This rat study (2014) found that repeated LSD administration to rats exhibits an anti-depressive effect in the animals, which the authors discuss in terms of a rebalancing of neurological signaling.
A re-balance of postsynaptic serotonin (5-HT) receptor signalling, with an increase in 5-HT1A and a decrease in 5-HT2A signalling, is a final common pathway multiple antidepressants share. Given that the 5-HT1A/2A agonist lysergic acid diethylamide (LSD), when repeatedly applied, selectively downregulates 5-HT2A, but not 5-HT1A receptors, one might expect LSD to similarly re-balance the postsynaptic 5-HT signalling. Challenging this idea, we use an animal model of depression specifically responding to repeated antidepressant treatment (olfactory bulbectomy), and test the antidepressant-like properties of repeated LSD treatment (0.13 mg/kg/d, 11 d). In line with former findings, we observe that bulbectomised rats show marked deficits in active avoidance learning. These deficits, similarly as we earlier noted with imipramine, are largely reversed by repeated LSD administration. Additionally, bulbectomised rats exhibit distinct anomalies of monoamine receptor signalling in hippocampus and/or frontal cortex; from these, only the hippocampal decrease in 5-HT2 related [35S]-GTP-gamma-S binding is normalised by LSD. Importantly, the sham-operated rats do not profit from LSD, and exhibit reduced hippocampal 5-HT2 signalling. As behavioural deficits after bulbectomy respond to agents classified as antidepressants only, we conclude that the effect of LSD in this model can be considered antidepressant-like, and discuss it in terms of a re-balance of hippocampal 5-HT2/5-HT1A signalling.
LSD is a serotonergic hallucinogen with high affinity for multiple serotonin receptor subtypes, notably 5-HT1A and 5-HT2A. Earlier research indicates that long-term treatment with conventional antidepressants tends to downregulate 5-HT2A receptors (particularly in frontal cortex) while increasing hippocampal 5-HT1A responsiveness, and that repeated—but not acute—administration of LSD selectively downregulates 5-HT2A without affecting 5-HT1A. This pattern raises the possibility that repeated LSD might ‘‘re-balance’’ postsynaptic 5-HT signalling in a manner analogous to established antidepressants. Buchborn and colleagues set out to test this idea using an animal model that specifically responds to repeated antidepressant treatment: bilateral olfactory bulbectomy in rats. The study aimed to determine whether repeated LSD administration (subchronic dosing) would produce antidepressant-like effects on a conditioned active avoidance (pole-jumping) task and whether it would normalise forebrain 5-HT1A/5-HT2 signalling. Because LSD is not selective, the investigators also measured broader monoaminergic signalling (beta-adrenergic, dopamine, noradrenaline) to assess specificity. Behavioural testing and receptor assays (radioligand binding and [35S]-GTP-γ-S functional coupling) were the principal outcome measures.
