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.     

Fear-potentiated startle response is remarkably similar in two laboratories

The fear-potentiated startle response paradigm is used to investigate anxiolytic properties of drugs. The first objective of the present study was to further investigate the predictive validity of this paradigm. The anxiolytics chlordiazepoxide (2.5–10 mg/kg IP) and oxazepam (1–10 mg/kg PO) and the putative anxiolytic flesinoxan (1–10 mg/kg PO) decreased startle potentiation dose-dependently, indicating an anxiolytic effect. The antidepressant fluvoxamine (5–20 mg/kg PO) did not affect startle potentiation. Ideally, anxiolytic drugs attenuate startle potentiation without affecting control startle levels, although some studies report altered control startle amplitudes. The second objective was to investigate whether different effects on control startle amplitudes are related to different startle devices. Therefore, the drugs were tested in two laboratories. Results showed no significant differences between laboratories, indicating that equipment is not a critical factor in the drug-induced alteration of control startle levels. In an additional experiment, it was shown that flesinoxan (10 mg/kg PO) did not affect strychnine-induced startle potentiation, supporting the idea that the attenuating effect of flesinoxan on the fear-potentiated startle response is due to its anxiolytic properties. Thus, the fear-potentiated startle response paradigm appears a valid and reliable model for anxiolytic properties of drugs.     

Diazepam withdrawal: effects of diazepam and gepirone on acoustic startle-induced 22 kHz ultrasonic vocalizations

It has proven difficult to demonstrate and study the anxiogenic quality of drug withdrawal states in animals. Ultrasonic vocalizations (USV) in response to acoustic startle stimuli have shown promise as a measure of affect and may represent distress responses during diazepam withdrawal. Three experiments evaluated the association between USV and distress by comparing the effects of diazepam as a prototypic benzodiazepine agonist and the putative anxiolytic gepirone with affinity for 5-hydroxytryptamine (5-HT_1A) receptors in naive and diazepam-withdrawn subjects. Adult male Long-Evans rats were exposed to acoustic startle sessions consisting of nine 105 dB and nine 115 dB stimuli. USV at 20–30 kHz were readily emitted during startle and often commenced after the third or fourth stimulus presentation. Acutely, intraperitoneal (IP) administration of diazepam (0.1–3 mg/kg) and gepirone (0.1–1 mg/kg) decreased USV dose-dependently without affecting the startle reflex; gepirone also decreased tail flick latency. Startle-induced USV were also sensitive to the anxiogenic effects of withdrawal from diazepam exposure (0, 2.5, 5, 10 mg/kg b.i.d. IP×5 days). Twenty-four hours after the last diazepam injection, rats were hyperreactive to startle stimuli and doubled their rate of USV over vehicle-treated controls. Gepirone (0.1–1 mg/kg IP), but not diazepam (3–20 mg/kg IP) antagonized the increased rate of USV in rats withdrawn from 10 mg/kg b.i.d. diazepam. Diazepam (2.5–10 mg/kg IP) antagonized the increased rate of USV in rats withdrawn from 2.5 mg/kg b.i.d. diazepam. USV induced by acoustic startle stimuli are sensitive to the anxiolytic effects of benzodiazepine and 5-HT_1A receptor agonists and permit the assessment of the anxiogenic properties of diazepam withdrawal. The potent effect of gepirone on USV suggests a serotonergic amelioration of the anxiogenic aspects of diazepam withdrawal.     

Conditioned taste aversion and place preference with buspirone and gepirone

The effects of the nonbenzodiazepine anxiolytics buspirone and gepirone were compared to diazepam at 1, 3, and 10 mg/kg using the conditioned taste aversion (CTA) paradigm. Buspirone and gepirone produced stronger CTA than diazepam (3 and 10 mg/kg) across repeated conditioning trials, indicating that these nonbenzodiazepine anxiolytics may have stronger aversive properties than diazepam. The effects of buspirone and gepirone (1 and 3 mg/kg) were also assessed using the conditioned place preference (CPP) paradigm. Both buspirone (1 and 3 mg/kg) and gepirone (3 mg/kg only) produced CPP, indicating that these drugs may have rewarding properties, and that buspirone is more potent than gepirone in producing CPP. These findings demonstrate that buspirone and gepirone have affective properties similar to abused drugs, and may therefore have abuse potential. It was also demonstrated that buspirone (3 mg/kg), but not gepirone (3 mg/kg), increased dopamine (DA) synthesis in the nucleus accumbens, a mesolimbic brain area thought to be involved in drug reward.     

