Cellular and behavioral effects of 5-HT1A receptor agonist 8-OH-DPAT in a rat model of levodopa-induced motor complications

5-HT1A autoreceptor stimulation can act to attenuate supraphysiological swings in extracellular dopamine levels following long-term levodopa treatment and may be useful in the treatment and prevention of the motor complications. The purpose of this study was to investigate cellular and behavioral effects of 5-HT1A receptor agonist 8-OH-DPAT in a rat model of levodopa-induced motor complications. Two sets of experiments were performed. First, animals were treated with levodopa (50 mg/kg with benserazide 12.5 mg/kg, twice daily), intraperitoneally (i.p.) for 22 days. On day 23, animals received either 8-OH-DPAT (1 mg/kg, i.p.) or 8-OH-DPAT plus WAY-100635 (0.1 mg/kg, i.p) or vehicle with each levodopa dose. In the second set, animals were treated either with levodopa (50 mg/kg, i.p.) plus 8-OH-DPAT (1 mg/kg, i.p.) or levodopa (50 mg/kg, i.p.) plus vehicle, administered twice daily for 22 consecutive days. Our study showed that 8-OH-DPAT plus levodopa both prolonged the duration of the motor response and reduced peak turning. 8-OH-DPAT plus levodopa also decreased the frequency of failures to levodopa. Co-administration of WAY-100635, a 5-HT1A receptor antagonist, with 8-OH-DPAT eliminated the effect of 8-OH-DPAT on motor complications indicating that the observed 8-OH-DPAT responses were probably mediated at the 5-HT1A autoreceptor. Moreover, 8-OH-DPAT plus levodopa significantly reduced hyperphosphorylation of GluR1 at serine 845, which was closely associated with levodopa-induced motor complications.     

Partial antagonism of 8-OH-DPAT'S effects on male rat sexual behavior with a D2, but not a 5-HT1A, antagonist

The serotonin agonist 8-hydroxy-di-propylaminotetralin (8-OH-DPAT), injected systemically or directly into the medial preoptic area (MPOA), reduces the ejaculatory threshold in male rats. While 8-OH-DPAT has been characterized as an agonist at the 5-HT_1A receptor, it also acts at other receptor sites including the dopamine D₂ receptor. The current experiments investigated whether 8-OH-DPAT injected into the MPOA facilitates male sexual behavior through stimulation of the 5-HT_1A receptor or the dopamine D₂ receptor. Experiment 1 co-administered 8-OH-DPAT (6 μg) with either the 5-HT_1A antagonist 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzamide hydrochloride (MPPI) (10 μg) or the D₂ antagonist raclopride (10 μg). Raclopride blocked 8-OH-DPAT's facilitative effects on ejaculation frequency and latency, while the 5-HT_1A antagonist was ineffective. In Experiment 2, 8-OH-DPAT (500 μM), retrodialyzed into the MPOA through a microdialysis probe, enhanced male copulatory behavior similarly to the microinjection, increasing ejaculation frequency and decreasing ejaculation latency, postejaculatory interval and mount frequency. Retrodialyzing 8-OH-DPAT through a microdialysis probe in the MPOA had been previously shown to increase extracellular levels of dopamine and serotonin. The data from the present studies suggest that the effects of 8-OH-DPAT in the MPOA on male rat copulatory behavior may be mediated, at least in part, either directly through 8-OH-DPAT's activity at D₂ receptors or indirectly through 8-OH-DPAT's ability to increase extracellular dopamine.     

Effects of local application of 5-HT into the median and dorsal raphe nuclei on male rat sexual and motor behavior

The local application of 10 micrograms 5-hydroxytryptamine (5-HT) into the dorsal or median raphe nucleus was found to facilitate male rat sexual behavior, as evidenced by a decrease in time to ejaculation, and in number of intromissions preceding ejaculation. The application of a higher dose, 40 micrograms, at either site, inhibited the initiation of sexual behavior. There was a clear distinction between the motor effects observed after local application of 5-HT into the dorsal or the median raphe nuclei. Injections into the median raphe produced a dose-dependent increase, whereas injections into the dorsal raphe nucleus produced a dose-dependent decrease, in motor activity. Present results suggests an inhibitory and excitatory role of the median and the dorsal raphe serotonergic projections, respectively, as regards motor behavior, whereas projections from both nuclei appear to have an inhibitory role in the mediation of male rat sexual behavior.     

