Interaction between phencyclidine (PCP) and Gaba-ergic drugs: Clinical implications

Pretreatment (IP) of mice with (?) baclofen, muscimol, 4,5,6,7-tetrahydroisoxazolo (S,4-c) pyridin-3-ol hydrate (THIP), aminooxyacetic acid (AOAA) or γ-acetylenic GABA caused a dose-dependent inhibition of the locomotor stimulant effect of phencyclidine (PCP, 8 mg/kg). Although (?) baclofen was found to be the most effective PCP antagonist, its (+) isomer was inactive. The maximum blocking effect of AOAA was seen in animals treated 3 and 6 hr earlier. Except for γ-acetylenic GABA, none of these drugs significantly blocked the locomotor stimulant effect of d-amphetamine (3 mg/kg, IP). Diazepam reduced d-amphetamine response, but failed to influence PCP-induced stimulation. The locomotor stimulant effect of PCP, unlike that of d-amphetamine, may be the result of a specific GABA antagonistic effect at certain dopamine-rich areas of the brain. It seems that (?) baclofen may prove to be useful in the management of PCP intoxication.Administration of higher doses of PCP (20 and 50 mg/kg) in mice pretreated with (?) baclofen resulted in the development of surgical anesthesia manifested as the loss of a) righting reflex, b) pain sensation and c) corneal reflex. The duration of the general anesthetic response was found to be a function of the doses of both (?) baclofen and PCP. The possible use of (?) baclofen as an adjuvant to general anesthetic is discussed.     

Relationship between the development of behavioral tolerance and the biodisposition of phencyclidine in mice

Mice trained on a differential reinforcement of low rate 10-sec schedule (DRL 10) were treated daily with either IP saline or 10 mg/kg of phencyclidine hydrochloride (PCP). After 21 consecutive days of treatment, dose-effect determinations for PCP were obtained in both groups. Chronic treatment with PCP resulted in approximately 1.5-fold development of tolerance to the PCP-induced reduction of reinforcement rate. Following completion of the dose-effect determinations, the mice were treated for an additional 13 days with either saline or PCP (10 mg/kg, IP). On the fourteenth day, the biodisposition of 3H-PCP-HCl (10 mg/kg, IP) was studied in both groups. The ratio of the brain levels of PCP in the saline-trained animals to that in the PCP-trained animals was 1.3 to 1 which accounted in large part for the development of tolerance. It appears that dispositional factors are involved in the development of tolerance of mice to the disruptive effects of PCP on DRL performance.     

The effects of serotonin antagonists in a behavioral despair procedure in mice

In view of the controversy as to whether antisecretory agents such as H2 antagonists and antimuscarinics might be cytoprotective like the PGs, the oral activity of atropine, ranitidine and PGE2 against absolute ethanol-induced lesions was evaluated in rats. The results showed that atropine and PGE2, but not ranitidine, were effective in preventing absolute ethanol-induced gastric damage. The effects were related to the doses of the ulcerogenic agent and of the cytoprotective compound. The anti-ulcer activity of atropine is considered to be an expression of cytoprotection, since the pathogenesis of ethanol-induced gastric damage was independent of gastric pH and atropine, like PGE2, does not affect basal acid secretion at a fully cytoprotective dose. Some studies were undertaken to elucidate the mechanism of gastric cytoprotection by atropine. The possibility that the anti-muscarinic agent might work as a mild irritant was ruled out since, like PGE2, the agent was still effective in PG-deficient rats. The evidence that neostigmine markedly aggravated gastric damage caused by low doses of absolute ethanol and that atropine completely prevented this damage postulates mechanisms involving specific muscarinic receptor interactions.     

Acute and chronic behavioral interactions between phencyclidine (PCP) and amphetamine: evidence for a dopaminergic role in some PCP-induced behaviors

Amphetamine and phencyclidine (PCP) are both proposed to exert effects on unconditioned behavior through dopaminergic mechanisms. However, a relatively complete characterization of their effects in rats reveals markedly different response profiles. Furthermore, whereas acute co-administration of amphetamine and PCP resulted in an increase in one component of stereotypy, repetitive head movements, two measures of locomotor activation, i.e., ambulation and nonfocused sniffing, were unchanged, and rearings were reduced. In addition, the response alterations which occur with repeated administration of these drugs did not display cross-sensitization. Thus, although repeated daily injections of amphetamine, which produced progressive locomotor augmentation, sensitized animals to the locomotor-stimulating effects of PCP, repeated PCP treatment, which also resulted in locomotor augmentation, decreased the locomotor response to a challenge injection of amphetamine. These findings suggest significant differences in the mechanisms underlying the effects of acute and repeated administration of PCP and amphetamine.     

