8-Hydroxy-2-(di-n-propylamino)tetralin, a selective serotonin1A 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 serotonin1A (5-HT1A) 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 micrograms, 8-OH-DPAT significantly reduced the immobility of rats when administered into the nucleus raphe dorsalis, but only 5 micrograms 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 micrograms 8-OH-DPAT into the nucleus raphe medianus. The effect of an infusion of 1 micrograms 8-OH-DPAT into the nucleus dorsalis was prevented by infusing 2.5 micrograms (-)-propranolol or 2.5 micrograms (-)-pindolol into the same area 5 min before 8-OH-DPAT or by treating the animals with sulpiride systemically (100 mg/kg i.p.) or centrally (in the nucleus accumbens; 1 microgram/0.5 microliter). 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-HT1A receptor agonists may constitute a novel class of antidepressant agents.     

Potential antidepressant properties of 8-hydroxy-2-(di-n-propylamino)tetralin, a selective serotonin1A receptor agonist

8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective serotonin1A 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 1-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 micrograms 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 serotonin1A agonists such as 8-OH-DPAT could constitute a novel class of rapid-acting antidepressant agents.     

Anticonflict effect of the putative serotonin receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)

The putative 5-HT agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) produced in rats an increase in the number of shocks accepted in a modified Vogel's conflict test design. Subchronic pretreatment with p-chlorophenylalanine (PCPA) similarly caused release of the punished behavior. This anticonflict effect of PCPA was antagonized by both 5-hydrotryptophan and 8-OH-DPAT. Thus in naive animals 8-OH-DPAT exerting anticonflict effects acted like a 5-HT antagonist, whereas in subchronically PCPA-pretreated animals with presumably supersensitive 5-HT receptors, 8-OH-DPAT decreasing the number of accepted shocks acted like a 5-HT agonist.     

8-Hydroxy-2-(di-n-propylamino)tetralin, a 5-HT1A receptor agonist, impairs performance in a passive avoidance task.

The effects of various subcutaneous doses (30, 100 and 300 micrograms/kg) of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a serotonin (5-HT)1A receptor agonist, were studied on the performance of rats in a one-trial passive avoidance task. When administered 30 min before the training trial and the retention test, 8-OH-DPAT significantly reduced retention latencies at all doses. Similar results were obtained when 8-OH-DPAT was administered before either the training trial or the retention test. When administered 5 min after the training trial, 100 and 300 micrograms/kg 8-OH-DPAT significantly reduced the retention latencies whereas 30 micrograms/kg caused a non-significant tendency to a reduction. A dose of 300 micrograms/kg 8-OH-DPAT significantly raised the thresholds for various responses (flinch, jump and vocalization) elicited by electric shock applied to the grid floor while 30 and 100 micrograms/kg had no effect. When administered 30 min before the retention test to rats that could choose between a punished and unpunished compartment, 8-OH-DPAT at 100 and 300 micrograms/kg facilitated re-entry to either compartment but, like control animals, most 8-OH-DPAT-treated animals preferred the unpunished compartment. Although the effects of 8-OH-DPAT on pain perception, general activity or emotional behavior may interfere with the performance of rats in the passive avoidance task, the results suggest that at 100 and 300 micrograms/kg 8-OH-DPAT interferes with mechanisms related to the acquisition and consolidation of memory.     

Potential anxiolytic properties of 8-hydroxy-2-(Di-N-propylamino)tetralin,a selective serotonin1A 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 g/0.5 l 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. The data support the hypothesis that brain serotonin is involved in the mechanisms mediating behavioural suppression in the presence of aversive stimuli.     

Para-chlorophenylalanine prevents feeding induced by the serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT)

The effects of para-chlorophenylalanine pre-treatment (PCPA, 150 mg/kg IP daily for 3 days) on feeding and stereotyped behaviour elicited by the serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in rats were investigated. PCPA depleted brain serotonin and 5-hydroxyindoleacetic acid concentrations by 90% and increased feding during a 2-h day-time test. 8-OH-DPAT (60–4000 μg/kg SC) increased food intake in control animals but decreased in in PCPA-treated animals during the 2-h test. PCPA treatment had no effect on 8-OH-DPAT-induced locomotion or serotonin-related stereotyped behaviour (i.e. forepaw treading, headweaving, wet dog shakes, etc). Since PCPA prevents the operation of pre-synaptic serotonergic mechanisms, the failure of 8-OH-DPAT to increase food intake in PCPA-treated rats suggests that 8-OH-DPAT-induced hyperphagia is autoreceptor mediated.     

