Hallucinogens potentiate responses to serotonin and norepinephrine in the facial motor nucleus

The present investigation was designed to determine the effect of hallucinogens on the facilitating action of serotonin (5-HT) and norepinephrine (NE) in the facial nucleus. Intravenous administration of d-lysergic acid diethylamide (LSD, 5–10 μg/kg), mescaline (0.5–1.0 mg/kg), or psilocin (0.5–1.0 mg/kg) had no effect by themselves on the glutamate-induced excitation of facial motoneurons. In contrast, the facilitation of facial neuron excitation by iontophoretically applied 5-HT and NE was enhanced 6–10 fold by these hallucinogens. The LSD-enhanced responses to 5-HT and NE continued for at least 4 hours after administration of the hallucinogen. Iontophoretic application of LSD or mescaline (low currents) also markedly potentiated the facilitating effect of 5-HT and NE. Higher currents of LSD (15–40 nA) temporarily antagonized the response to 5-HT. The nonhallucinogen ergot derivatives lisuride and methysergide failed to potentiate the facilitating effects of 5-HT or NE. These observations suggest that hallucinogens potentiate the effect of monoamines on facial motoneurons by increasing the sensitivity of 5-HT and NE receptors. A novel mechanism regarding the psychedelic effects of hallucinogens is discussed.     

Tricyclic antidepressant drugs: Attenuation of excitatory effects of d-lysergic acid diethylamide (LSD) on acoustic startle response

At a dose of 5 mg/kg, the tricyclic antidepressant drugs chlorimipramine (CIMI), desipramine (DMI), imipramine (IMI), and chlordesipramine (C-DMI) all blocked the excitatory effects of a low dose (30 μg/kg) of LSD on the acoustic startle response in the rat. Over a dose range from 1–5 mg/kg, CIMI and DMI were about equally potent in blocking the LSD effect, despite the fact that both drugs actually increased brain levels of LSD. In contrast, α-methyl-p-tyrosine did not block the effect of LSD on startle. By themselves, DMI, IMI and C-DMI increased startle amplitude 20–30% whereas CIMI alone had no effect on startle. The ability of CIMI and IMI to block the excitatory effect of LSD on startle is consistent with the hypothesis that prior cessation of raphe cell firing caused indirectly by these drugs with no resultant change in 5-HT availability should pre-empt the ability of LSD to increase startle by directly inhibiting raphe cell firing and decreasing 5-HT availability. The finding that the other tricyclics also block the effect of LSD is not explained by that hypothesis. Results are discussed in terms of the serotonin hypothesis of the action of hallucinogenic drugs on behavior.     

Electrophysiological assessment of putative antagonists of 5-hydroxytryptamine receptors: a single-cell study in the rat dorsal raphe nucleus

The intravenous administration of low doses of lysergic acid diethylamide (LSD) or of the selective 5-hydroxytryptamine1A (5-HT1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) depresses the firing activity of dorsal raphe 5-HT-containing neurons, presumably via the activation of 5-HT1A receptors. The present studies were undertaken to determine the effect of different types of 5-HT receptor antagonists on this effect of LSD and 8-OH-DPAT. (-)-Propranolol (2 mg/kg i.v.), methiothepin (2 mg/kg i.p., twice daily for 4 days followed by an additional dose of 2 mg/kg i.p., prior to the experiment), pelanserine (0.5 mg/kg i.v.), and indorenate (125 micrograms/kg i.v.) failed to block the effects of either LSD or 8-OH-DPAT on the firing activity of 5-HT neurons of the dorsal raphe nucleus. However, spiperone (1 mg/kg i.v.) significantly reduced the effect of both LSD and 8-OH-DPAT. These results indicate that, among the five putative 5-HT receptor antagonists tested, only spiperone can antagonize the suppressant effect of 5-HT receptor agonists on the firing of dorsal raphe 5-HT neurons.     