Further studies on the rat posterodorsal medial amygdala: dendritic spine density and effect of 8-OH-DPAT microinjection on male sexual behavior

The rat posterodorsal medial amygdala (MePD) is a component of the neural network that modulates male sexual behavior. Dendritic spines were counted in Golgi-impregnated bitufted and stellate neurons and from cells located in the medial and lateral MePD subregions. It was also studied the effect of 8-OH-DPAT, a 5-HT1A receptor agonist, microinjected into the MePD on male sexual behavior. There were no significant differences in the dendritic spine density obtained from multipolar bitufted and stellate neurons (n = 48 cells in each group; p > 0.05) or in the data from the medial or the lateral MePD (n = 48 neurons per region; p > 0.05). Rats were stereotaxically microinjected into the MePD with saline (0.2 microl, n = 6) or 8-OH-DPAT (0.1 and 1.0 microg/0.2 microl, n = 6 and 5, respectively). Behavioral recordings prior to surgery and "non-target" microinjections served as additional control data. 8-OH-DPAT 1.0 microg decreased the latencies to intromission and ejaculation, the postejaculatory refractory period and the mount frequency when compared to control pre-surgery data (p < 0.05). When compared among groups, 8-OH-DPAT 1.0 microg promoted the highest percentage reduction in the postejaculatory refractory period. Saline and injections in the vicinity of MePD did not promote relevant effects on ejaculation (p > 0.05). Results indicate that a similar dendritic spine density can be found in morphologically different populations of MePD neurons and, 8-OH-DPAT can facilitate male sexual behavior by acting on postsynaptic 5-HT1A receptors in this brain area.     

Physiological effects of selective 5-HT1a and 5-HT1b ligands in rat hippocampus: comparison to 5-HT

The responses of CA1 neurons to topical application of serotonin (5-HT) and selective 5-HT1a and 5-HT1b agonists were examined with intracellular recording in the hippocampal slice. 5-HT produced a uniform hyperpolarizing response associated with an increase in K conductance as previously reported. In addition a marked reduction was recorded in slow afterhyperpolarization (AHP) which follows a burst discharge. 8-OH-DPAT, ipsapirone and LY165,163 partially mimicked the hyperpolarizing response to 5-HT when first applied to the slice. However, these 5-HT1a ligands antagonized responses to subsequent applications of 5-HT. Topical application of the 5-HT1b ligand TFMPP on the slice did not produce the direct or antagonistic action seen with the 5-HT1a ligands. It is suggested that the physiological response to 5-HT in the rat hippocampus is mediated by a 5-HT1a receptor. The currently available 5-HT1a ligands show a low agonist potential and a high antagonist action towards the responses of hippocampal neurons to 5-HT. Definite classification of the hyperpolarizing response to 5-HT awaits development of more specific ligands having a pure agonistic activity.     

Effects of 5-HT and 8-OH-DPAT on forebrain monoamine synthesis after local application into the median and dorsal raphe nuclei of the rat

Summary 5-HT (10 and 40 g) and 8-OH-DPAT (1 and 5 g) were locally applied into the dorsal or median raphe nuclei in awake, unrestrained, rats. All animals were also treated with the 5-HTP and DOPA decarboxylase inhibitor NSD-1015, 100mg kg^–1 SC, 30 min before decapitation. 5-HT or 8-OH-DPAT were administered 5 min before NSD-1015. The regional brain in vivo rate of tyrosine and tryptophan hydroxylase activity was estimated by measuring the accumulation of DOPA and 5-HTP. The following brain regions were sampled: neocortex, hippocampus, dorso-lateral neostriatum, ventro-medial neostriatum, nucleus accumbens, olfactory tubercle, globus pallidus, septum and the amygdala.Compared to normal controls, there were small and inconsistent effects on forebrain 5-HTP accumulation by saline injections into the dorsal or the median raphe (an increase in 3 out of 36 experiments), whereas strong effects by the injection procedure were noted on forebrain DOPA accumulation (an increase in 15 out of 36 experiments).Injections of 5-HT (same effect by 10 or 40 g) into the dorsal raphe, produced a decrease in 5-HTP accumulation in all forebrain areas except for the hippocampus and the septum, whereas no effects were seen in any area after median raphe injections. In contrast, 8-OH-DPAT preferentially produced a decrease in forebrain 5-HTP accumulation after median raphe injections and less, but statistically significant effects by dorsal raphe injections. The 8-OH-DPAT injection into the median raphe primarily affected limbic forebrain areas (hippocampus, nucleus accumbens, ventro-medial neostriatum, amygdala and the septum).This dissociation of the effects of 5-HT and 8-OH-DPAT on forebrain 5-HT synthesis after local application into the dorsal or the median raphe strongly supports the contention of heterogeniety in the brain 5-HT receptor population in terms of receptor subtypes and/or receptor regulation.     