Papers cited by this study that are also in Blossom
Bonson, K. R. · Neuropsychopharmacology (1996)
Carhart-Harris, R. L., Leech, R., Williams, T. M. et al. · British Journal of Psychiatry (2018)
Cohen, S. · Journal of Nervous and Mental Disease (1980)
Grob, C. S., Danforth, A. L., Chopra, G. S. et al. · JAMA Psychiatry (2011)
Male Wistar rats (average ~400 g) were housed under standard laboratory conditions. At seven weeks of age animals underwent either bilateral olfactory bulbectomy or sham surgery; completeness of ablation was checked after behavioural experiments. Bulbectomy followed standard stereotactic aspiration of the olfactory bulbs, with sham animals receiving identical surgical handling except for bulb removal. Lysergide [(R,R)-tartrate] was administered subcutaneously at 0.13 mg/kg once daily for 11 days. Treatment began five days before behavioural testing and continued until 24 h before decapitation; injections were given two hours after each test session to minimise acute interference with learning. Control animals received saline. Assignment to the four experimental groups (sham/saline, sham/LSD, bulb/saline, bulb/LSD) was randomised. Behavioural outcome was assessed in the one-way active avoidance (pole-jumping) paradigm. Testing occurred eight weeks after surgery on five consecutive days (10 trials per day). Each trial presented an 80 dB buzzer conditioned stimulus (CS) followed from the fourth second by an overlapping electrical foot shock (unconditioned stimulus, US; 0.2–0.4 mA adjusted per animal). Trials lasted up to 20 s and were terminated if the rat jumped onto a pole; measures recorded were successful escapes (≤20 s) and avoidances (conditioned responses ≤4 s). Neurochemical assays were performed 24 h after the last treatment on dissected frontal cortex and hippocampus. 5-HT2A receptor density was estimated by ketanserin-sensitive [3H]spiroperidol binding on membrane preparations and expressed as fmol per mg protein. Functional receptor signalling was assessed by agonist-stimulated [35S]-GTP-γ-S binding, a measure of G-protein coupling; tissue was incubated with selective agonists (alpha-methylserotonin for 5-HT2, 8-OH-DPAT for 5-HT1A, isoprenaline for β-adrenergic, plus serotonin, dopamine and noradrenaline) and results expressed as Emax (% stimulation over basal). Neurochemical determinations were performed at least in duplicate; neurochemical sample sizes reported as n=4–6 per group for mean+SEM values. Statistical analysis of avoidance learning used a two-factor ANOVA with repeated measures (mixed model) to test time and group effects, followed by pairwise contrasts. Intergroup comparisons for specifically bound radioactivity used planned nonparametric Mann–Whitney U-tests. Significance was set at p<0.05.
Behavioural results: Bulbectomised rats showed marked deficits in active avoidance learning in the pole-jumping task, consistent with previous reports. Repeated LSD treatment largely reversed these avoidance-learning deficits in the bulbectomised group, whereas sham-operated rats did not show performance benefits from LSD. The extracted text does not provide the detailed ANOVA statistics or exact group n for the behavioural measures. 5-HT2A receptor binding ([3H]spiroperidol, ketanserin-sensitive): In the hippocampus, bulbectomy produced a trend towards increased ketanserin-sensitive binding compared with sham/saline (sham/saline vs bulb/saline: U=4, p=0.095). Repeated LSD partially counteracted this trend; the direct comparison between bulb/saline and bulb/LSD fell short of significance (U=6, p=0.063), and there was no significant difference between sham/saline and bulb/LSD (U=11, p=0.46). In sham animals, repeated LSD did not affect hippocampal ketanserin-sensitive binding (sham/saline vs sham/LSD: U=11, p=0.46). In the frontal cortex, bulbectomy had no significant effect on ketanserin-sensitive binding (sham/saline vs bulb/saline: U=9, p=0.27), but LSD induced a significant increase in frontal ketanserin-sensitive binding in sham animals (sham/saline vs sham/LSD: U=0, p=0.002). [35S]-GTP-γ-S binding (agonist-stimulated G-protein coupling): The hippocampal decrease in alpha-methylserotonin (alpha-MS) stimulated [35S]-GTP-γ-S binding seen after bulbectomy was reversed by subchronic LSD (bulb/saline vs bulb/LSD: U=6, p=0.032). By contrast, in sham-operated animals LSD caused a desensitisation of alpha-MS stimulated hippocampal [35S]-GTP-γ-S binding (sham/saline vs sham/LSD: U=3, p=0.0015). Other bulbectomy-associated changes included a hippocampal decrease in isoprenaline- and noradrenaline-stimulated signalling (sham/saline vs bulb/saline: U=0, p=0.004; U=2, p=0.057, respectively); these effects were not reversed by LSD. Frontocortical increases in alpha-MS, 8-OH-DPAT and isoprenaline stimulated [35S]-GTP-γ-S binding associated with bulbectomy were reported but were not normalised by LSD. Hippocampal signalling stimulated by 8-OH-DPAT (5-HT1A), serotonin and dopamine showed no significant influence of bulbectomy or of the interaction with LSD (all reported as non-significant). Finally, in the frontal cortex of sham animals, LSD led to sensitisation of multiple receptor signalling measures, including 5-HT2 (sham/saline vs sham/LSD: U=3.5, p=0.022). The neurochemical results are reported as mean±SEM with n=4–6 for the assays; several comparisons showed only trends rather than formal significance. Some fragments in the extracted results text were incomplete, and the precise numerical values for behavioural ANOVA and some neurochemical group means were not provided in the extraction.