Behavioral and biochemical evidence for serotonergic actions of tetrahydro-β-carbolines

In two groups of rats trained to discriminate LSD (0.1 mg/kg or 0.24 mg/kg) from saline, tetrahydro-β-carboline (THBC; 1–12 mg/kg as free base) and its derivative 6-methoxy-THBC (1–12 mg/kg as free base) substituted partially for LSD. The substitution of THBC for 0.1 mg/kg of LSD was analyzed further with antagonism tests in 16 animals and was attenuated by the serotonin (5-HT) antagonist BC-105 (pizotifen; 3 mg/kg) but not by the dopamine (DA) antagonist haloperidol (0.1 mg/kg). It was abolished by pre-treatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (100 mg/kg/day for 3 days). In addition, THBC was found to inhibit ³H-LSD binding to homogenates of rat frontal cortex with an IC₅₀ value of 4 μM which is similar to that previously reported for other 5-HT agonists. These data indicate that THBCs exert potent 5-HT agonist actions. Since THBCs have recently been found in mammalian brain and other tissues, the present results are of interest in relation to a possible role of these substances in endogenous psychosis.     

Electrophysiological evidence for a dopaminergic action of LSD: depression of unit activity in the substantia nigra of the rat.

LSD (25–50 μg/kg, i.v.) significantly decreased the firing rate of 78% of the dopamine-containing neurons in the substantia nigra of chloral hydrate anesthetized rats. In a subgroup of neurons (22%), LSD either had no clear effect or caused a slight excitation. On the other hand, brom-LSD (100 μg/kg, i.v.), a non-hallucinogenic congener of LSD, had no effect on 71% of dopaminergic cells and slightly reduced the firing rate with 29% of the units. Pretreatment with haloperidol (0.1 mg/kg) blocked the inhibitory effects of LSD, and haloperidol injected following LSD reversed its depressive effects. Non-dopaminergic neurons in the region of the substantia nigra typically showed large increases in firing rate in response to LSD administration. The inhibitory effects of LSD on dopamine-containing neurons are probably not attributable to the serotonergic properties of LSD, since 5-methoxy N,N dimethyltryptamine (25–100 μg/kg), which has central serotonergic properties similar to those of LSD, produced exclusively excitatory effects on the firing rate of dopaminergic cells. These electrophysiological results are consistent with recent behavioral and neurochemical data which suggest that LSD can act as a dopamine agonist in the CNS.     

Alterations of serotonin and LSD receptor binding following repeated administration of LSD.

Repeated administration of LSD to rats (100 μg/kg every 6 hours for 4 days) resulted in significant decreases in both the K_D (?17 &; ?23%) and Bmax (?25 %&; ?30%) for [³H]—5HT binding in forebrain and brainstem plus spinal cord. [³H] — LSD binding showed significant changes in Bmax values (?19%) in forebrain and brainstem plus spinal cord, while K_D values were not significantly changed. Neither a single injection of LSD (100 μg/kg) nor repeated administration of brom-LSD (100 μg/kg every 6 hours for 4 days) produced any significant changes in binding. In addition, repeated LSD administration produced no significant changes in [³H] — spiroperidol binding.     

Concurrent Determination of Brain Dopamine and 5-Hydroxytryptamine Turnovers in Individual Freely Moving Rats Using Repeated Sampling of Cerebrospinal Fluid

5-Hydroxytryptamine (5-HT) turnover and dopamine (DA) turnover values were obtained in individual conscious rats by measuring the rates of accumulation of 5-hydroxyindoleacetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in cisternal CSF samples taken from each rat at 0, 30, and 60 min after probenecid (200 mg/kg i.p.) administration. In a separate experiment, 5-HT and DA turnover values were determined in CSF, striatum, and rest of brain of groups of rats killed 0, 30, or 60 min after probenecid. Whole brain turnover values were calculated from striatal and rest of brain values. Mean turnover values using CSF were comparable with both procedures. DA turnover values were greater when based on total (i.e., free + conjugated) DA metabolites than when based on free metabolites. After partial inhibition of monoamine synthesis with the decarboxylase inhibitor DL-alpha- monofluoromethyl -DOPA ( MFMD , 100 mg/kg p.o.) DA and 5-HT turnover values were comparably reduced in whole brain, rest of brain, and CSF but more markedly reduced in the striatum. Mean DA and 5-HT turnover values obtained using CSF were similar with probenecid doses over the range 150-250 mg/kg i.p. but were variable when repeatedly determined in the same rats after administration of 200 mg/kg probenecid. Results in general show that the CSF procedure may be used to determine concurrently both 5-HT and DA turnover (when estimated from the sum of total but not free metabolites) and that it provides a good index of whole brain turnover of these transmitters in the conscious individual rat.     

Turning in MFB-lesioned rats and antagonism of neuroleptic-induced catalepsy after lisuride and LSD.

