Effects of 8-OH-DPAT and buspirone in a passive avoidance test and in the elevated plus-maze test in rats

Benzodiazepines are generally reported to be active in tests based on punished responding and in procedures involving exploratory behaviour, but the effects of 5-HT drugs thus far reported are inconsistent. The effects of the two 5-HT(1A) agonists 8-OH-DPAT and buspirone were studied in a passive avoidance test and in an elevated plus-maze test. In the passive avoidance test 8-OH-DPAT and buspirone, as well as diazepam and chlordiazepoxide, were effective, while, in the elevated plus-maze test, the two benzodiazepines were active whereas buspirone and 8-OH-DPAT were not. Comparing the effects of the 5-HT(1A) agonists with the two benzodiazepines in the passive avoidance test it is suggested that this test can be predictive for drugs influencing anxiety. The elevated plus-maze test has many advantages, such as the absence of noxious stimuli, compared to punishment procedures, but since the 5-HT(1A) agonists do not act as anxiolytic compounds in this test, it is suggested that the test does not provide a suitable model of anxiety.     

The 5-HT1A agonists 8-OH-DPAT, buspirone and ipsapirone attenuate stress-induced anorexia in rats

The effects of 5-HT agonists and antagonists, benzodiazepine anxiolytics and tricyclic antidepressants on restraint stress-induced anorexia in rats were examined. The selective 5-HT(1A) agonists 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT), buspirone and ipsapirone, when injected 2 h after the termination of stress, attenuated stress-induced anor exia and body weight loss. The effects of 8-OH-DPAT on stress-induced anorexia were blocked by the 5-HT(1A) antagonist spiperone but not by the 5-HT(2) antagonist ketanserin. The preferential 5-HT(1B) agonists RU-24969 and quipazine induced anorexia in unstressed rats and tended to supplement the anorectic effects of stress. The benzodiazepines chlordiazepoxide and diazepam and the 5-HT antagonist cyproheptadine had no effect on stress-induced anorexia, when given (like the 5-HT(1A) agonists) 2 h after the stress. Similarly, daily injection for 2 weeks of the tricyclic antidepressants desipramine and sertraline had no beneficial effect. The data suggest that 8-OH-DPAT, buspirone and ipsapirone attenuate stress-induced anorexia in rodents by a hyperphagic action on 5-HT(1A) receptors.     

Acoustic startle, conditioned startle potentiation and the effects of 8-OH-DPAT and buspirone in rats selectively bred for differences in 8-OH-DPAT-induced hypothermia.

HDS and LDS rats are the result of selective breeding for differences in the hypothermic effects of the 5-hydroxytryptamine-1A (5-HT1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT); HDS (high DPAT sensitivity) rats exhibit a much greater hypothermic response than do LDS (low DPAT sensitivity) rats. It is possible that this genetically-based difference in sensitivity to the hypothermic effects of the 5-HT1A agonist is associated with a change in other behaviours modulated by 5-HT neurotransmission. The present study examined the acoustic startle response, the classically conditioned enhancement of startle, and the effects of 8-OH-DPAT and buspirone treatments on these measures, in HDS and LDS rats. On four test sessions, HDS and LDS rats were exposed to 20 acoustic startle stimuli (115 dB; 40 ms in duration). For each test session, 10 trials were presented in the dark (Noise Alone trials) and 10 were presented at the end of a 3500 ms presentation of a 15 W signal light (Light + Noise trials). LDS rats exhibited greater startle amplitude than did HDS rats on Noise Alone trials. Initially, there was no difference in startle amplitude on the Light + Noise versus Noise Alone trials in either LDS or HDS rats. By the end of the first test session, however, and continuing throughout the remainder of the four test sessions, startle amplitude on the Light + Noise trials was significantly greater than in the Noise Alone trials. The magnitude of this startle-potentiated startle (SPS) effect did not differ in HDS versus LDS rats. SPS testing was continued for three additional sessions; in these sessions the effects of acute treatment with the 8-OH-DPAT (125 microg/kg, subcutaneously (s.c.)), the novel anxiolytic buspirone (4 mg/kg, intraperitoneally (i.p.)) or vehicle (distilled water) were determined. Both 8-OH-DPAT and buspirone treatment increased baseline (Noise Alone) startle amplitude in LDS rats but not in HDS rats. With respect to the conditioned enhancement of startle, buspirone reduced the SPS effect in both HDS and LDS rats, whereas 8-OH-DPAT did not change the conditioned enhancement effect in either rat line. These findings suggest that the selective breeding for differences in 8-OH-DPAT-induced hypothermia has resulted in changes in other behaviours and also changes in the response to 5-HT1A agonist treatment. Moreover, these findings are consistent with the hypotheses that: (a) 5-HT1A agonist actions underlie the buspirone-induced and 8-OH-DPAT-induced increases in Noise Alone startle amplitude; whereas (b) the buspirone-induced reduction in potentiated startle is not the result of 5-HT1A agonist actions of this compound.     