MDMA stimulus generalization to the 5-HT(1A) serotonin agonist 8-hydroxy-2- (di-n-propylamino)tetralin

The abused substance N-methyl-1-(3, 4-methylenedioxyphenyl)-2-aminopropane, or MDMA, serves as a training drug in animals. Because the 5-HT(1A) receptor antagonist NAN-190 has been shown to partially antagonize the MDMA stimulus, and because NAN-190 binds at several different types of receptors, in the present study we examined other agents (e.g., adrenergic, dopaminergic, sigma) in tests of stimulus generalization and stimulus antagonism to determine their influence on the MDMA stimulus. Each of these agents (i.e., clenbuterol, S(-)propranolol, R(+)SCH-23390, amantadine, NANM) was without effect on MDMA-appropriate responding. The finding that NAN-190 behaves as a 5-HT(1A) partial agonist in some studies prompted examination of the 5-HT(1A) receptor agonist 8-OH DPAT and its optical isomers. MDMA-stimulus generalization occurred to racemic 8-OH DPAT (ED(50) = 0.3 mg/kg), R(+)8-OH DPAT (ED(50) = 0.2 mg/kg), and to the 5-HT(1A) receptor partial agonist S(-)8-OH DPAT (ED(50) = 0.4 mg/kg). The results suggest that the MDMA stimulus might possess a 5-HT(1A) component of action. Furthermore, because 8-OH DPAT is known to enhance the stimulus effects of hallucinogens as discriminative stimuli, and because MDMA reportedly enhances the effects of hallucinogenic agents in humans ("flipping," "candy flipping"), this latter MDMA-induced phenomenon might involve a 5-HT(1A) mechanism.     

(+)-cis-8-Hydroxy-1-methyl-2-(di-n-propylamino)tetralin: a potent and highly stereoselective 5-hydroxytryptamine receptor agonist

C1-Methylated derivatives of the potent 5-hydroxytryptamine (5-HT) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 1) were synthesized and tested for central 5-HT and dopamine receptor activity by use of a biochemical test method in rats. cis-8-Hydroxy-1-methyl-2-(di-n-propylamino)tetralin (8) was found to be a 5-HT receptor agonist. The (+)-enantiomer of 8 had a potency equal to that of 1, whereas (-)-8 and the trans isomer (+/-)-9 were inactive.     

Stimulation of corticosterone secretion by the selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in the rat

The selective 5-HT1A receptor agonist 8-OH-DPAT increased serum corticosterone concentration in rats in a dose-dependent manner. The synthetic corticoid dexamethasone lowered the serum corticosterone level and abolished its rise induced by 8-OH-DPAT. The corticosterone response to 8-OH-DPAT was also antagonized by spiperone, (+/-)- and (-)-pindolol and (+/-)-propranolol, all of which have been shown to have a high affinity for 5-HT1A receptors, though in most cases no complete blockade was found. A partial antagonism of the response was also observed after flumazenil, a benzodiazepine antagonist. On the other hand, the 5-HT1B receptor antagonist 21009, the 5-HT2 receptor antagonists ketanserin and pirenperone, the 5-HT3 receptor antagonist ICS 205-930, the alpha 2-adrenoceptor antagonists yohimbine and idazoxan, the beta-adrenoceptor blocker with no affinity to 5-HT1 receptors, atenolol, the dopaminergic antagonist pimozide, the histamine receptor blocker chloropyramine and the opiate receptor antagonist naloxone did not affect the hormonal response to 8-OH-DPAT. The 8-OH-DPAT-induced corticosterone secretion was not affected either in rats pretreated with p-chlorophenylalanine (PCPA, an inhibitor of tryptophan hydroxylase) or p-chloroamphetamine (PCA, a drug-inducing lesion of serotonergic nerve terminals). It is concluded that 8-OH-DPAT-induced increase in serum corticosterone concentration results from its action at a site different than the adrenal cortex and is mediated by postsynaptic 5-HT1A receptors, whereas other subtypes (5-HT1B, 5-HT2, 5-HT3) of 5-HT receptors do not participate in this response.(ABSTRACT TRUNCATED AT 250 WORDS)     