The effects of lisuride, d-lysergic acid diethyl amide (LSD) and apomorphine were studied in rats with unilateral destruction of nigro-striatal nerve terminals either with 6-hydroxydopamine (6-OHDA) or 5, 6-dihydroxytryptamine (5,6-DHT). Lisuride at the dose of 50 μg kg^?1 i.p. induced contralateral turning for more than 4 hours while the circling induced by LSD (200 μg kg^?1) and apomorphine (1 mg kg^?1) persisted for only one hour. Lisuride, a compound stimulating both dopamine (DA) and 5-hydroxytryptamine (5-HT) receptors induced a more intense turning in 6-OHDA than in 5,6-DHT lesioned rats. This might indicate a modulation of 5-HT on rotational behavior. Haloperidol (1 mg kg^?1 i.p.) antagonized both lisuride- and LSD-induced turning. LSD, and much more persistently lisuride, counteracted the prochlorperazine-induced catalepsy. These findings correlate with the biochemical data indicating that lisuride is a very potent agonist at central dopaminergic receptors.     

Dose-dependent dual effect of corticosterone on cerebral 5-HT metabolism

The action of 1.0 and 10.0 mg/kg (i.p.) of corticosterone on serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) contents and on serotonin turnover, measured by an MAO-inhibitor method, was studied at 30 and 120 min after administration. A 1.0 mg/kg dose of corticosterone increased the serotonin content and turnover in the hypothalamus and mesencephalon 30 min after administration; however, it was ineffective on dorsal hippocampus and frontal and parietal cortex. 5-HIAA content did not change significantly in any of the brain areas studied. A 10.0 mg/kg dose of corticosterone decreased the serotonin content and turnover in the hypothalamus and mesencephalon; it was ineffective in other brain areas investigated. 5-HIAA content significantly decreased in the hypothalamus while it increased in the mesencephalon and dorsal hippocampus. In the parietal and frontal cortex, 5-HIAA content did not change following administration of 10.0 mg/kg of corticosterone. At 120 min after corticosterone administration, neither 5-HT content and turnover nor 5-HIAA content showed any change in the brain areas investigated. The results suggest that corticosteroids might change the activity of the brain serotoninergic system in a dose- and time-dependent manner, and in this way the serotoninergic system might play an important role in mediation of the corticosteroid effect exerted on brain function.     

LSD and related drugs as DA antagonists: Receptor-mediated effects on the synthesis and turnover of DA

We have earlier shown that d-lysergic acid diethylamide, LSD and its 2-bromo derivative, BOL like the dopamine (DA) antagonists haloperidol increased the rate of the $\text{in vivo}$ tyrosine hydroxylation in the striatum measured as the accumulation of DOPA after decarboxylase inhibition.Now we have found that several agents structurally similar to LSD increase the $\text{in vivo}$ tyrosine hydroxylation in the striatum. Psilocybin (50 mg/kg i.p.) and N,N-dimethyltryptamine (50 mg/kg i.p.) caused a short-lasting increase of DOPA accumulation, while mescaline (10 – 100 mg/kg i.p.) did not increase the DOPA accumulation. A marked increase of DOPA accumulation was observed after the 5-hydroxytryptamine (5-HT) antagonist cyproheptadine. The effects of LSD and structurally related drugs on the DOPA accumulation in the striatum appear to be mediated via DA antagonism at receptor level. However, these agents may control the DOPA accumulation via other receptors than DA receptors e.g. 5-HT receptors. A control of DOPA accumulation via receptors other than DA receptors appears to be predominant after treatment with N,N-dimethyltryptamine or psilocybin.     

Effects of Methiothepin and Lysergic Acid Diethylamide on Serotonin Release In Vitro and Serotonin Synthesis In Vivo: Possible Relation to Serotonin Autoreceptor Function