Effects of triazolam, 8-OH-DPAT,and buspirone on repeated acquisition in squirrel monkeys

The nonserotonergic benzodiazepine, triazolam, was compared with two 5-HT1A receptor agonists, 8-OH-DPAT and buspirone, in squirrel monkeys responding under a repeated-acquisition procedure. In each session, subjects acquired a 4-response sequence by responding sequentially on 3 keys in the presence of 4 discriminative stimuli (colors). Response sequences for each session were maintained by food presentation under a second-order fixed-ratio schedule. Errors produced a brief time-out but did not reset the sequence. In general, all of the drugs produced dose-dependent decreases in overall response rate and increases in the percentage of errors as the cumulative dose was increased. Together, these results indicate that 5-HT1A receptor agonists disrupt learning in squirrel monkeys by producing rate-decreasing and error-increasing effects in a manner comparable with the nonserotonergic benzodiazepine triazolam.     

Inhibition of histamine turnover by 8-OH-DPAT,buspirone and 5-hydroxytryptophan in the mouse and rat brain

Summary The effects of 5-hydroxytryptamine (5-HT) receptor agonists on histamine turnover in mouse and rat brains were examined. The histamine turnover rate was estimated from the accumulation of tele-methylhistamine 90 min after i.p. injection of pargyline (65 mg/kg). In whole mouse brains, the histamine turnover was significantly inhibited by the 5-HT_1A agonists, 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) (> 0.5 mg/kg) and buspirone (> 2 mg/kg) injected s. c. 10 min before pargyline treatment. 5-hydroxytryptophan (20 mg/kg) also significantly inhibited histamine turnover. Injections of the 5-HT_1B agonist m-trifluoromethylphenylpiperazine (10 and 20 mg/kg) or the 5-HT₂ agonist (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (1, 2 and 5 mg/kg)), however, did not affect histamine turnover. The inhibitory effect of 8-OH-DPAT (1 mg/kg) on histamine turnover was significantly antagonized (by 40%) by pindolol (20 mg/kg) and slightly antagonized (by 29%) by spiperone (10 mg/kg), while methysergide (20 mg/kg) and ketanserin (10 mg/kg) demonstrated no antagonistic effects. 8-OH-DPAT (0.3 and 1 mg/kg) also showed an inhibiting effect on histamine turnover in various regions of rat brains. Although the extent of inhibition was slightly larger in the striatum and cerebral cortex, there was no marked regional difference. These results suggest that histaminergic activity in the brain is regulated by 5-HT_1A receptors. Send offprint requests to R. Oishi at the above address     

Prenatal stress influences 8-OH-DPAT modulated startle responding and [3H]-8-OH-DPAT binding in rats