Buchborn and colleagues interpret their findings as evidence that repeated LSD produces an antidepressant-like effect in the olfactory bulbectomy model, because LSD largely reversed the bulbectomy-induced avoidance-learning deficits and selectively normalised a hippocampal 5-HT2-related signalling abnormality. They emphasise that the behavioural benefit was specific to bulbectomised rats and absent in sham-operated animals, arguing that this specificity supports an antidepressant-like action rather than a general cognitive enhancer or acute mood effect. The investigators link the biochemical and behavioural data by proposing a re-balancing of hippocampal 5-HT2 versus 5-HT1A signalling as a plausible mechanism. Specifically, bulbectomy-associated desensitisation of hippocampal alpha-MS (a proxy for 5-HT2) stimulated G-protein coupling was restored by LSD, whereas hippocampal 5-HT1A signalling was not significantly altered by bulbectomy or by LSD in the present assays; this pattern is taken to indicate selective engagement of 5-HT2-related pathways. The authors additionally discuss how such receptor regulation could interact with hippocampal neurogenesis and brain-derived neurotrophic factor (BDNF) signalling: they speculate that LSD, by re-sensitising 5-HT2 signalling while activating 5-HT1A, might recalibrate opposing trophic influences and thereby improve the neuronal turnover or stress integration needed for avoidance learning. The authors label this mechanistic model as speculative and in need of further study. Several important nuances are highlighted. Receptor regulation by hallucinogens can be complex and region-specific, varying with dosage, regimen, animal strain or behavioural context; accordingly, LSD increased frontocortical receptor signalling in sham animals without producing behavioural effects, which the investigators attribute to the absence of a pre-existing pathological bias in those rats and to the timing of dosing (two hours after learning sessions). They acknowledge that LSD is not selective and binds multiple monoamine receptors; however, because overall dopamine signalling was not affected and because LSD normalised hippocampal 5-HT2 but not beta-adrenergic signalling, the authors focus discussion on 5-HT2/5-HT1A balance. Suggested directions for future research include co-application of selective antagonists with LSD, combining selective 5-HT1A and 5-HT2A agents, or use of selective dual agonists to more precisely dissect receptor contributions, though practical and interpretative complications are recognised. Finally, the authors situate the findings in a clinical and psychotherapeutic context, noting that hallucinogens are unlikely to be straightforward acute antidepressants but may assist psychotherapy by facilitating access to emotion-salient cognitions and by correcting mood-relevant cognitive biases via receptor regulation. They caution that the mechanistic links and translational relevance require further investigation and replication. The extracted text does not present additional formal limitations such as exact sample sizes for behavioural groups or power calculations, beyond acknowledging the need for more targeted receptor-manipulation studies.
