Acute and chronic effects of LSD and 3,4-dimethoxyphenylethylamine on shuttlebox escape/avoidance in rats

Three experiments were conducted in rats to study the effects of acute and chronic LSD and 3,4-dimethoxyphenylethylamine (DMPEA) on acquisition of shuttlebox escape/avoidance and of acute DMPEA on performance in the shuttlebox of pretrained poor performers. In Experiments 1 and 2, separate groups of male hooded rats were injected (i.p.) either once with LSD (0.1 or 0.5 mg/kg),DMPEA (25, 50, or 100 mg/kg) or saline or daily for 5 days with LSD (0.5 mg/kg), DMPEA (25 or 100 mg/kg) or saline before an initial acquisition test. The acute drug groups were retested 24 h later under saline. In Experiment 3, pretrained rats which had achieved a low, stable baseline rate of shuttlebox performance were injected once with DMPEA (50 mg/kg) before a performance test and retested 24 h later under saline. It was found that all LSD treatments decreases escape/avoidance latencies (excitatory effect) on the acquisition test and saline retest, while all DMPEA treatments were without effect.This research was supported by grants No. ID5TI MH 6418, No. 5 KO5 MH 04177, and No. 5T5-GM1674 from the National Institutes of Health, U.S.A.     

Comparison of the action of lysergic acid diethylamide and apomorphine on the copulatory response in the female rat

The effects of lysergic acid diethylamide (LSD) and apomorphine were compared using female copulatory behavior (lordosis response), in ovariectomized estrogen + progesterone-treated rats. Both serotonin and dopamine are implicated in the inhibition of this behavior. Each compound inhibited lordosis behavior dose dependently and with a similar time-course. Pimozide (0.1; 0.5 mg/kg) blocked the apomorphine (0.2 mg/kg)-induced decrease of lordosis response, while only a certain abbreviation of the LSD (0.10 mg/kg) inhibition was achieved by pimozide (0.5 mg/kg). Chlorpromazine (0.5 mg/kg) in a dose without effects on lordosis of its own had an action similar to pimozide on the LSD effect.It is concluded that the predominant action of LSD on the female coupulatory response is not mediated by increased dopamine receptor activity but that the LSD effect might be modulated by decreased dopaminergic activity.     

Subjective effects of narcotic antagonists cyclazocine and nalorphine on the Addiction Research Center Inventory (ARCI)

The subjective effects of two doses of cyclazocine (0.6 mg and 1.2 mg/70 kg), nalorphine (16 and 32 mg/70 kg), no-drug and placebo were compared with 32 opiate addicts using drug sensitive scales of the Addiction Research Center Inventory (ARCI) items. The effects of these narcotic antagonists were highly similar on ARCI scales and items. Both drugs produced a general drug effect, difficulty in focusing eyes, physical weakness, tiredness, poor motivation, moodiness, misery, anxiety, tension, hallucinations, changes in sensation and perception, and inefficiency of physical, cognitive and social functions. Cyclazocine was 15–26 times more potent than nalorphine. The effects of cyclazocine and nalorphine were differentiated from the effects of other drugs such as morphine, pentobarbital and LSD when the overall pattern of effect was considered.     

Delineation of mu-antagonist, partial kappa agonist and non-opioid agonist activity of cyclazocine using urinary output of rats

The effects of cyclazocine (SC) were studied under a variety of test conditions to determine its various activities on urinary output. Cyclazocine antagonized the morphine-induced (20 mg/kg) antidiuretic effect in water-loaded (3 ml/100 g b.wt.) rats at low doses (0.08, 0.16 and 0.32 mg/kg). At higher doses (1.25, 5 and 20 mg/kg), cyclazocine caused diuresis in normally hydrated rats. The diuresis produced by 1.25 and 5, but not 20 mg/kg, was antagonized by naloxone (10 mg/kg). In water-deprived rats and in normally hydrated rats, cyclazocine, in a dose-related fashion, antagonized the diuretic effects of 0.08 mg/kg of bremazocine. These results are compatible with the interpretation that cyclazocine has mu-antagonist activity at low doses, then partial kappa-agonist activity at intermediate doses, followed by non-opioid agonist activities at the higher doses.     