The present study was to investigate some aspects of the 5-HT1A receptor system in adult-aged rats (50-60 days) that were either exposed to prenatal stress (PS) or not exposed to prenatal stress (CON). In the first series of experiments, rats were pretreated with vehicle, the 5-HT1A agonist 8-OH-DPAT or the 5-HT1A antagonist, WAY-100635 and exposed to 120 acoustic startle stimuli (95 dB) using a 30 s inter-trial interval. 8-OH-DPAT produced a dose-dependent increase in acoustic startle responding in CON and PS rats, with the PS rats exhibiting greater responding than CON rats. WAY-100635 depressed startle amplitudes only in the CON group. Finally, radioligand binding studies using [3H]-8-OH-DPAT indicated a significant decrease in receptor density in hippocampal homogenates from PS rats but no difference in [3H]-8-OH-DPAT binding from homogenates of the amygdala. Our results are consistent with earlier reports indicating that prenatal stress alters the serotonergic system. Specifically, our results indicate that gestational exposure to chronic mild stress enhances startle amplitudes following 8-OH-DPAT administration, prevents the depression in startle amplitudes following WAY-100635 administration and reduces [3H]-8-OH-DPAT binding in hippocampal preparations.     

Perinatal AZT exposure alters the acoustic and tactile startle response to 8-OH-DPAT and apomorphine in adult rats

The present study was designed to assess the dopaminergic and serotonergic contributions of the acoustic startle response (ASR) and the tactile startle response (TSR) in adult rats that had been perinatally exposed to AZT (azidothymidine, zidovudine; an antiretroviral agent). Each dam was randomly assigned to a treatment group: non-treated, AZT0, 100 or 150 mg/kg. Once daily gastric intubation began prenatally on gestational day (G) 19 and continued to G22 and then the pups were intubated between postnatal day (PND) 2-20. On PND60, animals were tested for responses to both acoustic and tactile stimuli following a challenge of vehicle, 0.25 or 0.5 mg/kg 8-OH-DPAT, a 5-HT(1A) agonist, or 0.75 or 2.0 mg/kg apomorphine (APO, a dopaminergic agonist) IP. Both DPAT and APO increased startle magnitude as expected. Additionally, perinatal AZT exposure enhanced startle responses following both DPAT and APO, an effect not due to perinatal handling or intubation. Similarly, perinatal AZT increased tactile responses following drug challenge in a gender-specific manner. Perinatal AZT also prolonged startle latencies, a change which may indicate that perinatal AZT alters conduction velocity. Therefore, the administration of AZT during the perinatal period results in long-term functional alterations within the startle reflex pathways.     

Circadian rhythm in the response of central 5-HT1A receptors to 8-OH-DPAT in rats

Circadian rhythm in the behavioral responsiveness to the selective 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was studied in rats. Rats were subcutaneously injected with 8-OH-DPAT at one of the following times of day: 0000, 0400, 0800, 1200, 1600, 2000 hours. The postsynaptic 5-HT_1A receptor behavioral syndrome, that is, forepaw treading, head weaving, and flat body posture, were measured after the administration of 8-OH-DPAT. Circadian rhythms were found in each of the behavioral responses to 8-OH-DPAT. Peak responses were observed in the mid-dark phase (1200 hours) while the weakest responses were observed in the midlight phase (0000 hours). In a subsequent experiment, 8-OH-DPAT was administered intracerebroventricularly during the mid-dark phase and the mid-light phase. The behavioral responses to the drug in the middark phase were significantly higher than those in the mid-light phase. These results suggest that the function of central postsynaptic 5-HT_1A receptor exhibits circadian rhythm.     

The effects of long-term treatment with 8-OH-DPAT on the lordosis response and hypothermia in female rats.

The effects of long-term treatment with a low dose of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on steroid hormone-dependent copulatory behaviour in female rats, the lordosis response, and on the hypothermic response of female rats were studied. Female rats were treated for 15 days, once daily, and tested on days 1 and 15 of treatment. They received 25 micrograms/kg on test days and 50 micrograms/kg on all other days. Subsensitivity was not induced to the inhibitory effect of 8-OH-DPAT on the lordosis response. In contrast, however, the acute effect of 8-OH-DPAT on body temperature was abolished by the long-term treatment. The results presented indicate that the induction of subsensitivity to the effects of 8-OH-DPAT is not primarily dependent on the pre- or post synaptic locus of action. Our data suggest that hormonal mechanisms are involved.     