5-HT1A agonists and dopamine: the effects of 8-OH-DPAT and buspirone on brain-stimulation reward

Summary Two specific 5-HT_1A agonists, 8-OH-DPAT (0–300 g/kg), and buspirone (0–3.0 mg/kg), were tested on variable-interval, threshold-current self-stimulation of rat lateral hypothalamus. Buspirone produced a prolonged monotonic depression of responding, whereas the effects of 8-OH-DPAT were biphasic: 3.0 g/kg produced a sustained enhancement of responding while higher doses (100–300 g/kg) produced a relatively short-lasting depression. This biphasic pattern parallels previously reported effects of 8-OH-DPAT on food intake and on various other behaviours. Threshold-current self-stimulation is highly sensitive to alterations in dopaminergic transmission but relatively insensitive to changes in 5-HT. Thus the facilitatory effect of low-dose 8-OH-DPAT seems most plausibly interpreted in terms of enhanced dopaminergic transmission. This could be brought about by 5HT_1A autoreceptor-mediated inhibition of 5-HT release and consequent disinhibition of dopaminergic transmission. Depression of self-stimulation by higher doses of 8-OH-DPAT may reflect the activity of 8-OH-DPAT at postsynaptic 5-HT receptors, with consequent inhibition of DA transmission. Suppression of responding after buspirone at all doses tested may reflect the action of this compound as a partial agonist at postsynaptic 5-HT receptors, and/or its effects on other systems.     

Role of 5-HT1A receptors in the mediation of acute citalopram effects: a 8-OH-DPAT challenge study

(1) The study was aimed to investigate the effects of the minimal effective doses of acute citalopram (5 mg/kg), (+/-)-8-hydroxydipropylaminotetralin HBr (8-OH-DPAT; 0.1 mg/kg), and their combined treatment on the rat open field and forced swimming behaviour and post-mortem monoamine content. (2) The animals were prospectively divided into the vehicle- and para-chlorophenylalanine (p-CPA)-pretreated (350 mg/kg) groups. (3) Acute citalopram (5 mg/kg), 8-OH-DPAT (0.1 mg/kg), or their combined treatment had no major effect on the rat open field and forced swimming behaviour. (4) The post-mortem catecholamine content in four brain regions studied was unchanged in all treatment groups. (5) The combined 8-OH-DPAT (0.1 mg/kg) and citalopram (5 mg/kg) treatment partially reversed the p-CPA-induced decrease of serotonin (5-HT) and 5-hydroxy-indolacetic acid (5-HIAA) content. (6) The present experiments demonstrate that the 5-HT1A receptors mediate some of the selective serotonin reuptake inhibitor (SSRI)-induced biochemical phenomena.     

Dopamine and sexual behavior in the male rat: a reevaluation

Summary In castrated male rats treated with a low dose of testosterone propionate (0.40 mg/kg per week), the dopamine agonists amphetamine and amfonelic acid reduced mount latency without affecting other aspects of sexual behavior. Apomorphine, in doses between 0.05 and 0.15 mg/kg, and 1-DOPA 5 –45 mg/kg + carbidopa 50 mg/kg, lacked effect on sexual behavior. Both amphetamine and amfonelic acid increased locomotor activity in a dose-dependent manner. Apomorphine, in the lowest dose, produced a reduction whereas the higher doses of this drug as well as all doses of 1-DOPA lacked effect on this behavior. In castrated animals implanted with a testosterone-filled Silastic capsule, showing a level of sexual activity indistinguishable from that of intact animals, amphetamine and amfonelic acid did not affect sexual behavior. The dopamine receptor antagonists haloperidol and cis(Z)-flupentixol reduced sexual behavior, whereas pimozide was without effect in the dose range used. The doses of haloperidol and fiupentixol that were required to reduce sexual activity were such that they also affected motor execution measured in a treadmill test. It is suggested that increased dopaminergic neurotransmission may stimulate sexual behavior in an indirect way, augmenting behavioral arousal. The inhibitory effects of dopamine antagonists could be explaned either by a reduced arousal level or by motor deficiencies.     