Cross generalization with LSD and yohimbine in the rat

Rats trained to discriminate intraperitoneal injections of 0.16 mg/kg LSD from saline injections were found to show stimulus generalization with 0.31-5 mg/kg of yohimbine. Partial generalization also occurred with clonidine and xylazine. Rats discriminating intraperitoneal injections of 5 mg/kg of yohimbine from saline generalized LSD at doses of 0.08-0.63 mg/kg. The data establish an equivalence between LSD and yohimbine as to discriminative effects in rats. This equivalence is consistent with LSD and yohimbine producing at least partly similar subjective effects in humans.     

In vivo evidence of partial agonist activity exerted by purported 5-hydroxytryptamine antagonists

Using a food-reinforced two-lever operant method, rats (n = 9) were trained to discriminate 0.16 mg/kg LSD from saline. Tests for stimulus generalization in rats so trained indicated that the purported 5-HT antagonists cyproheptadine (1.25 and 10 mg/kg), methysergide (0.16 to 10 mg/kg) and mianserin (2.5 to 40 mg/kg) produced partial generalization with LSD. The hallucinogens mescaline (5 to 40 mg/kg) and quipazine (1.25 to 5 mg/kg) were also generalized with LSD. The data suggest that cyproheptadine, methysergide and mianserin may produce partial agonist effects in addition to their antagonist action at central 5-HT receptor sites.     

The effect of δ 9-tetrahydrocannabinol and LSD on the acquisition of an active avoidance response in the rat

The course of active avoidance learning of rats in a symmetrical Y-maze under the influence of 1, 3, and 9 mg/kg of ⁹-THC i.p., and 5, 20, and 100 g/kg of LSD was investigated. ⁹-THC in a dosage of 1 mg/kg had no effect on avoidance learning. Three and to a lesser extent 9 mg/kg produced more rapid learning with a significantly better performance. Learning under ⁹-THC proved to be statedependent. The withdrawal of ⁹-THC caused a decrease in the avoidance rate, which was dependent on the dosage. Upon renewal of the THC doses, the animals reattained their earlier performance. In the course of the experiment there was rapid tolerance development, especially of the sedative properties of THC.LSD retarded the rate of acquisition of the active avoidance response. Whereas the control animals displayed over 80% successful active avoidance from the 14th session onwards, this was achieved by the LSD groups only after the 20th session. However, in contrast to the control group the LSD animals were able to increase their avoidance rate to over 90%, and this was maintained to the end of the experiment (a total of 24 sessions with LSD). The sudden withdrawal of LSD produced a fall in avoidance rate, which was dependent on the previous training dosage; as with ⁹-THC state-dependent learning can also be assumed for LSD.     

Effect of LSD on prepulse inhibition and spontaneous behavior in the rat. A pharmacological analysis and comparison between two rat strains.

The goal of the present study was to better delineate the mechanisms of action of the prototypical hallucinogen LSD. LSD (0.03, 0.1 and 0.3 mg/kg, s.c.) produced locomotor hyperactivity, disruption of PPI and a number of behaviors indicative of 5-HT activation such as wet-dog shakes, back muscle contractions and forepaw treading. These various behavioral effects of LSD were studied in both Sprague-Dawley and Wistar rats, although with the exception of back muscle contractions which were more prominent in Sprague-Dawley rats, no major strain differences were detected. The PPI disruption induced by LSD (0.1 mg/kg) in Sprague-Dawley rats was completely reversed by pretreatment with the selective 5-HT(2A) antagonist MDL 100907 (0.5 and 1 mg/kg, s.c.). In contrast, pretreatment with antagonists at 5-HT(2C), (SB 242084 (0.5 mg/kg, i.p.)); 5-HT(2B/2C) (SDZ SER 082 (1 mg/kg, s.c.)); 5-HT(1A), ((+)-WAY 100135 (1 and 20 mg/kg, s.c.)) and 5-HT(6) receptors, (RO 04-6790 (30 mg/kg, i.p.)), all failed to influence LSD-induced disruption of PPI. The dopamine DA(2like) receptor antagonist, haloperidol (0.1 and 0.2 mg/kg, s.c.), was without effect against an LSD-induced disruption of PPI. Finally, selective blockade of 5-HT(2A) but not 5-HT(2C) receptors completely abolished the locomotor hyperactivity induced by LSD. These findings provide empirical evidence to support the view that the hallucinogenic effects of LSD are mediated by a direct agonist effect at 5-HT(2A) receptors.     