Safety signal withdrawal: a behavioural paradigm sensitive to both “anxiolytic” and “anxiogenic” drugs under identical experimental conditions

A new method involving the blockade of operant behaviour induced by the withdrawal of a conditioned signal for safety without presentation of a punishment signal has been developed for studying drugs with anxiolytic or anxiogenic properties. For this purpose, rats were trained under two alternating components of a multiple schedule of reinforcement FR8 (food)/FR1 (food) + RR 50% (shocks randomly delivered with 50±15% of the presses). The nonpunished and punished periods were signalled by one cue light above the right lever (safety signal) or the left lever (punishment signal), respectively. On the test session (safety signal withdrawal), the safety signal was turned off at the end of the first nonpunished period, but the punishment signal was not presented (every press was food rewarded and no shocks were delivered). During this period (4 min), rats exhibited a strong blockade of responding that lessened over time. This suppression seemed not to be caused by intervening events such as novelty, temporal conditioning, schedule of food delivery or ambiguity of the signal presented. The behavioural blockade induced by withdrawal of the safety signal was reduced by benzodiazepines: diazepam (0.5–4 mg/kg), chlordiazepoxide (4–8 mg/kg), nitrazepam (0.25–2 mg/kg), alprazolam (0.25–1 mg/kg), and partial agonists at benzodiazepine receptors: bretazenil (0.125–8 mg/kg) and ZK 91296 (32–64 mg/kg). Various 5-HT-related drugs also lessened the behavioural blockade: pCPA (3×150 mg/kg) and the 5-HT1A receptor agonists, buspirone (0.25–2 mg/kg), gepirone (0.25–1 mg/kg) but not 8-OH-DPAT. Compounds that may cause anxiety in humans further enhanced the blockade of lever pressing induced by the safety signal withdrawal at doses that did not modify baseline responding:d-amphetamine (0.125–0.5 mg/kg), caffeine (16 mg/kg) and picrotoxin (1 mg/kg). FG 7142 (8 mg/kg) and CGS 8216 (2–8 mg/kg) decreased responding during both components of the session. Therefore, the present paradigm seems sensitive to both anxiolytic and anxiogenic effects of drugs under identical procedural conditions.     

Predictive validity of the potentiated startle response as a behavioral model for anxiolytic drugs

The fear-potentiated startle (PSR) paradigm is a putative behavioral model for the determination of anxiolytic properties of drugs. The present study further investigated the predictive validity of the model. Predictive validity is high, when only drugs clinically used as anxiolytics attenuate PSR dose dependently. Results showed that startle potentiation decreased dose dependently after the administration of the anxiolytics CDP (2.5–10 mg/kg, IP) and alprazolam (1–3 mg/kg, IP). After administration of the clinically non-anxiolytic drugs amitriptyline (2.5–10 mg/kg, IP), carbamazepine (5–20 mg/kg, IP), fentanyl (0.0025–0.04 mg/kg, SC), naloxone (2.5–10 mg/kg, IP), nicotine (0.4–1.6 mg/kg, IP), alcohol (500–2000 mg/kg, IP), andd-amphetamine (0.6–2.4 mg/kg, IP), a dose-dependent decrease in startle potentiation was not found. The PSR correctly discriminated most of the drugs tested in clinically anxiolytic and clinically non-anxiolytic drugs. However, haloperidol behaved as a false positive, and results of nicotine and alcohol were at variance with results reported by others.     

Effects of the 5-HT1A partial agonists gepirone,ipsapirone and buspirone on local cerebral glucose utilization in the conscious rat

The azospirones gepirone (10 mg/kg), ipsapirone (10 mg/kg) and buspirone (10 mg/kg) were examined for their effect on regional cerebral glucose utilization in conscious rats using quantitative 2-deoxyglucose autoradiography. All three 5-HT_1A partial agonists reduced glucose utilization in the hippocampus and dentate gyrus by 20–25% and increased glucose utilization by 38–65% in the lateral habenular nucleus; an important relay between striatal/limbic areas and the mid-brain raphe nuclei. The findings emphasize the potential importance of the hippocampus as a site of action for 5-HT_1A receptor active drugs in vivo and also suggest that functional activity in the striatal/limbichabenular-raphe pathway may be influenced by gepirone, ipsapirone and buspirone.     