Lysergic acid diethylamide (LSD) is a serotonergic hallucinogen known to induce profound alterations of the human consciousness. When abused in an unsupervised context, hallucinogens can have detrimental effects on the individual; when used in a controlled environment, however, they might be of medical value. Although early and extensively recognised for an ability to facilitate certain strategies of psychotherapy, particularly in the context of anxiety neuroses and/or depressive reactions, the therapeutic potential of serotonergic hallucinogens has hardly been considered pharmacologically, i.e. in terms of their receptor profile. Sharing the indolethylamine moiety of the serotonin molecule, LSD is a suitable ligand for a variety of monoaminergic, notably serotonin (5-HT) receptors; with low-nanomolar affinity, for instance, it binds to 5-HT 1A and 5-HT 2A receptors. Both receptor subtypes regulate a variety of functions critically involved in the pathogenesis of depression; the pyramidal integration of excitatory input to the prefrontal cortex (PFC), the hypothalamic-pituitary-adrenal axis, as well as the hippocampal neurogenesis and/or cell proliferation. In accordance with their functional relevance, long-term treatment with diverse-class antidepressants has been shown to downregulate 5-HT 2A receptors in the frontal cortex, and to increase the responsiveness of hippocampal 5-HT 1A receptors in a time frame consistent with their delayed therapeutic onset. As repeated LSD, acting as an agonist at both receptor subtypes, also downregulates 5-HT 2A , but not 5-HT 1A receptors (in areas, such as the frontal cortex or the hippocampus), one might expect it to re-balance the postsynaptic 5-HT signalling in a way similar to antidepressants. And indeed, given that crosstolerance between hallucinogens and antidepressant-class drugs develops, a mechanistic overlap seems plausible. Challenging this idea of a mechanistic overlap, we here evaluate whether LSD exerts antidepressant-like effects within an established animal model of depression. In the forced swim test, an animal model that responds to one-time antidepressant application, LSD fails to act antidepressant-like. Thus, in line with our assumption that 5-HT 2A regulation (which requires a repeated LSD regimen)) is important for an antidepressant-like effect to occur, an animal model responding to repeated antidepressant treatment might be of more validity. From the few animal models, which meet such a criterion, we have selected here the olfactory bulbectomy because it is the only one considered highly reliable and specific. Following the bilateral dissection of the olfactory bulbs, rodents show a variety of behavioural disturbances, such as stress-associated hyperlocomotion or avoidance learning deficits, which reliably ameliorate in response to the (sub-)chronic, but not acute application of drugs specified as antidepressants. The bulbectomy induced hyperlocomotion is considered to be of dopaminergic originand might model symptoms of agitated depression. Avoidance learning deficits, on the other hand, involve the serotonin system) and appear to have more general implications for the human situation. According to cognitive theory, depression primarily arises from biases in cognitive processing, including attention and memory, which as a consequence corrupt emotional integrity (e.g.. As (serotonergic) antidepressants are thought to act on these biases, rather than on mood itself, avoidance learning deficits of bulbectomised rats seem to be an optimal proxy for depressive-like cognition biases and their responsiveness to the 5-HT-related action of antidepressant-class drugs. Thus, for evaluating the antidepressant-like action of LSD, we here repeatedly apply the hallucinogen to bulbectomised rats and investigate the effect on avoidance learning and forebrain 5-HT 1A /5-HT 2 signalling. As LSD, despite having high affinity, is not selective for 5-HT 1A and 5-HT 2A receptors, we additionally investigate its effect on beta, overall 5-HT, dopamine and noradrenaline signalling. Methodologically, we use the conditioned pole-jumping paradigm and radioligand binding techniques, respectively.
For experiments, male Wistar rats (average (Ø) 400 g) (HsdCpb:WU; Harlan Winkelmann, Germany) were used. The animals were housed in groups of five each cage, and held under controlled laboratory conditions (temperature 20±2°C, air humidity 55-60%, light/dark cycle 12:12 (light on at 06:00.)) with standard food pellets (TEKLAD Global Diet, Harlan-Teklad, UK) and tap water ad libitum. All experiments conducted complied with the regulations of the National Act on the Use of Experimental Animals (Germany), as approved by the Tierschutzkommission Sachsen-Anhalt.