Abstract: An in vitro system characterizing the presyn- aptic serotonin (5-HT) autoreceptor which controls the release of 5-HT from rat brain slices is described. Using this system, methiothepin (1–10 μ M) demonstrated 5-HT autoreceptor antagonist activity -by enhancing 5-HT release, while several recognized postsynaptic 5-HT receptor antagonists were inactive: mianserin, cinanserin, cyproheptadine, methysergide. The activity of methiothepin was highest in hypothalamic slices and lowest in striatal slices and was inhibited by the autoreceptor agonists lysergic acid diethylamide (LSD) and 5-methoxy- tryptamine (5-MT). The reversal of the methiothepin-enhanced 5-HT release from hypothalamic slices by LSD was not influenced by 0.3 μ M tetrodotoxin. The peripheral administration of LSD to rats has been shown to reduce 5-HT synthesis and release by a mechanism thought to involve, in part, an autoreceptor-mediated reduction in impulse flow of 5-HT neurons. In the present experiments, intraperitoneal injection of methiothepin antagonized the LSD-induced reduction in hypothalamic 5-HT synthesis (5-hydroxytryptophan accumulation) while exerting no influence by itself. Conversely, compounds which were not active as 5-HT autoreceptor antagonists in vitro (i.e., cyproheptadine, methysergide, cinanserin) did not influence the effect of LSD on 5-HT synthesis. Further, the reduction in 5-hydroxytryptophan (5-HTP) accumulation by LSD showed regional differences in inhibition by methiothepin (hypothalamus > cortex > striatum) which paralleled the autoreceptor antagonist activity of methiothepin in vitro. These data suggest that similar autoreceptor mechanisms control 5-HT release and synthesis in terminal 5-HT projection areas and that the reduction in 5-HT accumulation by LSD and the antagonism by methiothepin may represent a useful biochemical measure of 5-HT autoreceptor activity in vivo.     

Perturbation of Rat Brain Serotonergic Systems Results in an Inverse Relation Between Substance P and Serotonin Concentrations Measured in Discrete Nuclei

Since substance P (SP) has been demonstrated to coexist with serotonin (5-HT) in the same population of neurons in the descending raphe system, we have studied the possibility of interactions between these neurotransmitters in other brain areas. Brain nuclei were punched from frozen 300-micron slices of rat brain and extracted with 0.1 M HCIO4 or 2 M acetic acid prior to assay, respectively, of 5-HT content by HPLC with electrochemical detection or SP content by specific radioimmunoassay. Ten days after injection of rats with the 5-HT neurotoxin P-chloroamphetamine (PCA, 10 mg/kg, B.W., i.p.) or 3 days after 5-HT synthesis blockade with p-chlorophenylalanine (PCPA, 300 mg/kg, B.W., i.p.), the 5-HT content of all brain nuclei studied was reduced by means of, respectively, 50% and 81%. In PCA-treated animals, the SP content of the periaqueductal grey matter was significantly increased; PCPA treatment caused, in addition, large increases in the SP content of five other brain nuclei. Blockade of 5-HT receptors by methysergide (15 mg/kg for 5 days) did not significantly change 5-HT levels or turnover, but resulted in 50-200% increases in the SP content of 10 of the 28 brain nuclei studied. Significant decreases in the SP content of numerous areas were seen following treatments (pargyline 30 mg/kg, alone or in combination with 5-hydroxytryptophan, 60 mg/kg) that simultaneously increased 5-HT levels. These results illustrate the modulation of distinct SP-containing systems of the rat brain by perturbation of central serotoninergic pathways and indicate a reciprocal relationship between the SP and 5-HT concentrations of numerous brain nuclei, in particular n. striae terminalis, n. raphe dorsalis, n. accumbens, n. septi, substantia grisea centralis, and n. raphes medianus.     

Stress-accentuation of the LSD-induced disaggregation of brain polysomes

The application of three types of stress; restraint, food deprivation or epinephrine injection markedly accentuated the disaggregation of rabbit brain polysomes to monosomes induced by LSD (25 μg/kg) whereas no shift of polysomes to monosomes was found with any of the stress treatments alone. LSD when administered intravenously at a very low dose of 1 μg/kg and combined with the restraint procedure produced a massive brain polysome shift. LSD alone at this dosage did not induce a disaggregation of polysomes. Elevations in plasma corticosteroid levels relative to control were found following LSD administration with or without the stressing procedures. LSD and certain elements of environment and physiological arousal appear to have a synergistic effect on disrupting the protein synthesis apparatus of brain.     