Blockade of potentiated startle responding in rats by 5-hydroxytryptamine1A receptor ligands

A potentiated whole-body startle response was produced in rats by pairing intense acoustic stimuli with a light (conditional stimulus) formerly presented contiguously with electric shock. Administration of the selective serotonin (5-HT) 1A ligand 8-hydroxy-2-(di-n-propylamino)tetralin (0.125 and 0.5 mg/kg) blocked the potentiation of startle induced by the conditional stimulus. 1-[3-Chlorophenyl]piperazine, a non-anxiolytic 5-HT1B/1C agonist, did not block potentiated startle, even at a dose (1.0 mg/kg) that induced significant overall decreases in startle amplitude. The non-benzodiazepine anxiolytics buspirone (1.25-5.0 mg/kg), gepirone (3.0-10.0 mg/kg) and the related 5-HT1A ligand ipsapirone (1.0-10.0 mg/kg) blocked potentiated startle, though effects of the non-selective serotonin antagonist methysergide (0.3-10.0 mg/kg) fell short of significance. These data support a role for the 5-HT1A binding site in the anti-anxiety effects of buspirone and related compounds over a range of behavioral procedures.     

Cocaine: Excitatory effects on sensorimotor reactivity measured with acoustic startle

Cocaine (2.5–10 mg/kg) caused a dose-related increase in the amplitude of the acoustic startle reflex in rats. In contrast, procaine (5–40 mg/kg) caused a dose-related decrease in startle, indicating that the effects of cocaine could not be ascribed to its local anesthetic effects. Cocaine's excitatory effects were blocked by pretreatment with haloperidol (0.5 mg/kg) but not by cyproheptadine or prazosin. The excitatory effects of cocaine (10 mg/kg) were markedly attenuated by pretreatment with reserpine (5 mg/kg 24 and 18 h earlier) but not by -methyl-p-tyrosine (100 mg/kg 1 h earlier). In contrast, comparably sized excitatory effects of d-amphetamine were blocked by -methyl-p-tyrosine and greatly enhanced by pretreatment with reserpine. Neither pretreatment blocked excitatory effects of apomorphine on startle. The data indicate that cocaine increases startle by acting through reserpine-sensitive pools of dopamine and provide further support for the conclusion that acoustic startle is enhanced by activation of dopamine receptors.     

Effects of d- and l-amphetamine on habituation and sensitization of the acoustic startle response in rats

In a series of 3 experiments the effects of 2, 4, 8, or 16 mg/kg d-amphetamine and 4, 8, 16, or 32 mg/kg l-amphetamine on acoustic startle amplitude in the rat were investigated. d-Amphetamine was 4–5 times as potent as l-amphetamine in augmenting startle amplitude. Startle potentiation was associated with vigorous stereotypies but the resultant cage movement could not account for the change in startle. Pretreatment with -methyl-p-tyrosine (100 mg/kg, 1 hr before) had only a slight depressant effect on startle but essentially eliminated augmentation of startle by either d-amphetamine (8 mg/kg) or l-amphetamine (32 mg/kg). d-Amphetamine did not have a direct effect on startle but instead enhanced sensitization produced by the startle stimuli without altering sensitization produced by background white noise or habituation. The results suggest that startle sensitization is enhanced by increased availability of catecholamines and, by virtue of the different potencies of the d- and l-isomers, that dopamine and norepinephrine may affect startle differently.     