Behavioral effects of 5-methoxy-N,N-dimethyltryptamine and dose-dependent antagonism by BC-105

The discriminative effects of 5-methoxy-N,N-dimethyltryptamine (5-OMeDMT) were studied in rats trained to discriminate 1.5 mg/kg or 3.0 mg/kg 5-OMeDMT from saline. A series of antagonist and generalization tests revealed that (1) antagonism of the 5-OMeDMT stimulus response by the presumed serotonin antagonist BC-105 depended on the dose of 5-OMeDMT, (2) the 5-OMeDMT stimulus generalized to LSD, and (3) like 5-OMeDMT, antagonism of the LSD generalization response by BC-105 depended on the dose of LSD. In a second study, with rats responding under a variable-interval (VI) 15-s schedule of reinforcement, doses of 1.0-3.0 mg/kg 5-OMeDMT significantly decreased response rate. Furthermore, the decrease in responding produced by the administration of 1.5 mg/kg (but not by 3.0 mg/kg) 5-OMeDMT was blocked by BC-105. This dose-dependent antagonism was of particular interest since the 1.5 mg/kg and 3.0 mg/kg dose of 5-O-MeDMT had essentially the same effect on responding when given alone. The results of both studies emphasize the importance of 5-OMeDMT dose in antagonism experiments.     

Cross-tolerance studies of serotonin receptors involved in behavioral effects of LSD in rats

Like hallucinogenic 5-HT₂ agonists, LSD (d-lysergic acid diethylamide) produces characteristic decreases in locomotor activity and investigatory behaviors of rats tested in a novel environment. Because LSD is an agonist at both 5-HT_1A and 5-HT₂ receptors, however, the respective influences of these different receptors in the behavioral effects of LSD remain unclear. In particular, the paucity of selective 5-HT_1A antagonists has made it difficult to assess the specific contribution of 5-HT_1A receptors to the effects of LSD. An alternative approach to the delineation of receptor-specific effects is the use of cross-tolerance regimens. In the present studies, rats were pretreated with saline, 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) (0.5 mg/kg SC), 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (1.0 mg/kg SC), or LSD (60 µg/kg SC), every 12 h for 5 or 8 days. Thirty-six hours later, rats were tested in a behavioral pattern monitor 10 min after injection of saline, 0.5 mg/kg 8-OH-DPAT, 1.0 mg/kg DOI, or 60 µg/kg LSD. As expected, tolerance to the decreases in locomotor activity produced by acute administrations of 8-OH-DPAT, DOI, or LSD occurred when rats were pretreated chronically with 8-OH-DPAT, DOI, or LSD, respectively. Furthermore, pretreatment with either 8-OH-DPAT or DOI produced cross-tolerance to LSD. These results support the hypothesis that the effects of LSD in this model reflect a combination of 5-HT_1A and 5-HT₂ effects and support the view that there is an interaction between 5-HT_1A and 5-HT₂ receptors.     

Discriminative properties of pentobarbital after repeated noncontingent exposure in gerbils

Lysergic acid diethylamide (LSD), 0.05 mg/kg and 0.20 mg/kg, significantly decreased plasma prolactin (PRL) levels in male rats. LSD, 0.20 mg/kg, also inhibits the increase in plasma PRL levels produced by chlorpromazine (CPZ), 5 mg/kg, and alpha-methylparatyrosine (AMPT), 50 mg/kg, both of which interfere with dopaminergic inhibition of PRL secretion. LSD was more potent than methysergide, a serotonin receptor blocker, in lowering plasma PRL levels and more potent than apomorphine, a known direct acting dopamine agonist, in blocking the increase in plasma PRL produced by quipazine, a 5-HT agonist. These results suggest LSD has potent dopamine agonist properties on the rat pituitary or hypothalamic dopamine receptors which directly or indirectly inhibit PRL secretion.     