Neuroendocrine response to clonidine and 8-OH-DPAT in rats following chronic administration of desipramine or sertraline.

1. Rats were administered either desipramine (DMI) or sertraline daily at doses 7.5 mg kg-1 or 10 mg kg-1, i.p., respectively and the effects on the functional state of hypothalamic neuroendocrine control mechanisms assessed by measurements of plasma hormones following acute drug challenge. The effects of treatment on gross behaviour and brain adrenoceptor density were also determined. 2. Both DMI and sertraline caused significant reduction in activity measured as ambulation and rearing at 14 days of treatment. 3. All animals were chronically cannulated after 14 days of treatment and tested for neuroendocrine response to acute i.v. clonidine (50 micrograms kg-1) or 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 250 micrograms kg-1) after 21 or more days of treatment. 4. Rats treated with DMI but not sertraline showed a virtually complete suppression of the growth hormone (GH) secretion elicited by clonidine in controls, while the secretion of corticosterone was augmented. 5. Treatment with DMI but not sertraline led to a significantly greater 8-OH-DPAT-induced secretion of prolactin than in the control rats, while the plasma concentrations of corticosterone following 8-OH-DPAT were not influenced by either DMI or sertraline treatment. 6. The density (but not the affinity) of cerebral cortical binding of [3H]-dihydroalprenolol was significantly reduced by DMI treatment. 7. These results show that DMI treatment blunted the sensitivity of post-synaptic alpha 2-adrenoceptors, accompanied by complex interactions manifested as increased responsiveness of alpha 1-adrenoceptors and 5-HT1A receptors. Sertraline had no significant neurendocrine effects at a dose which significantly reduced gross activity.     

Serotonin does not mediate anxiolytic effects of buspirone in the fear-potentiated startle paradigm: comparison with 8-OH-DPAT and ipsapirone

The present study evaluated the role of various neurotransmitter systems in mediating buspirone's blockade of the fear-potentiated startle effect, where acoustic startle amplitude is normally increased in the presence of a light previously paired with a shock. Large lesions of the dorsal and median raphe nuclei or IP injections of the serotonin antagonists cinanserin (10 mg/kg) or cyproheptadine (5 mg/kg) did not alter fear-potentiated startle, nor did these treatments prevent buspirone (5 or 10 mg/kg SC) from blocking fear-potentiated startle. The 5-HT_1A agonist 8-OH-DPAT (2.5–10.0) did not block fear-potentiated startle even at doses that produced a marked 5-HT syndrome. Another 5-HT_1A agonist, ipsapirone (10–20 mg/kg), blocked potentiated startle only at a very high dose (40 mg/kg).p-Chlorophenylalanine andp-chloroamphetamine did not alter fear-potentiated startle. Finally, pretreatment with the benzodiazepine receptor antagonist RO-15-1788 (1 mg/kg); the opiate antagonist naloxone (2 mg/kg) or the ₂-adrenergic antagonist yohimbine (5 mg/kg) did not reduce fear-potentiated startle, nor did they prevent buspirone from blocking fear-potentiated startle. Taken together, the data do not support the hypothesis that buspirone's anxiolytic effects are mediated by actions at 5-HT_1A receptors and more generally indicate that serotonergic neurons do not play an important role in fear-potentiated startle.     

Inhibition of the shake response in rats by adenosine and 2-chloroadenosine

Shaking movements, similar to those made by a dog when wet, were elicited in rats by a) immersion in ice-water, b) injections of icilin, a chemical that produces sensations of cold, and c) naloxone-precipitated morphine withdrawal. Adenosine and 2-chloroadenosine produced dose-dependent inhibition of shaking to ice-water and icilin. The 2-chloroadenosine effect was mediated centrally because the ICV dose required to produce inhibition was not effective when given IP. Caffeine antagonized the inhibitory effects of adenosine and 2-chloroadenosine. 2-Chloroadenosine suppressed morphine-abstinence shaking as well as the body weight loss that normally accompanies withdrawal.     