Determination of Brain 5-Hydroxytryptamine Turnover in Freely Moving Rats Using Repeated Sampling of Cerebrospinal Fluid

A simple technique is described for repeated sampling of cerebrospinal fluid (CSF) from the freely moving rat and its use in the determinations of 5-hydroxytryptamine (5-HT) turnover validated. A catheter, constructed from polyethylene tubing (PP10) was implanted via a cranial approach into the cisterna magna and x-ray studies confirmed that the catheter avoided the cerebellum. 5-HT turnover was determined from the rate of rise of 5-hydroxyindoleacetic acid (5-HIAA) in both CSF and brain following an injection of probenecid (200 mg/kg i.p.). Concentrations of 5-HIAA, 5-HT and tryptophan were determined by high pressure liquid chromatography. Turnover values for individual rats were obtained using CSF samples. After p-chlorophenylalanine treatment (when brain 5-HT was depleted by 43%) 5-HT turnover values obtained were comparably reduced whether determined from CSF (-67%) or brain (-74%). Thus differences of rat brain 5-HT turnover are proportionately reflected by CSF measurements. The method for sampling of CSF should be applicable in a wide range of pharmacological and physiological situations.     

The contribution of serotonin 5-HT2C and melanocortin-4 receptors to the satiety signaling of glucagon-like peptide 1 and liragultide, a glucagon-like peptide 1 receptor agonist, in mice

Glucagon-like peptide 1 (GLP-1), an insulinotropic gastrointestinal peptide produced mainly from intestinal endocrine L-cells, and liraglutide, a GLP-1 receptor (GLP-1R) agonist, induce satiety. The serotonin 5-HT2C receptor (5-HT2CR) and melanoroctin-4 receptor (MC4R) are involved in the regulation of food intake. Here we show that systemic administration of GLP-1 (50 and 200 μg/kg)-induced anorexia was blunted in mice with a 5HT2CR null mutation, and was attenuated in mice with a heterozygous MC4R mutation. On the other hand, systemic administration of liraglutide (50 and 100 μg/kg) suppressed food intake in mice lacking 5-HT2CR, mice with a heterozygous mutation of MC4R and wild-type mice matched for age. Moreover, once-daily consecutive intraperitoneal administration of liraglutide (100 μg/kg) over 3 days significantly suppressed daily food intake and body weight in mice with a heterozygous mutation of MC4R as well as wild-type mice. These findings suggest that GLP-1 and liraglutide induce anorexia via different central pathways.     

Local Cerebral Glucose Utilisation Following Indoleamine- and Piperazine-Containing 5-Hydroxytryptamine Agonists

Substances with varying structural components have been shown to have 5-hydroxytryptamine (5-HT)-like properties in the CNS. In this study, putative 5-HT agonists with indoleamine moeities--lysergic acid diethylamide (LSD) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT)--and with piperazine moieties--quipazine (Quip) and 6-chloro-2-(1-piperazinyl)pyrazine (6-CPP) were administered to rats. Local cerebral glucose utilisation was measured using the [14C]2-deoxyglucose autoradiographic technique. It was found that in most cerebral structures, these substances produced dose-dependent reductions in glucose utilisation. However, Quip and 6-CPP increased glucose utilisation in specific areas of the diencephalon (e.g., nucleus reuniens) and produced a biphasic effect in some but not all extrapyramidal structures (e.g., ventromedial caudate nucleus). No such increases in local cerebral glucose utilisation were measured following LSD or 5-MeODMT administration. These results indicate that although similarities exist between the effects of indoleamine- and piperazine-containing 5-HT agonists on local cerebral glucose utilisation there are also significant differences in the overall patterns of response produced.     

Effects of serotine receptors agonists, TFMPP and CGS12066B, on regional serotonin synthesis in the rat brain: an autoradiographic study

The effects of acute and repeat administration of the serotonin (5-HT)(1) agonists TFMPP [N -(3-trifluoromethyl)phenylpiperazine hydrochloride] and CGS12066B [7-trifluoromethyl-4- (4-methyl-1-piperazinyl)pyrrolo[1,2-a ]-quinoxaline dimaleate] were evaluated on 5-HT synthesis rates using the alpha-[(14) C]methyl-l-tryptophan (alpha-MTrp) autoradiographic method. In the acute treatment study, TFMPP (10 mg/kg) and CGS12066B (5 mg/kg) were injected intraperitoneally 30 min before an alpha-MTrp injection. In an acute study TFMPP reduced overall brain 5-HT synthesis, in the dorsal and median raphe, and in almost all of their projection areas, with the exception of the parietal, sensory-motor, and frontal cortices, the accumbens nucleus, and the caudate. Acute CGS12066B treatment did not have overall significant effect, but the rates did decrease in the cell body areas of 5-HT neurons. In a 7-day treatment with TFMPP (10 mg/kg/day) or CGS12066B (5 mg/kg/day), the 5-HT synthesis rates (24 h after last dose) decrease, with both compounds, in almost all of the nerve terminal structures. TFMPP reduced the synthesis in the dorsal and median raphe, while CGS12066B reduced it only in the dorsal raphe. This data suggests that after a 7-day treatment with TFMPP and CGS12066B, the rate of 5-HT synthesis in the dorsal raphe is restored and is reduced in many projection areas. The observed effects in the 7-day treatment could also be related to actions through the postsynaptic 5-HT(1B) sites and/or other 5-HT receptors since this compounds have limited selectivity.     