LSD as an agonist at mesolimbic dopamine receptors

The dopamine agonist apomorphine (1.0 mg/kg i.p.) produced an enhanced stimulation of locomotor activity compared to control animals in rats injected bilaterally 14 days previously with 6-hydroxydopamine (6OHDA) into the nucleus accumbens. (+)-Lysergic acid diethylamide (LSD) also produced a marked stimulation of locomotor activity in the 6OHDA treated animals at a dose (1.0 mg/kg i.p.) which was ineffective in control rats. (+)-Bromo-lysergic acid diethylamide (2.0 mg/kg i.p.) did not stimulate locomotor activity in 6OHDA treated rats. The locomotor stimulation produced by LSD was blocked by pretreatment with the dopamine antagonist pimozide (0.5 mg/kg i.p.). It is suggested that LSD acts as an agonist at mesolimbic dopamine receptors.     

Facilitation and disruption by mescaline and 3,4-dimethoxyphenylethylamine of shock avoidance in rats

The effects of mescaline hydrochloride (4.95–79.2 mg/kg i.p.) and its non-hallucinogenic analogue 3,4-dimethoxyphenylethylamine hydrochloride (DMPEA) (12.5–100 mg/kg i.p.) on shock avoidance in a shuttlebox were studied in male Long-Evans rats trained to high (above 88%, good performers) or low (below 6%, poor performers) stable base-line avoidance rates. In good performers, mescaline and DMPEA caused a dose-dependent decrease in avoidance rate (ED 50's 44.6 and 39.2 mg/kg, respectively) without affecting presession (5-min adaptation peroid) or intertrial shuttlebox crossings. In poor performers, mescaline caused a dose-dependent increase in avoidance rate (ED 50=24.8 mg/kg) and intertrial crossings, without affecting presession crossings. The results suggest that mescaline, but not DMPEA, has dual facilitative and disruptive effects on avoidance behavior at similar dose ranges. The facilitative, but not the disruptive, effect may be related to changes in motor activity.     

The effect of serotonin depletion on the discriminability of LSD

Nine groups of rats were trained to discriminate LSD (0.12 mg/kg) from saline in a two-lever, water-reinforced, drug discrimination procedure. After stable discriminative performance was obtained (>95% correct), groups were administered one of several treatments which lower the concentration of serotonin (5-HT) in brain: (1) 12.5, 25, 50, 100 or 200 microgram of 5,7-dihydroxytryptamine (5,7-DHT) intraventricularly (IVT); (2) 3 X 100 mg/kg of p-chlorophenylalanine (PCPA) intraperitoneally (IP); or (3) 20 mg/kg of p-chloroamphetamine (PCA) IP. Control rats received either IVT injections of 5,7-DHT vehicle or IP injections of PCA or PCPA vehicles. Beginning 12 days after treatment, lever preference following various doses of LSD was determined. The results indicated that only the 200 microgram dose of 5,7-DHT and PCPA caused a significant potentiation of LSD-lever responding at the 0.03 mg/kg dose of LSD while all treatments except 12.5 and 25 microgram of 5,7-DHT resulted in significant depletion of 5-HT. Moreover, amount of 5-HT and percent LSD responding following 0.03 mg/kg LSD were not significantly correlated. It was concluded that 5-HT depletion, per se, cannot account for supersensitivity to the behavioral effects of LSD.     