Inhibitory effect of buspirone and diazepam, but not of 8-OH-DPAT, on maternal behavior and aggression

The action of diazepam (0.0, 1.0, and 2.0 mg/kg) and the serotonergic compounds buspirone (0.0, 2.5, and 5.0 mg/kg) and 8-OH-DPAT (0.0, 0.1, and 1.0 mg/kg) on maternal behavior and aggression were studied. An activity test was made after these treatments to control for unspecific actions due to motor impairment. Diazepam and buspirone dose-dependently inhibited the expression of maternal aggression and the active components of maternal behavior such as retrieving and nest building. 8-OH-DPAT did not affect these behaviors. 8-OH-DPAT (1.0 mg/kg) provoked the serotonergic syndrome and hypothermia; however, ovariectomized animals showed more signs of the syndrome and a decrease in body temperature after 8-OH-DPAT than lactating rats. Buspirone, but not the other anxiolytics, reduced motor activity. The role of drugs acting at the serotonergic, dopaminergic, and GABA-benzodiazepine systems in the control of maternal behavior and aggression is discussed.     

Effect of flibanserin (BIMT 17), fluoxetine, 8-OH-DPAT and buspirone on serotonin synthesis in rat brain

In male rats, the effects of the administration of the novel serotonergic agent flibanserin on the synthesis of 5-HT were evaluated in the frontal cortex (FC), hippocampus (Hip) and brainstem (Br). The selective serotonergic uptake blocker, fluoxetine, and two serotonin_1A (5-HT_1A) agonists, 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) and buspirone, were used as reference compounds. The synthesis of 5-HT was assessed by measuring the accumulation of 5-hydroxytryptophan (5-HTP) after blockade of aromatic amino acid decarboxylase induced by m-hydroxybenzylhydrazine (NSD-1015), at 100 mg/kg i.p., 30 min before sacrifice. Flibanserin, 8-OH-DPAT and buspirone were given 15 min before NSD-1015, while fluoxetine 120 min before NSD-1015. In our experimental conditions, a different efficacy, expressed as percentage of maximal inhibition (Max) of 5-HTP accumulation, and a different potency, expressed in terms of minimal effective dose (MED), were observed in different brain areas with tested compounds. Flibanserin (1–32 mg/kg) decreased 5-HT synthesis with preferential activity in the FC, compared to the Hip and Br, both in terms of potency (MED=2 mg/kg in FC, 16 mg/kg in Hip and Br) and efficacy (Max=65% in FC, 44% in Hip and 29% in Br). Fluoxetine (1–30 mg/kg) decreased 5-HT synthesis with preferential activity in FC than in Hip and Br, only in terms of potency (MED=3 mg/kg in FC, 10 mg/kg in Hip and Br), this result being similar to that observed for flibanserin. In contrast, it showed greater efficacy both in FC and Hip (Max about 60%), than in Br (Max=49%). On the contrary, 8-OH-DPAT (0.3–3 mg/kg) decreased 5-HT synthesis with the same potency in all brain regions (MED=3 mg/kg) and showed the greatest efficacy in FC than in Hip and Br (Max=56% in FC, 49% in Hip and 40% in Br). Furthermore, buspirone (3–30 mg/kg), while inhibiting 5-HTP accumulation in all areas with the same efficacy (Max about 30%), seemed to have higher potency in Br than in FC and Hip (MED=3 mg/kg in Br, 10 mg/kg in FC and Hip). The results in terms of regional differences are discussed.     

Effects of the novel anxiolytics gepirone,buspirone and ipsapirone on free feeding and on feeding induced by 8-OH-DPAT

The effects of the novel anxiolytics gepirone, buspirone and ipsapirone on free feeding and on feeding induced by the 5-HT_1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), were examined. Gepirone dose-dependently increased feeding 2 and 4 h after injection, the magnitude of the response being larger than previously observed with any other 5-HT_1A receptor ligand. Previous studies have suggested that buspirone and ipsapirone can block some of the behavioural effects of 8-OH-DPAT. However, gepirone, buspirone and ipsapirone did not inhibit feeding induced by 8-OH-DPAT. These results indicate that gepirone is a very efficacious appetite stimulant in rats and suggest that gepirone, buspirone and ipsapirone act as 5-HT autoreceptor agonists in the feeding model.     