The effects of idazoxan and 8-OH-DPAT on sexual behaviour and associated ultrasonic vocalizations in the rat

Two experiments were performed studying the effects of 8-OH-DPAT and idazoxan on sexual behaviour and ultrasonic communication of male rats. In addition, the reactions of the females towards drug-treated males were studied. 8-OH-DPAT (a very specific 5-HT1A agonist) and idazoxan (an alpha 2-adrenergic antagonist) differentially affected sexual behaviour: 8-OH-DPAT (0.1 and 0.4 mg/kg IP) markedly facilitated ejaculations, a feature indicated by decreased numbers of mounts and intromissions preceding ejaculation and a reduction in ejaculation latency. This drug concomitantly reduced the postejaculatory refractory period. Idazoxan reduced the number of intromissions before ejaculation only at the highest dose (10 mg/kg IP), but did not markedly facilitate other parameters. Both drugs markedly and dose-dependently suppressed the postejaculatory 22 kHz ultrasounds normally recorded during the postejaculatory refractory period. Ultrasound frequencies above 30 kHz first appear at the end of the absolute refractory period, even when the refractory period is shortened by 8-OH-DPAT. Idazoxan increased the number of these 30 kHz ultrasounds, whereas 8-OH-DPAT had no effect on them. No effects were observed on ultrasound production (either 22 kHz or above 30 kHz) before an ejaculation. The behaviour of the females towards 8-OH-DPAT-treated males was also affected, with the females showing more darting and lordosis before and after ejaculation, but less sitting after ejaculation. Idazoxan treatment of the males resulted in more hopping and earwiggling of the females before ejaculation. Following ejaculation, females treated with the antagonist showed more darting, hopping, earwiggling and lordosis, but sitting was decreased. It has been suggested in the rat that the emergence of ultrasounds higher than 30 kHz indicates the end of the absolute refractory period and signals to the female that the male is capable of resuming sexual activity. The significance of 22 kHz ultrasound in sexual behaviour remains puzzling because these vocalizations could be easily uncoupled from the refractory period by drugs acting via different receptor mechanisms without disturbing sexual behaviour per se. A failure to produce postejaculatory sounds appears to disinhibit (proceptive) behaviour by the females.     

Behavioral effects of 8-OH-DPAT injections into pontine and mesencephalic areas containing 5-HT-immunoreactive perikarya in the pigeon

This study examined the distribution of 5-HT-immunoreactive perikarya (5-HT-IRp) and the effects of local injections of 8-OH-DPAT into 5-HT-IRp-containing pontine and mesencephalic regions on feeding and drinking behaviors in free-feeding pigeons. When infused into the midline 5-HT-IRp-containing areas, 8-OH-DPAT (6.1 nmol) reliably elicited drinking and, to a lesser extent, feeding responses during the first hour after injection. These responses were significantly higher than the ingestive indexes observed (1) after vehicle (ascorbic acid 0.1%, 200 nl) injections at the same sites and (2) after 8-OH-DPAT injections into adjacent sites devoid of 5-HT-IRp. Increases in drinking were proportionally higher than those observed in feeding and a significant negative correlation was observed between water and food after midline 8-OH-DPAT injections. Similar dipsogenic responses were observed after injections of different 8-OH-DPAT doses (0.6, 2.0, and 6.1 nmol). Pretreatment with local injections of p-MPPI (an antagonist of 5-HT1A receptors) attenuated the ingestive responses evoked by 8-OH-DPAT injections. Injections of 8-OH-DPAT into lateral 5-HT-IRp-containing sites evoked only inconsistent and weak ingestive responses. These results indicate that 5-HT1A receptor-mediated circuits located in the midline superior raphe system of the pigeon may play an important role in mechanisms controlling water intake, similar to that observed in mammals.     