Differential effects of CGP 37849 and MK-801, competitive and noncompetitive NMDA antagonists,with respect to the modulation of sensorimotor gating and dopamine outflow in the prefrontal cortex of rats

In the present study we compared effects of the competitive and non-competitive NMDA antagonists CGP 37849 and MK-801, respectively, on sensorimotor gating in rats, measured as prepulse-induced inhibition of the acoustic startle response, and the outflow of dopamine in the rat prefrontal cortex. CGP 37849 (10, 20 mg/kg), decreased the amplitude of the acoustic startle response, but was without effect on the prepulse-induced inhibition of the acoustic startle response. MK-801 (0.4 but not 0.2 mg/kg) enhanced the amplitude of the acoustic startle response and its doses of 0.2 and 0.4 mg/kg markedly attenuated the prepulse-induced inhibition of the acoustic startle response. The effects of MK-801 (0.4 mg/kg) on the prepulse-induced inhibition of the acoustic startle response were not antagonized by the selective antagonists of D-2 and D-1 dopaminergic receptors, S(–)sulpiride (25 mg/kg) and SCH 23390 (0.1 mg/kg), respectively. When given alone, S(–)sulpiride attenuated the amplitude of the acoustic startle response and failed to altered the prepulse-induced inhibition of the acoustic startle response. SCH 23390 (0.1 mg/kg) failed to alter the amplitude and prepulse-induced inhibition of the acoustic startle response. The effects of CGP 37849 and MK-801 also differed with respect to dopamine outflow. MK-801 (0.2 and 0.4 mg/kg) enhanced the outflow of dopamine in the rat prefronatl cortex, while CGP 37849 (10 and 20 mg/kg) was without any effect on the extracellular concentration of dopamine. Our data indicate that the blockade of phencyclidine binding sites, exerted by the noncompetitive antagonist MK-801, evoked effects qualitatively different from those induced — via blockade of the NMDA recognition — by the competitive NMDA receptor antagonist CGP 37849. It is postulated that — in contrast to the non-competitive antagonist of NMDA receptors — the competitive NMDA antagonist CGP 37849 is/ should be devoid of psychotomimetic and abusing properties. It is also evident that disruption of sensorimotor gating in rats induced by MK-801 does not involve any dopaminergic mechanisms, since it is not modulated by drugs blocking D-1 and D-2 dopamine receptors. Correspondence to: K. Wdzony at the above address     

Antidepressant-like activity of ipsapirone, buspirone and gepirone in the forced swimming test in rats pretreated with proadifen

The antidepressant-like activity of ipsapirone, buspirone and gepirone was studied in rats in the forced swimming test (behavioural despair test). lpsapirone and buspirone administered in single doses (5-20 mg/kg) did not affect the immobility time in this test. When administered in the same doses in a three-injection course in 24 h, buspirone was also inactive, while ipsapirone slightly but significantly reduced the immobility time only after a dose of 5 mg/kg. On the other hand, gepirone administered both in single doses (2.5-20 mg/kg) and in a three-injection course (5-20 mg/kg) potently and dose-dependently shortened the immobility time. 1-(2-Pyrimidinyl)-piperazine (1-PP; 5-20 mg/kg), a common metabolite of all the three drugs, administered in single doses or in a three-injection course, was inactive in the forced swimming test. In rats pretreated with proadifen (50 mg/kg), a non-selective drug metabolism inhibitor, both ipsapirone and buspirone administered in single doses (5-20 mg/kg) reduced the immobility time in a dose-dependent manner. Proadifen also potentiated the anti-immobility effect of gepirone (5 and 10 mg/kg). The anti-immobility effect of single doses (20 mg/kg) of ipsapirone, buspirone and gepirone in proadifen-pretreated animals was completely abolished by 1-PP (4 mg/kg). These results indicate that the antidepressant-like activity of the examined drugs in the behavioural despairtest is masked (ipsapirone, buspirone) or attenuated (gepirone) by their metabolite 1-PP.     

Interactions of buspirone or gepirone with nicotine on schedule-controlled behavior of pigeons