A central serotonin receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin, has different effects on prolactin secretion in male and female rats

Male and female rats were compared with respect to alterations in prolactin secretion induced by the serotonin receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The dose-response curves after 8-OH-DPAT were irregular and had different shapes in the two sexes. In males, 0.1 and 0.3 mg/kg enhanced serum prolactin concentrations to about 200% of control values, whereas higher doses (1 and 3 mg/kg) had no effect on prolactin release. In females, in contrast, 0.1 mg/kg of 8-OH-DPAT tended to decrease serum levels of prolactin, while 0.3, 1, and 3 mg/kg elevated them in a dose dependent manner to maximally 700% of control values. The serotonergic agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (5 mg/kg), too, caused increased prolactin release in both sexes, and, again, females responded more forcefully. In males, but not in females, pretreatment with 8-OH-DPAT (1 mg/kg) reduced the 5-MeODMT-induced elevation of serum prolactin levels. The mechanism underlying the sexually differentiated effects of 8-OH-DPAT on prolactin secretion is discussed.     

Pentobarbital anaesthesia prevents the adrenaline-releasing effect of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin

Administration of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.25 mg/kg i.v.), to conscious rats increased plasma adrenaline and glucose levels for 30 and 60 min, respectively. Both 8-OH-DPAT-induced changes in plasma adrenaline and glucose levels were totally abolished in pentobarbital-anaesthetized rats. The present data indicate that pentobarbital anaesthesia, a procedure that is commonly used in pharmacological studies, prevents the release of adrenaline evoked by 5-HT1A receptor activation.     

Nicotine and its withdrawal modify dorsal raphe 8-hydroxy-2-(di-n-propylamino) tetralin feeding

Nicotine (NIC) and its withdrawal modify dorsal raphe (DR) serotonin (5-HT) neurotransmission in ways that may contribute to the body weight loss vs. gain associated with cigarette smoking vs. cessation, respectively. Modifications in feeding to DR infusions of the 5-HT-1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), were used to characterize these potential relationships in the DR-5-HT system during NIC administration vs. withdrawal. Two groups of female rats (total N=45) were implanted for 14 days with subcutaneous Alzet minipumps containing NIC (6 mg/kg/day) or saline. Mid-light cycle (1300-1500 h) 8-OH-DPAT feeding tests occurred three times: (1) 2 days after pump implant, (2) 12 days after pump implant, and (3) 2 days after pump removal. Each feeding test consisted of a 1-h measure of pre-feeding, then a 1-h measure of feeding after DR injection of 8-OH-DPAT (0.6 nmol) or 0.4 microl saline. NIC administration produced acute hypophagia, weight loss, and attenuated 8-OH-DPAT-induced feeding. NIC withdrawal produced acute hyperphagia, weight gain, and a transient increase in 8-OH-DPAT feeding. These findings provide behavioral evidence that systemic NIC modifies the DR 5-HT system in ways that may contribute to NIC's ability to alter feeding and body weight.     

Pharmacological characterization of enantiomers of 8-thiomethyl-2-(di-n-propylamino)tetralin,potent and selective 5-HT1A receptor agonists