At the age of seven weeks, rats were bulbectomised as described by. In brief, animals were anaesthetised with pentobarbital (40 mg/kg, intraperitoneal, 10 ml/kg injection volume) and fixed in a stereotactic instrument. The scalp was incised at the midline, and two holes (Ø 2 mm) were drilled into the skull (one above each olfactory bulb (6.5 mm anterior to bregma, 2 mm lateral to midline)). The bulbs were cut and gently removed by aspiration. The resulting cavities were filled with haemostatic sponges (Gelitaspon, Gelita Medical, The Netherlands), and the skin was closed by tissue adhesive (Histoacryl, Braun Aesculap AG, Germany). Extent and adequacy of the surgical ablation were assessed after decapitation at end of the behavioural experiments. Sham-operated rats were treated alike (including piercing of dura mater), except that their bulbs were not removed.
Treatment. Lysergide[(R,R)-tartrate]-anhydrate (THC Pharm, Germany) was applied for a period of 11 days, once every 24 h (0.13 mg/kg, subcutaneous, dissolved in isotonic saline, 10 ml/ kg). Treatment started five days before the behavioural experiments, and continued till 24 h before decapitation. The dose chosen was extrapolated from literature as adequate for activation of 5-HT 2A receptors (as indexed by the occurrence of wet dog shakes). The five days beforehand regimen was chosen so to allow 5-HT 2A (down-)regulation to precede the behavioural experiments. To avoid interference from LSD's acute effects, administration was performed two hours after each test session. Control animals received saline injections without LSD. Assignment of rats to conditions (sham/saline vs sham/LSD; bulb/saline vs bulb/LSD) occurred in a randomised fashion.
Eight weeks after surgery, on the sixth day of subchronic treatment, pole-jumping experiments were set in. On five days in a row, within 10 trials each day, rats had to learn to actively avoid electrical foot stimuli (unconditioned stimulus (US)) by jumping onto a pole. Every trial started with a sound from a buzzer (80 dB) (conditioned stimulus (CS)) which, from the fourth second onwards, was accompanied by the electrical foot stimulation (delivered through stainless steel rods of the test apparatus' floor, and adjusted to the rat's individual pain sensitivity (0.2-0.4 mA)). A trial was restricted to 20 s, but stopped earlier when a rat successfully jumped onto the pole. CS and US overlapped and were co-terminated. The intertrial-interval was stochastically varied (30-90 s). All five sessions were performed at about the same time during the light period. On the first day, rats were allowed five minutes for exploration of the test apparatus, on the following days only one minute was granted. For evaluation of learning, the numbers of successful escapes (instrumental reactions, ≤20 s) and avoidances (conditioned reactions, ≤4 s) were recorded.
5-HT 2A receptor binding. Twenty-four hours after the last treatment, rats were decapitated, brain regions of interest (frontal cortices and hippocampi) were removed and frozen in liquid nitrogen. For measuring ketanserin-sensitive [ 3 H]spiroperidol binding to 5-HT 2A receptors, thawed tissue was homogenised. Cell membranes were pelleted by centrifugation (10 min, 50,000×g, 4°C), washed in Tris buffer (pH 8.0), and resuspended in incubation buffer (50 mM Tris-HCI, containing 120 mM NaCl, 5 mM KCl, 2.5 mM CaCl 2 , 1 mM MgCl 2 , and 50 nM d-butaclamol (D 2 receptor mask) (Sigma-Aldrich, Germany), pH 8.0). Aliquots of the crude membrane suspension (150-250 µg protein) were incubated for 30 min at 37°C with [ 3 H]spiroperidol (specific activity: 800 GBq/mM (Perkin-Elmer, USA)). The membrane fraction was then collected on GF/A grade glass-fibre filters, washed with buffer (50 mM Tris-HCl, pH 8.0), and taken for liquid scintillation counting in a toluene-containing scintillation cocktail. Specific binding was calculated by subtracting