Effects of phencyclidine on aggressive behavior in mice

The effects of phencyclidine on aggressive behavior in mice and the possible mechanism of action for these effects were examined. PCP at a dose of 10.0 mg/kg significantly decreased the number of attacks by resident mice toward intruders. Significant increases in the number of attacks by non-drugged residents toward the intruders who were given high doses of PCP (6.0 and 10.0 mg/kg) were observed. Only the higher doses of PCP (6.0 and 10.0 mg/kg) significantly increased the duration of locomotion. The increase in locomotion was dependent upon the time after administration of the drug. Hyperactivity was present at 30 minutes for both doses and hypoactivity was present at three hours after administration of 3.0 mg/kg. PCP did not significantly alter the frequency of attacks in an unfamiliar test locale. Pretreatment with haloperidol (1 mg/kg) partially blocked the PCP-induced hyperactivity but pretreatment with methysergide (3 mg/kg) did not. Neither haloperidol nor methysergide blocked the suppressive effects of PCP on aggressive behavior. It is concluded that PCP does not increase aggressive behavior in mice but high doses will decrease aggression. PCP-treated intruder animals provoke more aggression by non-drugged animals. PCP-induced hyperactivity appears to be mediated by dopaminergic systems.     

Opposite effects of chlordiazepoxide and serotonin receptor antagonists on morphine-induced locomotor stimulation in mice

Chlordiazepoxide and two serotonin receptor antagonists showed opposite effects when tested for their influence on morphine-induced locomotor stimulation in mice. Chlordiazepoxide enhanced morphine-induced hyperactivity, which was antagonized by cyproheptadine and mianserin. The results indicate that the enhancement of morphine-induced locomotor stimulation is not attributable to an antiserotonergic action of the benzodiazepine compound.     

Microinjections of phencyclidine (PCP) and related drugs into nucleus accumbens shell potentiate medial forebrain bundle brain stimulation reward

 Microinjections of phencyclidine (PCP) into the ventro-medial portion of nucleus accumbens in rats potentiated the rewarding impact of lateral hypothalamic brain stimulation. Similar effects were found with nomifensine, which shares with PCP the ability to block dopamine uptake and thus elevate synaptic dopamine levels but does not share with PCP the ability to block NMDA receptors. Similar effects were also seen with dizocilpine (MK-801) and [3-((±)2-carboxypiperazin-4-yl)propyl-1-phosphonate] (CPP), which share with PCP the ability to block NMDA receptors but not to block dopamine uptake. Thus PCP’s properties as a dopamine uptake inhibitor and as an NMDA receptor antagonist each appear capable of producing reward-related actions in this brain region. The common denominator of these two PCP actions is decreased output of medium spiny neurons; these neurons are tonically activated by a glutamate projection from prefrontal cortex (PCP blocks this source of activation) and are tonically inhibited by a dopaminergic projection from the ventral tegmental area (PCP augments this inhibition). Received: 10 April 1996 / Final version: 5 August 1996     

Parametric analysis of the development and expression of ethanol-induced behavioral sensitization in female Swiss mice: effects of dose,injection schedule,and test context

Rationale  Repeated administrations of ethanol induce a progressive and enduring increase in its locomotor stimulant effects, a phenomenon termed behavioral sensitization that has not been systematically characterized. Objective  The aim of the present studies was to characterize the development and expression of ethanol sensitization in female Swiss mice by examining (1) the doses of ethanol that induce behavioral sensitization, (2) the doses of acute ethanol challenges that are necessary to express behavioral sensitization, (3) the effects of the intervals between administrations, and (4) the context dependency of ethanol sensitization. Materials and methods  Mice were i.p. injected for 8 days with various ethanol doses, and locomotion was recorded for 5 min. Two days after the last sensitization session, ethanol sensitization was tested in 30-min test sessions. Results  Mice repeatedly injected with 2.5 g/kg ethanol showed a progressive (200–300%) increase in locomotor activity. In response to a 2.5 g/kg ethanol challenge, the mice repeatedly treated with doses above 1.5 g/kg showed a significant sensitization. Following the induction of sensitization with the maximally effective sensitizing dose (2.5 g/kg), mice showed greater activation after challenges with 1.5, 2.0, 2.5, and 3.0 g/kg ethanol. The intervals (24, 48, or 96 h) between ethanol injections did not affect the induction or expression of sensitization. Finally, sensitization to 2.5 g/kg ethanol was expressed regardless of the context in which it was induced. Conclusions  Female Swiss mice develop a robust context-independent sensitization after repeated ethanol injections at all doses above 1.5 g/kg, including highly sedative doses such as 4 g/kg.     