The primary purpose of the present study was to examine the interaction of buspirone with nicotine in pigeons responding under a fixed-ratio 30 schedule of food presentation. The hypothesis was that the dopamine D2 receptor antagonist activity of buspirone would attenuate the rate-decreasing effects of nicotine. When administered alone, buspirone (0.3-10mg/kg) and (-)-nicotine (0.1-3.0mg/kg) decreased response rates in a dose-related manner, with ED(50) values (+/-95% C.L.) of 3.0 (1.7-5.1) mg/kg and 1.0 (0.7-1.5) mg/kg, respectively. Low doses of buspirone (0.3-1.0mg/kg) did not significantly shift the nicotine dose-response function, while doses of buspirone (3.0-10mg/kg) that produced rate-decreasing effects shifted the nicotine dose-response function to the left. There was no significant statistical interaction between buspirone and nicotine indicating that the shifts in the nicotine dose-response function were parallel. The buspirone analog gepirone (0.3-10mg/kg), which like buspirone is a serotonin (5-HT(1A)) agonist, but unlike buspirone is relatively devoid of D2 antagonist activity, was also tested in combination with nicotine. Gepirone was less potent in decreasing response rates compared with buspirone, with an ED(56) value of 4.5 (3.1-6.7) mg/kg. Rate-decreasing doses of gepirone (3.0-10mg/kg) in combination with nicotine resulted in parallel shifts to the left of the nicotine dose-response function. There was no statistically significant difference between the effects of buspirone and those of gepirone on the nicotine dose-response function. Isobolograms indicated that the pharmacological interactions between buspirone or gepirone and nicotine were not different from additivity. These results suggest that the combined effects of buspirone and nicotine on schedule-controlled behavior are independent of antagonism at D2 receptors.     

Effects of 8-OH-DPAT,Lisuride and some ergot-related compounds on the acoustic startle response in the rat

Five ergot-related compounds were examined for their effects on the acoustic startle response in the rat. The startle amplitude and the startle latency were registered. 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 0.5–8 mg/kg) and lisuride (0.05–0.8 mg/kg) were found to enhance the startle amplitude, while the mainly DA receptor active ergot derivatives pergolide (0.2–0.8 mg/kg), bromocriptine (5–20 mg/kg) and LY 141865 (5–20 mg/kg) had no, or even the reverse, effect. All five compounds caused a prolongation of the startle latency. The increased startle amplitude caused by 8-OH-DPAT (2 mg/kg) and lisuride (0.2 mg/kg) was successfully antagonized by the 5-HT receptor antagonist methiothepin (0.1 mg/kg) but not by metergoline (1 mg/kg). 5-Hydroxy-L-tryptophan (L-5-HTP; 12.5–50 mg/kg), administered to pargyline- and benserazide-pretreated animals, was included for comparison. The serotonin precursor caused a marked increase in the startle amplitude and a shortening of the startle latency.     

Oxytocin Reduces Background Anxiety in a Fear-Potentiated Startle Paradigm: Peripheral vs Central Administration

Oxytocin is known to have anti-anxiety and anti-stress effects. Using a fear-potentiated startle paradigm in rats, we previously demonstrated that subcutaneously administered oxytocin suppressed acoustic startle following fear conditioning compared with startle before fear conditioning (termed background anxiety), but did not have an effect on cue-specific fear-potentiated startle. The findings suggest oxytocin reduces background anxiety, an anxious state not directly related to cue-specific fear, but sustained beyond the immediate threat. The goal of the present study was to compare the effects of centrally and peripherally administered oxytocin on background anxiety and cue-specific fear. Male rats were given oxytocin either subcutaneously (SC) or intracerebroventricularly (ICV) into the lateral ventricles before fear-potentiated startle testing. Oxytocin doses of 0.01 and 0.1 μg/kg SC reduced background anxiety. ICV administration of oxytocin at doses from 0.002 to 20 μg oxytocin had no effect on background anxiety or cue-specific fear-potentiated startle. The 20 μg ICV dose of oxytocin did reduce acoustic startle in non-fear conditioned rats. These studies indicate that oxytocin is potent and effective in reducing background anxiety when delivered peripherally, but not when delivered into the cerebroventricular system. Oxytocin given systemically may have anti-anxiety properties that are particularly germane to the hypervigilance and exaggerated startle typically seen in many anxiety and mental health disorder patients.     

Effects of buspirone and gepirone on IV cocaine self-administration in rhesus monkeys