non-specific binding (as seen in presence of 0.25 nM [ 3 H]spiroperidol and 1 µM unlabelled ketanserin (Sigma-Aldrich, Germany)) from total binding (obtained with 0.25 nM [ 3 H]spiroperidol alone), and expressed in fmol per mg of protein (as determined by the Lowry Method). [ 35 S]-GTP-gamma-S binding. For measuring G-protein coupling by 5-HT 1A/2 , dopamine, and (beta) adrenergic receptors, tissue was homogenised in Tris buffer (50 mM Tris-HCl, 1 mM ethylene glycol tetraacetic acid (EGTA), 10 mM ethylene diamine tetraacetic acid (EDTA), pH 7.4) and pelleted by centrifugation. After resuspension in assay buffer (50 mM Tris-HCl, 3 mM MgCl 2 , 0.2 mM EGTA, 100 mM NaCl, pH 7.4), aliquots containing 15-20 µg protein were incubated with 3 µM guanosine diphosphate (GDP) and 0.05 nM [ 35 S]-GTP-gamma-S (specific activity: 46.3 TBq/mM (Perkin-Elmer, USA)) in the presence and absence of the relevant agonist (1 h, 30°C) (10 µM alpha-methylserotonin (alpha-MS for 5-HT 2 ), 100 µM 8-hydroxy-2-[di-n-propylamino] tetralin [8-OH-DPAT for 5-HT 1A ], 100 µM isoprenaline (for beta), 10 µM serotonin, 100 µM dopamine, and 10 µM noradrenaline (Sigma-Aldrich, Germany)). Incubation was terminated by rapid filtration, filters were rinsed in washing buffer (50 mM Tris-HCl, 3 mM MgCl 2 , 1 mM EGTA, pH 7.4), and taken for liquid scintillation counting of bound radioactivity. Total [ 35 S]-GTP-gamma-S binding was corrected for unspecific binding (in the presence of 10 µM unlabelled GTP-gamma-S), and expressed as E max , % stimulation over basal specific binding. All determinations were performed at least in duplicate.
A two-factor analysis of variance (ANOVA) with repeated measures on one factor (mixed model) was conducted to assess main effects and interaction of time and group in avoidance learning, and followed by pairwise contrast analysis. Intergroup differences in specifically bound radioactivity were analysed using nonparametric Mann-Whitney U-tests (a-priori planned comparisons). Calculations were carried out using SPSS and GraphPad Prism software. Statistical significance was assumed if the null hypothesis could be rejected at the 0.05 probability level.
5-HT 2A receptor binding. As shown in Figure, bulbectomy slightly increased the ketanserin-sensitive [ 3 H]spiroperidol binding in hippocampus. This trend of increase (sham/saline vs bulb/saline: u=4, p=0.095) was partially counteracted by the repeated LSD treatment. Although the difference between LSD and saline treated bulbectomised rats fell short of significance (bulb/saline vs bulb/LSD: u=6, p=0.063), the difference between LSD treated bulbectomised rats and saline treated, sham-operated controls was not significant either (sham/saline vs bulb/ LSD: u=11, p=0.46). As opposed to its decreasing effect in bulbectomised rats, repeated LSD treatment did not affect the hippocampal [ 3 H]spiroperidol/ketanserin binding of the shamoperated animals (sham/saline vs sham/LSD: u=11, p=0.46). In the frontal cortex, bulbectomy had no significant effect on the ketanserin-sensitive [ 3 H]spiroperidol binding (sham/saline vs bulb/saline: u=9, p=0.27); LSD, however, induced a significant increase (sham/saline vs sham/LSD: u=0, p=0.002) (Figure). [ 35 S]-GTP-gamma-S binding. which was reversed by subchronic LSD (bulb/saline vs bulb/ LSD: u=6, p=0.032) (Figure). In contrast to its resensitising effect in bulbectomised rats, LSD caused a desensitisation of alpha-MS stimulated [ 35 S]-GTP-gamma-S binding in the hippocampus of the sham-operated animals (sham/saline vs sham/ LSD: u=3, p=0.0015). Other significant effects and/or trends of bulbectomy, such as the hippocampal decrease in isoprenaline and noradrenaline stimulated receptor signalling (sham/saline vs bulb/saline: u=0, p=0.004; u=2, p=0.057), or the frontocortical increase in alpha-MS, 8-OH-DPAT, and isoprenaline induced [ 35 S]-GTP-gamma-S binding (sham/saline vs bulb/saline: u=4, p=0.were