Modification of sexual behavior of Long-Evans male rats by drugs acting on the 5-HT1A receptor

Modulation of the sexual behavior of male rats by the anxiolytic buspirone (S-20499) and its analog gepirone were compared to the effects of 8-OH-DPAT (or DPAT, a selective 5-HT1A reference agonist), and BMY-7378 (a selective 5-HT1A partial agonist). Long-Evans rats were used; modulation of copulatory behavior and alteration of penile reflexes were examined. Modulation of copulatory behavior was assessed by three indices: frequency and length of intromission, and latency of ejaculation. DPAT, at doses of 1-8 mg/kg, reduced these three indices in a time dependent manner such that the effects peaked at 45 min and normalized at 90 min. The dose-effect relationship (assessed 45 min after DPAT injection) is bell-shaped with an ED50 approximately 1 mg/kg on the ascending limb of the curve. The effects of buspirone (2 mg/kg) and gepirone (2 mg/kg) on copulatory behavior were indistinguishable from control. BMY-7378 alone and in combination with these other 5-HT1A agonists reduced copulatory behavior, though not statistically significant. Penile reflexes, including number of erections, cups and flips, were inhibited by these agents: DPAT>buspirone>gepirone (inactive at 2 mg/kg). Furthermore, the latency period to erection was at least doubled by DPAT (2 mg/kg). Buspirone and gepirone, however, reduced the latency period to erection. BMY-7378 inhibited penile reflexes when administered alone and even more in combination with DPAT or buspirone. Two butyrophenone analogs, spiperone (a 5-HT1A and dopamine D2 antagonist) and haloperidol (a D2 antagonist), were also tested for their interaction with DPAT. Both of these drugs (at 0.25 mg/kg, 60 min after administration) reduced all indices of penile reflexes and copulation. Furthermore, in combination with DPAT (2 mg/kg, 45 min), the effects were synergistic such that sexual activity came nearly to a standstill. These opposing effects on putatively brain originated copulatory behavior and spinal mediated penile reflexes indicate that the effects of buspirone and DPAT on sexual behavior in the male rat may be possible at different parts of the central nervous system. If a tentative shared target site by DPAT and buspirone is the 5-HT1A receptor, than the same 5-HT receptor sub-type at different locations (brain, raphe nuclei, spinal cord and autonomic ganglia) may modulate rat sexual behavior in opposing ways.     

Ethanol stimulates [3H]5-HT high-affinity uptake by rat forebrain synaptosomes: role of 5-HT receptors and voltage channel blockers.

We examined ethanol's interactions with serotonin (5-HT) receptor-mediated [3H]5-HT high-affinity uptake by adult rat forebrain synaptosomes. The serotonergic transport mechanism was chosen because ethanol consumption patterns can be manipulated by serotonin receptors and uptake blockers. We report that a dose of ethanol which causes general anesthesia in humans (54 mM) applied in vitro enhanced rat synaptosomal [3H]5-HT uptake after 5 min at 37 degrees C. Similar levels of stimulation by 54 mM ethanol were seen in hippocampal, cerebral cortex and brainstem synaptosomes. Significant inhibition of uptake was not detected until concentrations of ethanol reached 2.1 M, which is lethal in vivo. Ryanodine and the 5-HT2 agonist, DOI, are believed to cause an increase in intracellular Ca2+ levels. We observed that they also caused an elevation of [3H]5-HT uptake, and this stimulation was less than additive with the ethanol-induced increase. Inhibition of the 5-HT3, receptor-mediated Na+ channel with the antagonist ICS 205930, partially reversed ethanol's stimulatory effects on [3H]5-HT uptake. Blockade of voltage-dependent Na+ flux with tetrodotoxin and lidocaine, however, had no effect on the stimulation by ethanol. But tetraethylammonium, which blocks voltage-dependent K+ channels, partially counteracted ethanol's action on [3H]5-HT uptake. These compounds had no effect on uptake by themselves. These results indicate that ethanol's stimulation of [3H]5-HT uptake involves a rise in [Ca2+]i which is sensitive to voltage-dependent K+ flux and 5-HT3 receptor-mediated Na+ flux, and would decrease the availability of synaptic 5-HT.     