Buspirone and gepirone were evaluated as potential pharmacotherapies for cocaine abuse by studying the effects of acute and repeated treatment on IV cocaine self-administration in rhesus monkeys. Chlorpromazine was also evaluated as a positive control. Effects of IV drug pretreatments were tested during daily 60-min sessions with lever-pressing reinforced under a fixed-ratio 10 schedule of 0.02 or 0.05 mg/kg cocaine infusions. Acute pretreatment with buspirone (0.1 and 0.3 mg/kg, IV) increased rates of cocaine self-administration without disrupting food pellet consumption. Some doses of buspirone also produced changes in rates of cocaine self-administration without altering the within-session pattern of responding. In contrast, acute doses of gepirone had little effect on rates of cocaine self-administration, while disruptions in food consumption and changes in the within-session pattern of cocaine self-administration were obtained at the highest dose of gepirone tested (1.0 mg/kg). When either buspirone (0.1 and 0.3 mg/kg, IV) or gepirone (0.1 mg/kg, IV) were administered daily for 10 days, consistent effects on cocaine self-administration were not observed. Thus, the effects of acute buspirone administration on cocaine-maintained behavior were similar to the effects produced by chlorpromazine and other dopaminergic antagonists, whereas, gepirone was ineffective. These results provide some support for further evaluation of buspirone as a potential pharmacotherapy for cocaine abuse, although its lack of efficacy with repeated treatment is not encouraging. The negative results with gepirone provide less rationale for continued investigations with this drug, possibly because of its lesser involvement than buspirone with dopaminergic neurotransmission.     

Effects of benzodiazepine receptor partial inverse agonists in the elevated plus maze test of anxiety in the rat

The present series of experiments examined the effects of five benzodiazepine receptor (BZR) partial inverse agonists on the behaviour of rats on an elevated plus maze. The drugs were tested in a standard plus maze with 3-cm walls added to the open arms, as this has been shown to increase the sensitivity of the plus maze to anxiogenic-like drug effects (Jones and Cole 1995). The drugs tested were FG 7142 (0–100 mg/kg),-CCE (0–30 mg/kg), ZK 132 556 (0–100 mg/kg), ZK 90 886 (0–30 mg/kg) and Ro 15–4513 (0–30 mg/kg). In addition, to allow a comparison with previous studies, the effects of three reference substances, DMCM (0–2.5 mg/kg), pentylenetetrazol (PTZ; 0–30 mg/kg) and yohimbine (0–5 mg/kg), were also examined. These three reference compounds produced a dose-dependent reduction in the duration of open arm exploration and the total number of open arm entries, indicative of anxiogenic-like effects. DMCM produced significant effects at the doses of 1.25 and 2.5 mg/kg, PTZ at 30 mg/kg, and yohimbine at 5 mg/kg. The BZR partial inverse agonist FG 7142 (10, 30 and 100 mg/kg) also reduced the duration of open arm exploration and the total number of arm entries. The minimally effective dose resulted in a receptor occupancy of approximately 80%. Ro 15–4513 also produced anxiogenic-like effects, but only at a dose (30 mg/kg) that resulted in a receptor occupancy of approximately 95%. In contrast, the other BZR partial inverse agonists, ZK 132 553 and ZK 90 886, did not significantly reduce the duration of open arm exploration, even at doses that produced greater than 95% receptor occupancies.-CCE also did not reduce open arm exploration at any dose tested (0–30 mg/kg). The GABA shift, a biochemical index of intrinsic activity, indicates that these latter three compounds are more inverse agonistic than Ro 15–4513. In summary, these results demonstrate that not all BZR receptor partial inverse agonists have anxiogenic-like activity in the rat plus maze, and that the GABA shift, a biochemical index of intrinsic efficacy, does not predict which BZR partial inverse agonists are anxiogenic.     

Behavioral and neurochemical effects of the serotonin (5-HT)1A receptor ligand spiroxatrine

The effects of spiroxatrine, a putative antagonist with selectivity for the serotonin (5-HT)_1A receptor, were compared with compounds believed to function as agonists at the 5-HT_1A receptor. Schedule-controlled responding of pigeons was maintained under a multiple 30-response fixed-ratio (FR), 3-min fixed-interval (FI) schedule or under a schedule in which responding was suppressed by electric shock (conflict procedure). Under the multiple schedule, spiroxatrine (0.3–1.0 mg/kg) decreased FR responding but did not affect FI responding; responding was decreased in both schedule components at 3.0 mg/kg. When administered alone, buspirone, a compound believed to produce its anxiolytic effects through 5-HT_1A agonist actions, produced effects similar to those of spiroxatrine; in combination, the two drugs produced greater effects than when either was administered alone. As with 5-HT_1A agonists such as buspirone and 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) in the pigeon, spiroxatrine (0.01–1.0 mg/kg) increased punished responding. Spiroxatrine and buspirone were potent inhibitors of [³H]8-OH-DPAT binding to pigeon cerebral membranes with IC₅₀ values in the nM range. Neurochemical analyses of metabolite changes produced by spiroxatrine in pigeon cerebrospinal fluid showed buspirone-like effects, with increases in MHPG, DOPAC and HVA at doses that decreased 5-HIAA levels. Spiroxatrine dose-dependently blocked the behavioral effects of the dopamine agonist piribedil indicating that, like buspirone, it also is a potent dopamine antagonist. Spiroxatrine most likely functions as an agonist at the 5-HT_1A receptor. As with buspirone, however, spiroxatrine has a prominent dopamine antagonist component.     