not reversed by LSD (Figuresand). The hippocampal signalling stimulated by 8-OH-DPAT, serotonin, and dopamine was neither influenced by bulbectomy (sham/saline vs bulb/saline: u=15, u=18, and u=8, respectively, n.s.), nor by its interaction with repeated LSD (bulb/ saline vs bulb/LSD: u=14.5, u=15.5, and u=16, n.s.) (Figure). Finally, in the frontal cortex of the sham-operated animals, LSD led to a sensitisation of all receptors investigated, including 5-HT 2 (sham/saline vs sham/LSD: u=3.5, p=0.022) (Figure). S]-GTP-gamma-S binding to frontocortical membranes stimulated by various agonists (% of basal binding). Note that from the bulbectomy associated anomalies, none was normalised by LSD. Mean+standard error of the mean (SEM) (n=4-6); comparison of groups of interest, *p<0.05. NS refers to a non-significant trend (p<0.10). Alpha-MS: alpha-methylserotonin; 8-OH-DPAT: 8-hydroxy-2-[di-n-propylamino] tetralin; bulb: bulbectomised rats; sham: sham-operated rats.
Exploratory evidence suggests that serotonergic hallucinogenswhen psychotherapeutically embedded -might be of assistance in the treatment of neurotic-type depression, or emotional distress associated with advanced stages of cancer. However, as their acute effects on affection are highly variable and critically dependent on the pre-existing mood, hallucinogens should not be (mis-)conceptualised as acute mood-enhancers or antidepressants in a literal sense. Instead, they might rather be seen as a tool for psychotherapy to facilitate access to emotion-salient cognitions (e.g. memory) and work on the inherent biases that negatively prime the patient's affective mindset. Here, we refer to the idea that hallucinogens -in a similar way to that hypothesised relevant for repeated antidepressant treatment-might affect mood-relevant cognitive biases by regulation of 5-HT 1A/2A receptors. We repeatedly applied LSD to bulbectomised rats, and tested its effect on depressive-like avoidance learning deficits and forebrain 5-HT 1A/2 signalling. In keeping with former findings, we confirm that bulbectomised rats are deficient in active avoidance learning. Similarly as we noted earlier with imipramine under comparable experimental conditions, or as noted by other labs with amitriptyline or trazodone, repeated LSD treatment -in a dosage known to induce 5-HT 2A related wet dog shakeslargely reverses this deficiency. As the avoidance learning deficits after bulbectomy are reversible by drugs classified as antidepressant only, we infer that LSD's behavioural effect in this model can be considered antidepressant-like. Our inference is strengthened by the fact that LSD specifically helps bulbectomised, but not sham-operated, rats. In addition, we show that bulbectomised rats exhibit various anomalies of monoamine receptor signalling, with 5-HT 1A , 5-HT 2 and beta signalling being sensitised in the frontal cortex, and the latter two being desensitised in the hippocampus. From the given anomalies, the desensitisation of hippocampal 5-HT 2 signalling, as indicated by a decrease in alpha-MS stimulated [ 35 S]-GTPgamma-S binding, is the only one to be normalised by subchronic LSD. Despite alpha-MS being a mixed 5-HT 1/2 agonistrather than selective for 5-HT 2 receptors, we think 5-HT 2 receptors might be more specifically implicated, because neither bulbectomy nor its interaction with LSD significantly influences hippocampal 5-HT 1A signalling. Also, the relevance of hippocampal 5-HT 2A receptors might be inferred from our finding that bulbectomy is associated with trends for increased ketanserinsensitive [ 3 H]spiroperidol binding, and LSD to counteract it. Although these trends should be interpreted with caution, yet they are reminiscent of former findings about bulbectomy upregulating and/or antidepressants downregulating hippocampal 5-HT 2 receptors. Hippocampal 5-HT 2 anomalies might be a consequence of the bulbectomy induced