Biochemical and behavioral effects of lesions of raphe nuclei in aggressive mice

A decrease of brain 5-hydroxytryptamine turnover was described to be present in mice made aggressive by prolonged isolation. The lesion of brain serotoninergic pathways decreases both 5-hydroxytryptamine and 5-hydroxyindolacetic acid levels in the forebrain and completely abolishes the aggressive behavior in previously fully aggressive mice. No change of aggressive behavior or of serotonin levels was observed in aggressive mice submitted to lesions of other areas.     

Concurrent progressive-ratio schedules to compare reinforcing effectiveness of different phencyclidine (PCP) concentrations in rhesus monkeys

  Rationale: Progressive ratio (PR) schedules have become well accepted for testing the reinforcing effectiveness of drugs. This study extends the methods to concurrent PR schedules with different concentrations of orally delivered phencyclidine (PCP). Objective: The sensitivity of the procedure is tested by presenting different PCP concentrations with independently-operating PR schedules. Method: PCP self-administration was investigated in seven rhesus monkeys. Six different PCP concentrations (0.03–1.0 mg/ml) and water were randomly paired (21 pairings). Liquid delivery (24 ml) was contingent upon lip-contact responses on solenoid-operated drinking spouts; whereby, the response requirement or fixed-ratio (FR) increased (from 8 to 16, 32, 64, 128... to 4096) after each successful completion of a previous FR and subsequent liquid delivery. Monkeys self administered PCP during daily 3-h sessions, and each pair of concentrations was held constant until behavior had stabilized for at least 4 days. Results: The higher of the two PCP concentrations always maintained greater responding, PR break point (BP), or the last ratio completed, and liquid deliveries than did the lower concentration. However, the monkeys did not exclusively respond on the drinking spout that yielded the higher drug concentration. When examined across all drug pairings, the percentage of total available deliveries of the higher concentration was significantly greater than those of the lower concentration. The monkeys maximized the amount (mg) consumed for the response output. Responding, BPs and liquid deliveries maintained by 0.12 and 0.25 mg/ml PCP were significantly greater than other PCP concentrations; however, drug intake (mg) increased directly with PCP concentration. Conclusion: These results indicate that concurrent PR schedules using oral drug self-administration and a concurrent choice paradigm reliably provide an estimation of relative reinforcing strength, and behavior maintained by these schedules is sensitive to small changes in PCP concentration. Received: 18 September 1998 / Final version: 28 December 1998     

Effects of altering reinforcer magnitude and reinforcement schedule on phencyclidine (PCP) self-administration in monkeys using an adjusting delay task

Compared to nondrug reinforcers, few studies have examined delay discounting for drug reinforcers. The purpose of the present study was to examine delay discounting in rhesus monkeys using orally delivered phencyclidine (PCP) as the reinforcer and to examine the effects of manipulating reinforcer magnitude and cost on delay discounting for PCP using an adjusting delay task. Monkeys could choose between a single delivery of PCP available immediately or a bundle of PCP deliveries available following a titrated delay. The average of the delays, or the mean adjusted delay (MAD), served as the quantitative measure of delay discounting. In Experiment 1, reinforcer magnitude was manipulated by varying the PCP concentration and the size of the delayed reinforcer (6 or 12 deliveries). The concentration-effect curve for PCP deliveries assumed an inverted U-shaped function, but varying PCP concentration had little effect on MAD values or the choice between immediate and delayed reinforcers. Increasing the size of the delayed reinforcer produced an upward and leftward shift in the concentration-effect curve. In Experiment 2, the cost of reinforcers was manipulated by increasing the fixed ratio (FR) requirement for each choice. Increasing the FR led to increased MAD values and decreased PCP self-administration.     