Effects of gepirone,an aryl-piperazine anxiolytic drug,on aggressive behavior and brain monoaminergic neurotransmission

Summary Gepirone (BMY 13805), a buspirone analog, was used to determine the antianxiety mechanism of the arylpiperazine class of drugs. Because of the weak effects of these drugs on conflict behavior, isolation-induced aggressive mice were used as the antianxiety model. Gepirone, like buspirone, potently inhibited attacks against group housed intruder mice (ED₅₀ = 4.5 mg/kg i. p.) without causing sedation or ataxia. Inhibition of aggression was potentiated by co-administration of 0.25 mg/kg methiothepin or 2.5 mg/kg methysergide. Gepirone had variable effects on dopamine metabolism and reduced 5-hydroxytryptamine (5HT) metabolism about one third after a dose of 2.5 mg/kg. In contrast to buspirone, which markedly increased dopaminergic impulse flow, gepirone inhibited the firing of most cells recorded from the substantia nigra zona compacta in doses of 2.3–10 mg/kg i. v. and the effects were reversible by administration of haloperidol. The common metabolite of buspirone and gepirone, 1-(2-pyrimidinyl)-piperazine, caused increased firing rates only. Gepirone potently inhibited serotonergic impulse flow recorded from the dorsal raphe nucleus (88.3% after 0.04 mg/kg) and this effect was partially reversed by serotonergic antagonists. Both buspirone and gepirone displaced [³H]-5HT from the 5HT_1a binding site in the hippocampus with IC₅₀ values of 10 and 58 nM, respectively. Non-alkyl substituted aryl-piperazines displaced [³H]-5HT from both 5HT_1a and 5HT_1b binding sites. Thus, although gepirone may be a weak postsynaptic 5HT agonist, its primary effect is to decrease 5HT neurotransmission. In support of this conclusion was the observed potentiation of antiaggressive effects by blocking 5HT receptors wit small doses of methiothepin or methysergide, which would exacerbate the decreased release of 5HT caused by gepirone. These results are in harmony with reports that decreased serotonergic activity has anxiolytic-like effects in animal models of anxiety.Portions of this work were presented at the IVth World Congress of Biological Psychiatry, September, 1985 in Philadelphia Send offprint requests to B. A. McMillen at the above address     

Effects of blockade of 5-HT2 receptors and activation of 5-HT1A receptors on the exploratory activity of rats in the elevated plus-maze

Acute administration of gepirone, a 5-HT_1A agonist, caused a dose dependent (1–10 mg/kg, IP) reduction in the locomotor activity (open and closed arms) of rats tested in the elevated plus-maze. However, rats housed in individual cages and submitted to chronic treatment with gepirone (10 mg/kg PO) showed a marked increase in the percentages of number and time spent in the open arms as compared to controls. These results are compatible with the idea that the antiaversive effect due to long-term treatment with 5-HT_1A agonists is the result of a progressive desensitization of the somatodendritic 5-HT autoreceptor with the consequent recovery of firing rate of 5-HT neurons along with an activation of normosensitive postsynaptic 5-HT neurons. Ketanserin caused a biphasic effects on the exploratory behavior of rats in the plus-maze. The lower dose (0.5 mg/kg) decreased the aversion to the open arms and the higher dose (1.0 mg/kg) caused an unspecific decrease in the overall activity of the animals. Ketanserin is supposed to have antagonistic action on 5-HT₂ and on -adrenergic receptors. As prazosin (0.5–1.0 mg/kg), an -adrenergic receptor blocker, did not present any significant effect in the present work it is suggested that the effects of the lower dose of ketanserin was due to its high antagonistic action on 5-HT₂ receptors.