Contribution of spinal 5-HT1A and 5-HT7 receptors to locomotor-like movement induced by 8-OH-DPAT in spinal cord-transected mice

Growing evidence from in vitro studies suggests that spinal serotonin (5-HT) receptor subtypes 5-HTR(1A) and 5-HTR(7) are associated with an induction of central pattern generator activity. However, the possibility of a specific role for these receptor subtypes in locomotor rhythmogenesis in vivo remains unclear. Here, we studied the effects of a single dose (1 mg/kg, i.p.) of 8-hydroxy-2-(di-N-propylamino)-tetralin (8-OH-DPAT), a potent and selective 5-HTR(1A/7) agonist, in mice spinal cord transected at the low-thoracic level (Th9/10). The results show that 8-OH-DPAT acutely induced, within 15 min, hindlimb movements that share some characteristics with normal locomotion. Paraplegic mice pretreated with the selective 5-HTR(1A) antagonists, WAY100,135 or WAY100,635, displayed significantly less 8-OH-DPAT-induced movement. A similar reduction of 8-OH-DPAT-induced movements was found in animals pretreated with SB269970, a selective 5-HTR(7) antagonist. Moreover, a near complete blockade of 8-OH-DPAT-induced movement was obtained in wild-type mice pretreated with 5-HTR(1A) and 5-HTR(7) antagonists, and in 5-HTR(7)-/- mice pretreated with 5-HTR(1A) antagonists. Overall, these results clearly demonstrate that 8-OH-DPAT potently induces locomotor-like movement in the previously paralysed hindlimbs of low-thoracic-transected mice. The results, with selective antagonists and knockout animals, provide compelling evidence of a specific contribution of both receptor subtypes to spinal locomotor rhythmogenesis in vivo.     

Partial agonistic activity of R- and S-enantiomers of 8-OH-DPAT at 5-HT1A receptors.

In this study, the 5-HT1A agonistic activity of R- and S-enantiomers of the prototypical 5-HT1A agonist 8-OH-DPAT was investigated using in vivo microiontophoresis and the hypothermic response in rats. Both the R- and S-enantiomers suppressed current-dependently the firing activity of dorsal hippocampus CA3 pyramidal neurons. The number of spikes suppressed/nA of R-(+)-OH-DPAT was about 2-fold greater than that of S-(-)-OH-DPAT, which indicates greater agonistic activity of the R-enantiomer. The determination of the effectiveness of 5-HT in suppressing the firing activity of CA3 pyramidal neurons prior to and during application of either the R- or S-enantiomer showed that both compounds antagonized the effect of 5-HT, thus demonstrating their partial agonistic activity. Racemic 8-OH-DPAT produced a dose-dependent hypothermia which was attenuated by the 5-HT1A antagonist pindolol, but not by the nonselective 5-HT antagonist methysergide. Similarly, both R- and S-enantiomers induced a dose-dependent hypothermia, which was greater and longer lasting in the case of R-(+)-OH-DPAT when compared to S-(-)-OH-DPAT. In conclusion, R-(+)-OH-DPAT, displayed a greater agonistic activity at 5-HT1A receptors than S-(-)-OH-DPAT, both in suppressing firing activity of CA3 pyramidal neurons and in decreasing body temperature. Nevertheless, both compounds behaved as partial agonists.     

Anxiolytic and sedative effects of 5-HT1A ligands, 8-OH-DPAT and MDL 73005EF, in mice

The actions of the 5-HT1A receptor ligands, MDL 73005EF and 8-OH-DPAT, were assessed in mice. They were confronted with a free exploratory test especially adapted to reveal sedation, and with a two-box light/dark choice situation validated for the detection of anti-anxiety agents. Both drugs were found to have sedative properties at high doses and anxiolytic-like effects at lower doses. The results show that both drugs have a comparable profile of action to that of benzodiazepines in the two-box light/dark procedure. These findings are in line with earlier reports describing anxiolytic effects of 5-HT1A receptor ligands in different animal models of anxiety.     