Synthesis and evaluation of substituted 2-phenylcyclobutylamines as analogues of hallucinogenic phenethylamines: lack of LSD-like biological activity

cis- and trans-2-(2,4,5-trimethoxyphenyl)cyclobutylamine and trans-2-(2,5-dimethoxy-4-methylphenyl)cyclobutylamine were synthesized as conformationally restricted analogues of hallucinogenic phenylisopropylamines. In rats trained to discriminate saline from LSD (0.08 mg/kg, ip) in a two-lever drug discrimination paradigm, no generalization of the LSD stimulus to the cis trimethoxy compound occurred at doses up to 20 mg/kg. For both of the trans compounds, partial generalization of the LSD cue occurred at doses of 5 mg/kg or greater. In contrast, complete generalization occurred with trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine. The ED50 for this compound and the doses of the trans cyclobutyl homologues at which significant drug-appropriate responding occurred indicate that the latter are on the order of 50-75 times less potent than the cyclopropylamine analogue. The lack of generalization to the cyclobutylamines indicates either that their discriminative stimulus properties differ from LSD or that they lack discriminative effects.     

Distinct temporal phases in the behavioral pharmacology of LSD: dopamine D<Subscript>2</Subscript> receptor-mediated effects in the rat and implications for psychosis

Rationale The effect of LSD in humans has been described as occurring in two temporal phases. The behavioral effects in rats also occur in two temporal phases: an initial suppression of exploration followed by increased locomotor activity.Objectives We decided to investigate this phenomenon from the perspective that the pharmacology might have relevance to the neurochemical mechanisms underlying psychosis.Methods Twenty-five male Sprague–Dawley rats were trained to discriminate LSD (186 nmol/kg, 0.08 mg/kg, i.p.) with a 30-min preinjection time (LSD-30, N=12) and LSD (372 nmol/kg, 0.16 mg/kg, i.p.) with a 90-min preinjection time (LSD-90, N=13) from saline, using a two-lever, food-reinforced operant conditioning task.Results LSD (186 or 372 nmol/kg, 0.08 or 0.16 mg/kg) given 30 min prior to training produced a cue that was completely antagonized by 5-HT_2A antagonists and lasted no longer than 1 h. LSD (372 nmol/kg, 0.16 mg/kg) injected 90 min before training produced a cue that was not fully blocked by 5-HT_2A antagonists, but instead was significantly inhibited by haloperidol. In these rats, substitution no longer occurred with the 5-HT₂ agonists DOI or LSD (30 min preinjection), but full substitution was obtained with the D₂ agonists apomorphine, N-propyldihydrexidine, and quinelorane.Conclusion The discriminative stimulus effect of LSD in rats occurs in two phases, and these studies provide evidence that the later temporal phase is mediated by D₂ dopamine receptor stimulation. A second temporal phase that involves dopaminergic pathways would be consistent with the widespread belief that excessive dopaminergic activity may be an underlying cause of paranoid psychosis.     

Potentiation of tetrabenazine-induced behavioural depression by imipramine on a discrete-trial avoidance escape schedule

The tetrabenazine-imipramine interaction has been studied on a discrete-trial avoidance escape schedule in rats. In a large dose, imipramine (30 mg/kg i.p.) failed to antagonize the 10 mg/kg s.c. tetrabenazine-induced behavioural depression. 3.0–6.0 mg/kg imipramine +0.5 mg/kg tetrabenazine induced a statistically significant depression, while the same drugs alone (in similar dose) had no significant effect on responding. The depressant action of 1.0 mg/kg tetrabenazine was potentiated by imipramine pretreatment.     

Stimulus effects of ibogaine in rats trained with yohimbine, DOM, or LSD.

The stimulus effects of ibogaine were compared with those of yohimbine, an alpha 2-adrenoceptor antagonist, 2,5-dimethoxy-4-methylamphetamine (DOM), a 5-hydroxytryptamine2 (5-HT2) agonist, and lysergic acid diethylamide (LSD), a nonspecific 5-HT agonist. Rats were trained with either yohimbine (6 mg/kg), DOM (0.6 mg/kg), or LSD (0.1 mg/kg) vs. no treatment in a two-lever discrimination task. Tests of generalization were then conducted with ibogaine. In yohimbine-trained animals, 39.7% of responses following ibogaine (15 mg/kg) were on the drug-appropriate lever, but this response level was not significantly different from no treatment-appropriate responding. A response distribution that was significantly different from responding under both drug and no treatment training conditions was observed in DOM-trained rats after administration of 15 mg/kg ibogaine. Pizotyline (BC-105) blocked all DOM-appropriate responding produced by ibogaine. In LSD-trained animals, 20 mg/kg ibogaine mimicked LSD. Pizotyline blocked LSD-appropriate responding produced by ibogaine in five of six animals. The present data suggest the involvement of 5-HT2 receptor activity, and the possibility of a 5-HT1A contribution, in the stimulus properties of ibogaine.     