Behavioral effects Of 8-OH-DPAT in chronically stressed male and female rats

The present study tested the hypothesis that chronic stress desensitizes serotonergic 5-HT(1A) receptors and alters behavioral changes following 5-HT(1A) agonist administration. Eating, acoustic startle response (ASR), and locomotor activity were measured in stressed and nonstressed male and female rats after 8-OH-DPAT administration. Stressed rats were paired and stressed by around-the-clock intermittent foot shock. Controllable stress (CS) rats could avoid/terminate shock for themselves and their yoked partners by pulling a ceiling chain, whereas their partners, the uncontrollable stress (UCS) rats, could not. Rats earned their entire daily ration of food by pressing a lever. In previous experiments, this paradigm was stressful, but not debilitating and rats continued to eat, groom, sleep, and avoid/escape greater than 99% of shock trials. Locomotor activity and ASR were measured in the present study after saline and 8-OH-DPAT administration (0.25 mg/kg, IP) before, 24 h, and 72 h after shock onset. 8-OH-DPAT only decreased food intake significantly in male and female rats after the first administration. Stress decreased food intake in both the CS and UCS rats, with UCS rats eating the least. However, the effects of stress and 8-OH-DPAT were not additive. 8-OH-DPAT significantly increased peak startle amplitude at 100 and 120 dB, and decreased latency to peak startle amplitude at 100 dB in male and female rats. In contrast, 8-OH-DPAT did not alter percent prepulse inhibition (%PPI) at 100 dB, but significantly decreased %PPI in males but not females at 120 dB. Stress did not have a consistent effect on ASR, but reduced %PPI in males, but not females. Neither stress nor 8-OH-DPAT significantly altered locomotor activity. Although the results do not show an increased sensitivity to 8-OH-DPAT in stressed rats, the unexpectedly weak effects of 8-OH-DPAT alone on the behavioral measures chosen limits the conclusions that can be drawn.     

Effect of flibanserin (BIMT 17), fluoxetine, 8-OH-DPAT and buspirone on serotonin synthesis in rat brain.

In male rats, the effects of the administration of the novel serotonergic agent flibanserin on the synthesis of 5-HT were evaluated in the frontal cortex (FC), hippocampus (Hip) and brainstem (Br). The selective serotonergic uptake blocker, fluoxetine, and two serotonin1A (5-HT1A) agonists, 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) and buspirone, were used as reference compounds. The synthesis of 5-HT was assessed by measuring the accumulation of 5-hydroxytryptophan (5-HTP) after blockade of aromatic amino acid decarboxylase induced by m-hydroxybenzylhydrazine (NSD-1015), at 100 mg/kg i.p., 30 min before sacrifice. Flibanserin, 8-OH-DPAT and buspirone were given 15 min before NSD-1015, while fluoxetine 120 min before NSD-1015. In our experimental conditions, a different efficacy, expressed as percentage of maximal inhibition (Max) of 5-HTP accumulation, and a different potency, expressed in terms of minimal effective dose (MED), were observed in different brain areas with tested compounds. Flibanserin (1-32 mg/kg) decreased 5-HT synthesis with preferential activity in the FC, compared to the Hip and Br, both in terms of potency (MED=2 mg/kg in FC, 16 mg/kg in Hip and Br) and efficacy (Max=65% in FC, 44% in Hip and 29% in Br). Fluoxetine (1-30 mg/kg) decreased 5-HT synthesis with preferential activity in FC than in Hip and Br, only in terms of potency (MED=3 mg/kg in FC, 10 mg/kg in Hip and Br), this result being similar to that observed for flibanserin. In contrast, it showed greater efficacy both in FC and Hip (Max about 60%), than in Br (Max=49%). On the contrary, 8-OH-DPAT (0.3-3 mg/kg) decreased 5-HT synthesis with the same potency in all brain regions (MED=3 mg/kg) and showed the greatest efficacy in FC than in Hip and Br (Max=56% in FC, 49% in Hip and 40% in Br). Furthermore, buspirone (3-30 mg/kg), while inhibiting 5-HTP accumulation in all areas with the same efficacy (Max about 30%), seemed to have higher potency in Br than in FC and Hip (MED=3 mg/kg in Br, 10 mg/kg in FC and Hip). The results in terms of regional differences are discussed.     