LY274600 and LY274601 are the S (?) and R (+) enantiomers, respectively, of 8-thiomethyl-2-(di-n-propylamino)tetralin (8-OH-DPAT). In in vitro studies, both enantiomers have high and selective affinity for the 5-HT_1A receptor. However, LY274600 produced submaximal inhibition of forskolin-stimulated cyclase activity, which indicates that it is a partial agonist, whereas LY274601 produced maximal inhibition of cyclase activity, which indicates that it is a full agonist in this model. Both of these enantiomers had potent in vivo pharmacological effects in rats that are characteristic of 5-HT_1A receptor agonists including (1) a reduction of hypothalamic 5-HIAA levels, (2) an increase in serum corticosterone levels, (3) a reduction in hypothalamic 5-HTP accumulation after decarboxylase inhibition, (4) an induction of 5-HT_1A behavioral responses, e.g., flat posture and lower lip retraction, and (5) a lowering of body temperature. In these general pharmacological tests, both compounds had a potency equal to or greater than 8-OH-DPAT but had a greater oral activity. LY274601 appeared to be either slightly more potent or efficacious than LY274600. In the drug-discrimination studies using pigeons trained to identify the effects of 8-OH-DPAT, LY274601 was significantly more potent than LY274600, but both were less potent than 8-OH-DPAT. Both enantiomers restored full sexual reflex function to rats that had reduced sexual capacity. In rats with normal capacity for sexual reflexes but reduced performance, the enantiomers caused decreases in ejaculatory latencies and postejaculatory latencies and increases in copulatory efficiency and rate. No consistent differences between the enantiomers could be demonstrated in these estimates of total sexual performance, erectile capacity, and sexual drive. Both enantiomers increased punished responding at lower doses than were needed to decrease unpunished responding in pigeons, an effect that is indicative of anxiolytic activity. LY274600, a partial agonist, produced a significantly greater change in punished responding than did LY274601, a full agonist. Both compounds induced dose-related decreases in immobility time and defecation rate in the rat forced swim model, which represent reductions in stress-induced “behavioral despair” and stress-induced gastrointestinal motility. Collectively, these pharmacological studies have shown that the substitution of a thiomethyl for hydroxyl group at the 8 position on the 2-(di-n-propylamino) tetralin structure resulted in selective and potent agonists for the 5-HT_1A receptor similar to that of 8-OH-DPAT but with improved oral potency. The preclinical efficacy studies demonstrated possible utilites for these compounds in the treatement of either sexual response disorders, anxiety, or depression. © 1995 Wiley-Liss, Inc.     

Low doses of the putative serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) elicit feeding in the rat

The effects of the putative serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) on food intake in non-deprived male rats were investigated. Low doses of 8-OH-DPAT (15–60 g/kg) significantly increased food intake, without affecting drinking, grooming, rearing or locomotion. Microstructural analysis of the elicited feeding behaviour revealed that the rate of eating after 8-OH-DPAT treatment was very similar to that previously reported following 16 h food deprivation. Higher drug doses (250–4,000 g/kg) also elicited feeding and caused locomotor stimulation and serotonin-related stereotyped behaviour (i.e. forepaw padding, headweaving, wet dog shakes, flat body posture). When feeding and stereotypy were observed concurrently, response competition was evident and feeding behaviour was fragmented into numerous short eating bouts. As drug-induced stereotypy declined with time, this fragmented pattern of eating was succeeded by long bouts of eating which were similar to those observed at doses of 15–60 g/kg 8-OH-DPAT. The induction of feeding by a serotonin agonist appears paradoxical, since drugs which enhance brain serotonergic activity usually inhibit feeding.     

Discriminative stimulus properties of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT)

Using a two-lever operant procedure, eleven rats were trained to discriminate 0.2 mg/kg of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT) from saline using a variable-interval 15 sec schedule of reinforcement. Once trained, these animals were used in a series of stimulus generalization and stimulus antagonism studies. The 8-OH DPAT-stimulus did not generalize to the 5-HT1B agonist 1-(3-trifluoromethylphenyl) piperazine (TFMPP) or the 5-HT2 agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), nor could it be attenuated by pre-treatment of the animals with the 5-HT2 antagonist ketanserin. Low doses of spiperone and propranolol were without effect on 8-OH DPAT-appropriate responding, whereas higher doses of these agents resulted in disruption of behavior. Some preliminary structure-activity data were also obtained using several related tetralin analogs. The results of this study demonstrate that the serotonin agonist 8-OH DPAT serves as a discriminative stimulus in rats and that it produces stimulus effects that are probably not 5-HT1B or 5-HT2-mediated.     