Naloxone enhancement of DMT and LSD-25 induced suppression of food-rewarded bar pressing behavior in the rat

The narcotic antagonist naloxone was tested to determine its possible interaction with N,N-dimethyltryptamine (DMT) and lysergic acid diethylamide-25 (LSD) in adult male Holtzman rats trained to press a bar on a fixed-ratio four schedule (FR₄), i.e., every fourth press earned a reward of 0.01 ml sugar sweetened milk. LSD (0.1 mg/kg) or increasing doses of DMT (1.0, 3.2, and 10.0 mg/kg) were administered i.p. to disrupt food-rewarded fixed ratio bar pressing in a dose related fashion. Pretreatment (5–10 min) with behaviorally ineffective doses of naloxone (1.0–5.6 mg/kg) dramatically enhanced the effects of DMT and LSD. The content of DMT in the brain and liver of rats injected with DMT alone (10 mg/kg) and with a 5 min pretreatment of naloxone (3.2 mg/kg) was determined by radiochemical analysis at 30 and 90 min after ¹⁴C-DMT injection. There was no significant difference for either brain or liver ¹⁴C-DMT levels when control DMT rats were compared with the naloxone pretreated rats. These results seem to rule out interference by naloxone with the metabolism of DMT as a mechanism of the observed behavioral potentiation.     

The acute effects of monoamine reuptake inhibitors on the stimulus effects of hallucinogens.

In a previous study it was observed that fluoxetine potentiates the stimulus effects of lysergic acid diethylamide (LSD). In the present investigation, stimulus control was established in groups of rats using as training drugs the hallucinogens lysergic acid diethylamide (LSD); 0.1 mg/kg), (-)-2,5-dimethoxy-4-methylamphetamine [(-)-DOM; 0.56 mg/kg], ibogaine (10 mg/kg), and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT; 3 mg/kg). A two-lever, fixed-ratio 10, positively reinforced task with saline controls was employed. The hypotheses tested were that (a) monoamine uptake inhibitors other than fluoxetine potentiate the discriminative effects of LSD, and (b) hallucinogens other than LSD are potentiated by acute pretreatment with monoamine uptake inhibitors. The effects of a range of doses of each of the training drugs were determined both alone and following pretreatment with the monoamine reuptake inhibitors fluoxetine, fluvoxamine, and venlafaxine. In LSD-trained subjects, all three reuptake inhibitors caused a significant increase in LSD-appropriate responding. Similar results were observed in rats trained with (-)-DOM and with ibogaine. In 5-MeO-DMT-trained subjects, only fluoxetine resulted in an enhancement of drug-appropriate responding. The reuptake inhibitors given alone elicited varying degrees of responses appropriate for the respective training drugs. For fluoxetine in rats trained with LSD and ibogaine, for venlafaxine in LSD trained, and for fluvoxamine in (-)-DOM trained, the degree of responding met our criterion for intermediate responding, i.e., significantly different from both training conditions. Subsequent experiments in (-)-DOM-trained subjects examined a range of doses of each of the reuptake inhibitors in combination with a fixed dose of (-)-DOM (0.1 mg/kg), which alone yielded about 50% (-)-DOM-appropriate responding. With the exception of the point obtained with the highest dose of venlafaxine, all data were compatible with additivity of effects rather than true potentiation. In summary, the present data extend our previous observation of the augmentation of the stimulus effects of LSD by fluoxetine to include other hallucinogens. The mechanisms by which these interactions arise and possible differential effects of acute and chronic treatment remain to be established.