Modification of behavioral effects of drugs in mice by neuroactive steroids

Rationale: Neuroactive steroids represent a novel class of potential therapeutic agents (epilepsy, anxiety, migraine, drug dependence) thought to act through positive allosteric modulation of the GABA_A receptor. A synthetically derived neuroactive steroid, ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), is in phase-II clinical trials for epilepsy. Unlike traditional anticonvulsants such as diazepam and phenobarbital, ganaxolone shows equipotent suppression of both the seizure activity and the behavioral effects of pentylenetetrazol (PTZ) administration. Objectives: The present study explored possible reversal by ganaxolone and related neuroactive steroids of some behavioral effects of additional pharmacological challenges. Methods: Direct behavioral observation and photocell-counted locomotor activity of male, Swiss-Webster mice were made with various compounds alone and in conjunction with ganaxolone. Results: Ganaxolone both prevented and reversed PTZ-induced locomotor depression in mice. Further, ganaxolone reversed the locomotor depression induced by other convulsant/anxiogenic stimuli: bicuculline, picrotoxin and, to a lesser extent, yohimbine. Ganaxolone failed to reverse the locomotor stimulation induced by cocaine, methamphetamine, dizocilpine, and phencyclidine. In addition to ganaxolone, the endogenous neuroactive steroids allopregnanolone and pregnanolone and the synthetic neuroactive steroid Co 2-1068 also reversed observed behaviors and locomotor depression induced by PTZ. Conclusions: The present findings support the unique pharmacological effects of neuroactive steroids as a novel class of positive allosteric modulators of GABA. Received: 19 December 1998 / Final version: 22 September 1999     

Sex differences in the escalation of oral phencyclidine (PCP) self-administration under FR and PR schedules in rhesus monkeys

Rationale Studies with male rats indicate that long access (LgA) vs short access (ShA) to i.v. cocaine and heroin self-administration leads to an escalation of drug intake and a subsequent upward shift of the dose-response function.Objective The purpose of this experiment was to extend these results to male and female rhesus monkeys and oral phencyclidine (PCP) self-administration under fixed-ratio (FR) and progressive-ratio (PR) schedules.Methods Adult rhesus monkeys (seven females and nine males) orally self-administered PCP (0.25 mg/ml) and water under concurrent FR 16 FR 16 schedules during daily ShA 3-h sessions. Since females weighed less than males, each liquid delivery (0.6 ml) represented a higher unit dose mg/kg for females than males, but drug concentration mg/ml remained constant. Concurrent PR PR schedules were then used to obtain a concentration-response function (0.125, 0.25, 0.5, and 1.0 mg/ml). Next, PCP and water were available during LgA 6-h sessions under concurrent FR 16 FR 16 schedules for 21 days. The monkeys were then retested under the concurrent FR 16 FR 16 and PR PR conditions during ShA sessions.Results Under the initial ShA concurrent FR 16 FR 16 schedules, females and males did not differ on PCP deliveries or intake (mg/kg); however, during LgA, males and females had more PCP deliveries compared with ShA. During LgA, males exceeded females in PCP deliveries, but females were higher than males in mg/kg PCP intake. Also, PCP (but not water) deliveries and mg/kg PCP intake significantly increased from the first 3 days to the last 3 days of the 21-day LgA period in both males and females. The subsequent ShA FR 16 FR 16 performance did not differ by sex, but it was significantly elevated above the first ShA period in both sexes. The concentration-response function for PCP break point under the PR PR schedules and PCP intake (mg/kg) were significantly shifted upward during the second (vs first) ShA period, and females mg/kg intake significantly exceeded males.Conclusions Male and female rhesus monkeys both showed escalation of PCP self-administration during LgA to PCP and during ShA that occurred after (vs before) LgA. Both showed vertical upward shifts in the concentration×intake (mg/kg) function under the PR schedule, and females exceeded males on this measure. These findings with PCP and monkeys are consistent with vertical upward shifts of cocaine dose-response functions in previous escalation studies in male rats and reports of sex differences (F>M) during several other phases of drug abuse.     

Effects of 6-methoxy-1,2,3,4-tetrahydro-beta-carboline (6-MeO-THbetaC) on audiogenic seizures in DBA/2J mice

It was found previously that 6-methoxy-1,2,3,4-tetrahydro-beta-carboline (6-MeO-THbetaC) increased brain concentration of the neurotransmitter serotonin (5-HT) and decreased the concentration of its metabolite 5-hydroxyindole acetic acid (5-HIAA) at the same time the compound attenuated audiogenic seizures (AGS) in DBA/2J mice. In the present study we determined the time-course and dose-response effects of 6-MeO-THbetaC for blockade of AGS. Drugs sharing common effects with 6-MeO-THbetaC were also tested. At a dose of 100 mg/kg, 6-MeO-THbetaC blocked AGS between 10 min and 12 hr after injection, with maximal inhibition at 1 hr at which time a dose-related decrease in AGS was also demonstrated. All of the drugs tested which blocked AGS, including 6-MeO-THbetaC, THbetaC, 5-Hydroxytryptophan, chlorimipramine and pargyline, have biochemical similarities suggesting that facilitating serotonin function may be responsible for seizure-attenuating effects.     

