those used in the forced swimming test was not significantly changed by various concentrations of 8-OH-DPAT administered into the nucleus raphe dorsalis, but was significantly increased by an infusion of 5 μg 8-OH-DPAT into the nucleus raphe medianus. The effect of an infusion of 1 μg 8-OH-DPAT into the nucleus dorsalis was prevented by infusing 2.5 μg (−)-propranolol or 2.5 μg (−)-pindolol into the same area 5 min before 8-OH-DPAT or by treating the animals with sulpiride systematically (100 mg/kg i.p.) or centrally (in the nucleus accumbens; 1 μg/0.5 μl). The results suggest that 8-OH-DPAT reduces the immobility of rats by activating dopamine transmission, probably in the nucleus accumbens, as a consequence of its ability to reduce the activity of 5-HT neurons that originate in the nucleus raphe dorsalis. In view of the similarities between the effects of well-established antidepressants and 8-OH-DPAT in the forced swimming test, it is suggested that 5-HT 1A receptor agonists may constitute a novel class of antidepressant agents.

8-hydroxy-2-(di- N-propylamino) tetralin, a selective serotonin 1A receptor agonist, blocks haloperidol-induced catalepsy by an action on raphe nuclei medianus and dorsalis

The selective serotonin 1A receptor agonist 8-hydroxy-2-(di- n-propylamino) tetralin (8-OH-DPAT) was studied for its ability to reverse haloperidol-induced catalepsy in rats. Given subcutaneously 8-OH-DPAT (0.06–0.5 mg/kg), dose-dependently antagonized the catalepsy induced by 1 mg/kg of haloperidol. Intraventricular injection of the serotonin (5-HT) neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), which caused marked depletion of 5-HT in brain, did not change haloperidol-induced catalepsy per se, but completely antagonized the anticataleptic effect of subcutaneously administered 8-OH-DPAT. When injected directly into the median or dorsal raphe nucleus, 8-OH-DPAT, in doses ranging from 0.2 to 5 μg/0.5 μl, reduced the catalepsy induced by haloperidol. The results suggest that the activation of 5-HT 1A receptors, probably those located presynaptically on 5-HT-containing cell bodies, reduces the catalepsy induced by haloperidol.

Potential anxiolytic properties of 8-hydroxy-2-(di-n-propylamino)tetralin, a selective serotonin 1A receptor agonist.

The effects of a selective serotonin 1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), were studied in two animal models of anxiety. Peripherally injected 8-OH-DPAT in doses ranging from 0.125 to 2.0 mg/kg did not increase black-white transitions (BWT) and black square entries (BSE) in a two-compartment exploratory test or punished responding in a test of conditioned suppression of drinking. With 2.0 mg/kg 8-OH-DPAT BSE and unpunished responding were reduced. In an investigation of the drinking time of water-deprived rats, naive or habituated to the test environment, 1.0 and 2.0 mg/kg 8-OH-DPAT increased the drinking time of naive rats but 2.0 mg/kg 8-OH-DPAT reduced that of habituated animals. In animals deprived of water for 48 h or subjected to immobilization stress for 2 h, 1.0 mg/kg 8-OH-DPAT increased BWT and BSE values in the two-compartment exploratory test. Infusions of 5 micrograms/0.5 microliter 8-OH-DPAT in the nucleus raphe medianus increased BWT and BSE values in the exploratory test and punished responding in the test of conditioned suppression of drinking, whereas the same dose of 8-OH-DPAT injected in the nucleus raphe dorsalis had no effect on punished but suppressed unpunished responding. The effects of 8-OH-DPAT are only detectable in the appropriate experimental conditions. When injected systemically, the effects are evident when a state of arousal of the animals contributes to the overall behavioural output. 8-OH-DPAT shows effects comparable to those of established anxiolytics such as benzodiazepines and barbiturates when it is injected in the nucleus raphe medianus, but not in the dorsalis.(ABSTRACT TRUNCATED AT 250 WORDS)

Potential antidepressant properties of 8-hydroxy-2-(di-n-propylamino) tetralin, a selective serotonin 1A receptor agonist