Effects of the putative 5-HT1A receptor agonist 8-OH-2-(di-n-propylamino)tetralin on nociceptive sensitivity in mice

The ability of 8-OH-2-(di-n-propylamino)tetralin (8-OH-DPAT) to alter nociceptive sensitivity in mice was studied using the tail-flick, hot-plate and formalin tests. Subcutaneous (SC) administration of 8-OH-DPAT (0.63-1.0 mg/kg) dose-dependently increased the temperature at which hindpaw lick occurred in a hot-plate test using slowly rising temperature and increased the latencies to hindpaw lick, but reduced the latencies to jump in a conventional hot-plate test. Intracerebroventricular (ICV) injections (0.25-1.0 microgram) produced similar results in the conventional hot plate test. Following intrathecal (ITH) injections (0.25-1.0 microgram), however, the latencies to hindpaw lick were elevated without any change in jump latencies. In the formalin test a low systemic dose of 8-OH-DPAT (0.063 mg/kg) elicited hyperalgesia, while hypoalgesia was found after a high dose (1.0 mg/kg). ICV injection of 1.0 microgram produced hypoalgesia in the formalin test while the same dose injected ITH was without effect. 8-OH-DPAT did not alter tail-flick latencies, either by SC, ICV or ITH administration. Previous studies have shown that 8-OH-DPAT stimulates central serotonergic receptors, and shows selectivity for the 5-HT1A recognition site. The present findings indicate an involvement of 5-HT1A receptors in the processing of nociceptive information both at spinal and supraspinal sites. However, stimulation of 5-HT1A receptors does not seem to affect spinal, nociceptive reflexes.     

8-Hydroxy-2-(di-n-propylamino)-tetralin inhibits food intake in fasted rats by an action at 5-HT1A receptors

The effects of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) on food intake were investigated in food-deprived rats. 8-OH-DPAT (25-100 microg/kg) administered subcutaneously immediately prior to the presentation of food produced a dose-related decrease in food intake in rats that had been fasted for 22 h. The hypophagic effect of 8-OH-DPAT (50 microg/kg) was abolished by pretreatment with the selective 5-HT1A receptor antagonist n-[2-(4-2-methoxyphenyl)-1-piperazinyl]-n-(2-pyridyl) cyclohexanecarboxamide (WAY 10063; 0.3 mg/kg). The results of this study show that the acute dose-dependent depressant effect of 8-OH-DPAT on food intake in fasted rats is mediated by an action at 5-HT1A receptors.     

Effects of 8-hydroxy-2-(di-n-propylamino)tetralin, a selective agonist of 5-HT1A receptors, on the cough reflex in rats.

The effects of the agonist of 5-HT1A receptors, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), on the capsaicin-induced cough reflex in rats were studied. I.p. injection of 8-OH-DPAT, at doses of 0.1 and 0.3 mg/kg, significantly decreased the number of coughs in a dose-dependent manner. The antitussive effect of 8-OH-DPAT (0.3 mg/kg) was blocked by prior injection of methysergide (3 mg/kg i.p.) and spiperone (0.3 mg/kg i.p.), whereas ketanserin (3 mg/kg i.p.) had no effect on the antitussive effect of 8-OH-DPAT. The antitussive effects of dihydrocodeine (1 mg/kg i.p.) and dextromethorphan (3 mg/kg i.p.) were also antagonized by methysergide and spiperone. However, these cough-depressant effects were not reduced by ketanserin. These results suggest that the antitussive action of 8-OH-DPAT may be related to the enhancement of the function of 5-HT1A receptors, and that antitussives interact with the 5-HT1A receptors.     

Reversal of Haloperidol-Induced Extrapyramidal Side Effects in Cebus Monkeys by 8-Hydroxy-2-(di-n-propylamino)tetralin and Its Enantiomers

(±)-8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), (+)-8-OH-DPAT, and (−)-8-OH-DPAT produced dose-related reversals of haloperidol-induced extrapyramidal side effects (EPS) in cebus monkeys, with all compounds producing similar almost complete reversals at 0.1 mg/kg IM. These compounds were more potent than apomorphine, which reversed haloperidol-induced EPS at 0.3, but not 0.1, mg/kg IM. The data indicate that the reversal of haloperidol-induced EPS by (±)-8-OH-DPAT and its enantiomers is mediated via effects at 5-HT_1A receptors, not dopamine D₂ receptors. Thus, inclusion of 5-HT_1A agonist activity in novel antipsychotics may reduce EPS liability.