THE EFFECTS OF REPEATED-LYSERGIC ACID DIETHYLAMIDE INJECTIONS ON CATECHOLAMINE LEVELS AND TYROSINE HYDROXYLASE ACTIVITY IN RAT BRAIN REGIONS

Daily injections of 100 μg/kg of d -lysergic acid diethylamide (LSD) for 14 days produced a significant decrease in the dopamine level in rat brain corpus striatum which was still apparent 15 days after the last LSD treatment. Further LSD injections did not change the amount of dopamine depletion. In cerebral cortex, 14 days of LSD injections produced a significant decrease in the norepinephrine level and a significant increase in tyrosine hydroxylase activity. The elevated tyrosine hydroxylase activity was still present 15 days after the final LSD injection but only in those animals receiving daily vehicle injections during this period. Pre-treatment of rats with daily saline injections for 2 weeks before the 2 week period of LSD treatment prevented both the reduced norepinephrine content and elevated tyrosine hydroxylase activity usually found 24 h after the last LSD injection.     

Increased behavioural activity of rats in forced swimming test after partial denervation of serotonergic system by parachloroamphetamine treatment

The present study aimed at characterizing the effect of partial 5-HT denervation by parachloroamphetamine (PCA), a 5-HT selective neurotoxin, on forced swimming behaviour and monoamine levels in several rat brain regions. PCA was administered intraperitoneally in two independent experiments in doses of 2, 4 and 6 mg/kg and in doses 1, 2, 4 mg/kg, respectively. PCA (2 mg/kg) reduced immobility in the forced swimming test in the Experiment 1 and according to Experiment 2 this is explained by increased swimming time. Dose-dependent reductions in 5-HT and 5-HIAA levels were found in all brain regions studied, and the maximal effects were of a similar magnitude. In septum, the effect of PCA took more time to develop. The effects of the lowest dose of PCA suggest that the neurotoxin affects not only the dorsal raphe projection areas but also the fine axons which arise from the median raphe. alpha2-Adrenoceptors and beta-adrenoceptors in cerebral cortex were not affected by the PCA treatment. Binding affinity of the 5-HT(1A) receptors was higher after all doses of PCA. On the second exposure to the forced swimming the time spent in swimming was found to be negatively and the time spent in immobile posture positively correlated with serotonin turnover in frontal cortex. The time spent in struggling on the second exposure to test was found to be negatively correlated with KD of beta-adrenoceptor binding in cerebral cortex. These data suggest that partial 5-HT denervation with low doses of PCA, which elicits a specific pattern of neurodegeneration, results in an increased behavioural activity, and that the traditional interpretation of the measures in forced swimming test, despite of the test's predictive power in revealing antidepressants acting on monoaminergic systems, is not adequate for studies on the neurochemical basis of depression.     

Dopamine agonist pretreatment alters LSD's electrophysiological action from dopamine agonists to antagonist.

LSD (50 μg/kg, i.v.) significantly depressed the discharge rate of dopamine-containing neurons in the substantia nigra of chloral hydrate anesthetized rats. However, when this same dose of LSD was administered to rats whose nigral cell discharge had been reduced 45% below baseline by d-amphetamine (mean dose = 1.45 mg/kg, i.v.), the discharge rate was significantly increased (typically returning to the pre-amphetamine baseline). A similar pattern was observed when LSD was administered to apomorphine-pretreated animals. Brom-LSD also produced these reversal effects. These effects of LSD resemble those of classical central dopamine antagonists such as haloperidol. We hypothesize that the shift in LSD's action from that of dopamine agonist to antagonist by prior dopamine agonist treatment may be mediated by a conformational shift in the state of the dopamine receptor.