8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective serotonin 1A receptor agonist, was studied for its anti-immobility activity in the forced swimming test after different schedules of treatment. Single doses of 0.250 and 0.500 mg/kg 8-OH-DPAT s.c. reduced the immobility time of rats with no effect on open-field activity. Similar results were obtained with a three-injection course of 8-OH-DPAT in 24 h (doses from 0.125 to 0.500 mg/kg s.c.) or with a once daily injection of 0.250 mg/kg s.c. 8-OH-DPAT for 7 or 21 days. Methiothepin 0.2 mg/kg s.c. and l-propranolol 20 mg/kg s.c. significantly antagonized the anti-immobility effect of three injections of 0.25 mg/kg s.c. 8-OH-DPAT but 2 mg/kg i.p. metergoline had no such effect. The effect of 8-OH-DPAT was also antagonized both by 0.5 mg/kg i.p. haloperidol and 100 mg/kg i.p. sulpiride, and in animals given an intracerebroventricular injection of 150 μg 5,7-dihydroxytryptamine to deplete brain serotonin levels. The results show that 8-OH-DPAT, by acting on serotonin neurons in the brain, produces disinhibitory effects in a rat model predictive of antidepressant activity and suggest that serotonin 1A agonists such as 8-OH-DPAT could constitute a novel class of rapid-acting antidepressant agents.

In vivo output of neurotransmitters and metabolite from the lateral ventricle in freely-moving rats

In the present study, a novel and exceptionally sensitive method of high-performance liquid chromatography coupled to coulometric detection, together with concentric dialysis probes, was exploited for an examination of the role of autoreceptors and heteroceptors in the modulation of dopamine, noradrenaline and serotonin levels in single samples of the frontal cortex of freely-moving rats.The selective D3/D2 receptor agonist, CGS 15855A [(±)-trans-1,3,4,4a,5,10b-hexahydro-4-propyl-2H-[1]benzopyrano[3,4-b]-pyridin-9-ol], and antagonist, raclopride, respectively decreased (−50%) and increased (+60%) levels of dopamine without significantly modifying those of serotonin and noradrenaline. The selective α2-adrenergic receptor agonist, dexmedetomidine, markedly decreased noradrenaline levels (−100%) and likewise suppressed those of serotonin and dopamine by −55 and −45%, respectively. This effect was mimicked by the preferential α2A-adrenergic receptor agonist, guanabenz (−100%, −60% and −50%). Furthermore, the α2-adrenergic receptor antagonist, RX 821,002 [2(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline], and the preferential α2A-adrenergic receptor antagonist, BRL 44408 [2-(2H-(1-methyl-1,3-dihydroisoindole)methyl)-4,5-dihydroimidazole], both evoked a pronounced elevation in levels of noradrenaline (+212%, +109%) and dopamine (+73%, +85%). In contrast, the preferential α2B/2C-adrenergic receptor antagonist, prazosin, did not modify noradrenaline and dopamine levels. RX 821,002 and BRL 44408 did not significantly modify levels of serotonin, whereas prazosin decreased these levels markedly (−55%), likely due to its α1-adrenergic receptor antagonist properties. The selective serotonin-1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), reduced serotonin levels (−65%) and increased those of dopamine and noradrenaline by +100% and +175%, respectively. The selective serotonin-1A antagonist, WAY 100,635 [N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)cyclo-hexanecarboxamide], which had little affect on monoamine levels alone, abolished the influence of 8-OH-DPAT upon serotonin and dopamine levels and significantly attenuated its influence upon noradrenaline levels. Finally, the selective serotonin-1B agonist, GR 46611 [3-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-N-(4-methoxybenzyl)acrylamide], decreased serotonin levels (−49%) and the serotonin-1B antagonist, GR 127,935 [N-[4-methoxy- 3-(4-methylpiperazin-1-yl)phenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)-biphenyl-4-carboxamide], which did not significantly modify serotonin levels alone, abolished this action of GR 46611. Levels of dopamine and noradrenaline were not affected by GR 46611 or GR 127,935.In conclusion, there is a complex pattern of reciprocal autoreceptor and heteroceptor control of monoamine release in the frontal cortex. Most notably, activation of α2-adrenergic receptors inhibits the release of noradrenaline, dopamine and serotonin in each case, while stimulation of serotonin-1A receptors suppresses serotonin, yet facilitates noradrenaline and dopamine release. In addition, dopamine D2/D3 autoreceptors restrain dopamine release while (terminal-localized) serotonin-1B receptors reduce serotonin release. Control of serotonin release is expressed phasically and that of noradrenaline and dopamine release tonically.