Direct effects of indorenate and 8-OH-DPAT on the blood pressure of pithed rats

Indorenate is a 5-HT_1A receptor agonist with antihypertensive properties. This study was aimed to determine if indorenate, like other 5-HT_1A receptor agonists, may also interact with α-adrenoceptors. Therefore, the effects of indorenate and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; which has affinity for 5-HT_1A receptors and, to a lesser extent, for α₁-adrenoceptors) on the blood pressure of pithed rats were compared. Both compounds produced dose-dependent increases in blood pressure; 8-OH-DPAT was the most potent whereas indorenate produced a higher maximum effect. Metitepine (a mixed 5-HT₁/5-HT₂ receptor antagonist), but not pindolol (a β-adrenoceptor and 5-HT₁ receptor blocker), antagonized the pressor responses produced by both agonists; only the pressor effects of 8-OH-DPAT, however, were antagonized by prazosin (an α₁-adrenoceptor antagonist). Interestingly, ketanserin (a 5-HT₂ and α₁-adrenoceptor blocker) strongly antagonized the pressor responses to indorenate whereas only a slight inhibition of 8-OH-DPAT responses was observed. Further, in pithed rats intravenously infused with norepinephrine (NE), 8-OH-DPAT, but not indorenate, produced dose-dependent hypotensive effects and both compounds were inactive in rats infused with quipazine. In conclusion, 8-OH-DPAT behaved as a partial agonist at α₁-adrenoceptors whereas indorenate produced pressor effects probably due to stimulation of 5-HT₂ receptors. Thus, 8-OH-DPAT, but not indorenate, showed activity at α₁-adrenoceptors in the pithed rat. © 1994 Wiley-Liss, Inc.     

Neurochemical changes in pigeon cerebrospinal fluid during chronic administration of buspirone or 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)

Cerebrospinal fluid (CSF), collected repeatedly from White Carneau pigeons chronically implanted with guide cannulae located in the lateral ventricles, was analyzed for metabolites of serotonin, dopamine and norepinephrine after acute and chronic administration of buspirone or 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Following the acute administration of 3.0 mg/kg buspirone, levels of 5-hydroxyindoleacetic acid (5-HIAA) decreased, while increases occurred in the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC). Decreases in 5-HIAA persisted throughout the chronic dosing regimen (36 days), while dopamine metabolites returned to control levels within 8 days. When chronic buspirone was discontinued, levels of 5-HIAA were restored to predrug control levels, while levels of HVA, DOPAC and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) decreased. All metabolites returned to predrug control levels within one week following buspirone discontinuation except for MHPG, which remained depressed. When the acute effects of buspirone were reexamined, levels of 5-HIAA were again significantly decreased, while HVA and DOPAC levels, as well as those of MHPG, increased significantly. Acute administration of the 5-HT1A receptor ligand 8-OH-DPAT (3.0 mg/kg) resulted in large decreases in 5-HIAA levels that persisted throughout the period of chronic administration. Neither acute nor daily administration of 8-OH-DPAT changed levels of HVA, DOPAC or MHPG. Large increases in 5-HIAA occurred when chronic 8-OH-DPAT was discontinued but declined within one week to control levels. Following a two-week drug-free period, 8-OH-DPAT again caused a significant reduction in 5-HIAA levels.(ABSTRACT TRUNCATED AT 250 WORDS)