Partial antagonism of 8-OH-DPAT'S effects on male rat sexual behavior with a D2, but not a 5-HT1A, antagonist

The serotonin agonist 8-hydroxy-di-propylaminotetralin (8-OH-DPAT), injected systemically or directly into the medial preoptic area (MPOA), reduces the ejaculatory threshold in male rats. While 8-OH-DPAT has been characterized as an agonist at the 5-HT_1A receptor, it also acts at other receptor sites including the dopamine D₂ receptor. The current experiments investigated whether 8-OH-DPAT injected into the MPOA facilitates male sexual behavior through stimulation of the 5-HT_1A receptor or the dopamine D₂ receptor. Experiment 1 co-administered 8-OH-DPAT (6 μg) with either the 5-HT_1A antagonist 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzamide hydrochloride (MPPI) (10 μg) or the D₂ antagonist raclopride (10 μg). Raclopride blocked 8-OH-DPAT's facilitative effects on ejaculation frequency and latency, while the 5-HT_1A antagonist was ineffective. In Experiment 2, 8-OH-DPAT (500 μM), retrodialyzed into the MPOA through a microdialysis probe, enhanced male copulatory behavior similarly to the microinjection, increasing ejaculation frequency and decreasing ejaculation latency, postejaculatory interval and mount frequency. Retrodialyzing 8-OH-DPAT through a microdialysis probe in the MPOA had been previously shown to increase extracellular levels of dopamine and serotonin. The data from the present studies suggest that the effects of 8-OH-DPAT in the MPOA on male rat copulatory behavior may be mediated, at least in part, either directly through 8-OH-DPAT's activity at D₂ receptors or indirectly through 8-OH-DPAT's ability to increase extracellular dopamine.     

Antagonism by pindolol,but not betaxolol,of 8-OH-DPAT-induced facilitation of male rat sexual behavior

Summary 8-OH-DPAT (0.25 mg/kg s.c.) produced a facilitation of the male rat sexual behavior, characterized by a decrease in the number of intromissions preceding ejaculation and in the time to ejaculation. This facilitation of the sexual behavior was antagonized by administration of the 5-HT and -adrenoceptor antagonist pindolol (4mg/kg i.p.), but not by the selective -adrenoceptor antagonist betaxolol (4 mg/kg i.p.). Neither pindolol (2–8 mg/kg), nor betaxolol (2–8 mg/kg), produced any statistically significant effects per se on the male rat sexual behavior, as observed here (mounts, intromissions, ejaculation latency or the post-ejaculatory interval). A higher dose (16mg/kg) of betaxolol produced a statistically significant reduction in the number of intromissions preceding ejaculation and in the ejaculation latency. The antagonism by pindolol of 8-OH-DPAT-induced effects on male rat sexual behavior suggests an involvement of 5-HT_1A receptors in the facilitation of this behavior produced by 8-OH-DPAT.     

5-HT depletion with 5,7-DHT, PCA and PCPA in mice: differential effects on the sensitivity to 5-MeODMT, 8-OH-DPAT and 5-HTP as measured by two nociceptive tests

Depletion of 5-hydroxytryptamine (5-HT) in mice was produced by intracerebroventricular injection of 5,7-dihydroxytryptamine (5,7-DHT, 80 micrograms) or by systemic injections of p-chloroamphetamine (PCA, 3 X 40 or 4 X 40 mg/kg), p-chlorophenylalanine (PCPA, 5 X 400 or 14 X 400 mg/kg) or combined PCA (3 X 40 mg/kg) + PCPA (11 X 400 mg/kg). Neither of the pretreatments altered nociception in the increasing temperature hot-plate test, whereas hyperalgesia was demonstrated in 5,7-DHT lesioned animals in the tail-flick test. 5,7-DHT-pretreatment enhanced the antinociceptive effect of the 5-HT agonists 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 5-hydroxytryptophan (5-HTP). This effect was observed after 2, 5 and 8 days in the tail-flick test and after 5 and 8 days in the hot-plate test. However, pretreatment with PCPA or PCA failed to alter the antinociception elicited by the 5-HT agonists, although a tendency towards enhancement of antinociception was found after combined treatment with PCA and PCPA. It is suggested that the injection of 5,7-DHT induces denervation supersensitivity of post-synaptic 5-HT receptors. The lack of such supersensitivity after PCPA-pretreatment which induces similar 5-HT depletion to 5,7-DHT, may suggest that other factors than the absence of 5-HT may contribute to the development of denervation supersensitivity. Alternatively, the three 5-HT depleting agents may produce a qualitatively different reduction of 5-HT.