Selective and nonselective serotonin antagonists block the aversive stimulus properties of MK212 and m-chlorophenylpiperazine (mCPP) in mice

Serotonin_2C (5-HT_2C) receptors have been implicated to treat mood disorders such as depression and anxiety. In the present study, the capacities of two 5-HT_2C agonists, MK212 and mCPP, to produce conditioned taste aversions in mice were evaluated. On two training days, Swiss-Webster male mice (19–34 g) were trained to associate the flavor of a novel solution with the injection of various doses of MK212 or mCPP. On two alternate training days, mice were trained to associate a different flavored solution with an injection of saline. For testing, both flavored solutions were presented simultaneously and an avoidance of the MK212 or mCPP-paired solution indicated conditioned taste aversion. Robust conditioned taste aversions were observed to solutions paired with 1.0 or 10 mg/kg MK212 or mCPP. Acquisition of conditioned taste aversions was blocked by nonselective serotonin antagonists cyproheptadine, bromo-LSD, metergoline, methysergide and mianserin. Selective 5-HT_2B/2C antagonist SB206,553 blocked both MK212- and mCPP-induced conditioned taste aversion although selective 5-HT_2B/2C antagonist SB200,646 only blocked mCPP-induced conditioned taste aversion. In a single-bottle procedure, MK212, bromo-LSD, and mianserin failed to alter acquisition rate of a LiCl-induced conditioned taste aversion. Taken together, these data indicate that the serotonin agonists MK212 and mCPP produce conditioned taste aversion and that these effects are mediated predominantly through 5-HT_2C receptors.     

Extracts of kava (<Emphasis Type="Italic">Piper methysticum</Emphasis>) induce acute anxiolytic-like behavioral changes in mice

Rationale Kava has been used for centuries by Pacific Islanders for its tranquilizing and sedative effects. Recent clinical trials suggest that kava has therapeutic value for the treatment of anxiety. Demonstration of kava's anxiolytic effects in animals under controlled conditions would provide additional support for its clinical potential as an anxiolytic and would facilitate investigation of its mechanism(s) of action.Objectives This study systematically characterized the acute dosage-dependent anxiolytic and sedative effects of kava extract in well established quantitative murine behavioral assays and compared kava- and diazepam-induced behavioral changes.Methods Various doses of an ethanolic extract of kava root or diazepam were administered intraperitoneally to BALB/cByJ inbred mice. Behavioral changes were measured in the mirrored chamber avoidance assay and elevated plus-maze assay. Reduced latency to enter and increased time spent in a normally avoided environment operationally defined anxiolysis. Sedation was defined by a significant decrease in locomotor activity in a circular arena.Results Kava extract produced statistically significant dose-dependent anxiolytic-like behavioral changes in both assays of anxiolysis. ED₅₀ values for kava-induced increases in time spent inside the mirrored chamber and on the open arms of the plus maze were 125 mg/kg and 88 mg/kg, respectively. Kava extract also caused a profound decrease in locomotor activity (ED₅₀ of 172 mg/kg). Flumazenil, a competitive benzodiazepine receptor antagonist, blocked both the anxiolytic and sedative effects of diazepam, but had no effect on kava's behavioral actions.Conclusions Kava extracts produce significant murine anxiolytic-like behavioral changes and sedation that are not mediated through the benzodiazepine binding site on the GABA_A receptor complex.     

Contribution of trichloroacetic acid to liver tumors observed in perchloroethylene (perc)-exposed mice

Perchloroethylene (perc), a solvent used in dry cleaning operations and industrial applications, has been found to produce increases in hepatocellular carcinomas and/or adenomas in mice in chronic inhalation bioassays. Perc is metabolized primarily to trichloroacetic acid (TCA), which is also a mouse hepatocarcinogen. The fractional conversion of perchloroethylene to TCA by mice was determined from physiologically based pharmacokinetic (PBPK) modeling of TCA in mouse blood at the conclusion of inhalation exposure of male and female B6C3F1 mice to 10, 50, 100, or 200 ppm perc for 6 h/day for 5 days. The dose-dependent bioavailability of TCA in B6C3F1 mice exposed to TCA in drinking water was estimated by optimizing the fit of time course blood, plasma, and liver TCA concentrations for TCA doses ranging from 12 to 800 mg/(kg day) to predictions of a previously published TCA PBPK model. Using the PBPK models, the area under the liver TCA concentration vs. time curve (liver TCA AUC) was calculated for TCA and perc bioassays. Benchmark dose analyses were conducted to determine the dose–response relationship between liver TCA AUC and the additional risk of hepatocellular adenomas or carcinomas (combined) in mice ingesting TCA. Using the dose–response relationships derived for the TCA-exposed mice, the contribution of TCA produced by metabolism to the additional risk of liver adenomas and carcinomas in mice exposed to perchloroethylene by inhalation was computed. The analysis indicated that the levels of TCA observed in perchloroethylene-exposed mice are sufficient to explain the incidence of liver adenomas and carcinomas.     

Effects of combining ethanol (EtOH) with gamma-hydroxybutyrate (GHB) on the discriminative stimulus, locomotor, and motor-impairing functions of GHB in mice

Rationale Gamma-hydroxybutyrate (GHB) is a drug of abuse that is often coabused with ethanol (EtOH) and has been implicated as a date rape agent in conjunction with EtOH. Much information is lacking regarding the manner in which GHB interacts with EtOH. Objective This study was designed to further characterize the behavioral effects of GHB alone and in combination with EtOH in male Swiss–Webster mice. Methods The effects of GHB (0.1–1.0 g/kg) and EtOH (2.0–5.0 g/kg) alone, as well as the effects of GHB in combination with EtOH, were examined using an automated locomotor activity procedure, a functional observational battery (FOB) and a GHB drug discrimination procedure. Results GHB decreased, whereas EtOH had little effect on locomotor activity. In the FOB, EtOH dose-dependently decreased activity in combination with 0.3 g/kg GHB. Alone, each drug had little effect on the righting reflex, but combining ineffective doses of GHB and EtOH significantly impaired righting. GHB and EtOH decreased forelimb grip strength. Combinations of ineffective doses of GHB and EtOH decreased forelimb grip strength when given together. GHB and EtOH impaired inverted screen performance, and EtOH increased the impairing effects of low, but not high, doses of GHB. GHB and EtOH increased hind limb splay, and EtOH increased the effects of 0.1 and 0.3 g/kg GHB on splay. GHB and EtOH decreased body temperature, and EtOH augmented the temperature-decreasing effects of GHB. EtOH produced less than 50% GHB-like discriminative stimulus effects, and GHB failed to alter the GHB-like discriminative stimulus effects of EtOH. Conclusions Overall, EtOH increased the effects of GHB on several gross measures of behavior and only partially occasioned the discriminative stimulus properties of GHB.     

Complex discriminative stimulus properties of (+)lysergic acid diethylamide (LSD) in C57Bl/6J mice

Rationale The drug discrimination procedure is the most frequently used in vivo model of hallucinogen activity. Historically, most drug discrimination studies have been conducted in the rat. With the development of genetically modified mice, a powerful new tool has become available for investigating the mechanisms of drug-induced behavior. The current paper is part of an ongoing effort to determine the utility of the drug discrimination technique for evaluating hallucinogenic drugs in mice.Objective To establish the training procedures and characterize the stimulus properties of (+)lysergic acid diethylamide (LSD) in mice.Methods Using a two-lever drug discrimination procedure, C57Bl/6J mice were trained to discriminate 0.45 mg/kg LSD vs saline on a VI30 sec schedule of reinforcement, with vanilla-flavored Ensure serving as the reinforcer.Results As in rats, acquisition was orderly, but the training dose was nearly five-fold higher for mice than rats. LSD lever selection was dose-dependent. Time-course studies revealed a rapid loss of the LSD stimulus effects. The 5-HT_2A/2C receptor agonist, 2,5-dimethoxy-4-bromoamphetamine [(–)DOB] (1.0 mg/kg), substituted fully for LSD and the 5-HT_1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) (1.6 mg/kg), substituted partially for LSD. Pretreatment with the 5-HT_2A receptor-selective antagonist, MDL 100907, or the 5-HT_1A-selective antagonist WAY 100635, showed that each antagonist only partially blocked LSD discrimination. Substitution of 1.0 mg/kg (–)DOB for LSD was fully blocked by pretreatment with MDL 100907 but unaltered by WAY 100635 pretreatment.Conclusions These data suggest that in mice the stimulus effects of LSD have both a 5-HT_2A receptor and a 5-HT_1A receptor component.