raphe degeneration, and the (associated) reduction in local serotonin. Remarkably, similar to that seen for avoidance learning deficiency, LSD's (counter-)regulatory action on 5-HT 2(A) receptors is specific for the pathological condition; in sham-operated animals, it desenitises alpha-MS signalling, and leaves ketanserinsensitive [ 3 H]spiroperidol binding unaffected. LSD exhibits high 5-HT 1A and 2A affinity, but it is not selective for these receptors. In fact, it binds to a variety of monoamine receptors, with beta and D 4 , for instance, complementing 5-HT 2A in LSD's behavioural profile. As neither bulbectomy nor LSD's interaction with bulbectomy, however, affects overall dopamine signalling, and LSD normalises hippocampal 5-HT 2 , but not beta signalling, we think it is reasonable to discuss the LSD induced normalisation of avoidance learning in terms of a re-balance of hippocampal 5-HT 2 vs 5-HT 1A signalling. Deficits in avoidance learning as well as their reversal by antidepressants have been linked to 5-HT 2A receptors, and LSD is known to affect learning via hippocampal 5-HT 2A regulation. Bulbectomy leads to deficient hippocampal neurogenesis, and to an upregulation of brain-derived neurotrophic factor (BDNF). Although generally considered antidepressant-like, too much BDNF might be detrimental and compromise avoidance learning. As a model of LSD's antidepressantlike activity one could, therefore, hypothesise that LSD (by activating 5-HT 1A and resensitising 5-HT 2 signalling) might re-balance the anti-BDNF effect of 5-HT 2A against the neurotrophic effect of 5-HT 1A receptors. Consequently, a more coordinated turnover of hippocampal neurons might occur, allowing the stress-integration system of bulbectomised rats to more effectively meet the demands of avoidance learning (compare. This model is speculative, however, and needs further investigation. Also, to more clearly establish the role of 5-HT 2A and 5-HT 1A receptors, future research might co-apply selective antagonists with LSD, combine a selective 5-HT 1A with a selective 5-HT 2A agonist, or use selective dual agonists instead. As the latter seem sparse, the repeated combination of two agents will raise pharmacokinetic problems, and 5-HT 2A antagonists act antidepressant-like themselves (e.g., though, such a study might be complicated. Intriguingly in the frontal cortex of the sham-operated rats, LSD significantly increases all binding parameters investigated (including those of 5-HT 2(A) ), which in bulbectomised animalsfor the most part -cannot be found. Likewise in the hippocampus, desensitisation of 5-HT 2 and dopamine signalling specifically occurs in the sham rats. Our results contrast with the notion that LSD selectively downregulates 5-HT 2A receptors). Yet, possibly varying with application scheme, strain and/or embedding of the rats into behavioural procedures, hallucinogens might provoke a more or less complex pattern of receptor regulation (e.g. 5-HT 1A downregulation for psilocybin, alpha 1 upregulation for DOI, or regional 5-HT 2A down-vs upregulation for DOM). The fact that LSD -despite regulating their neurochemistry -does not affect avoidance learning of the sham rats, underlines that our application scheme was well chosen. Repeatedly applying LSD -such as noted for antidepressant-class drugs -might have counteracted the neurochemical imbalance induced by bulbectomy (including hippocampal 5-HT 2 signalling), thus, normalising the learning capacity (or re-shifting the cognitive bias) of the bulbectomised rats. For the sham animals, in contrast, there had never been such an imbalance (or bias), and the only (or most likely) way in which LSD might have affected their avoidance learning would have been by acutely interfering with learning. Applying LSD two hours after each learning session, however, we minimised the chance of such interference (compare. Therefore, the LSD-induced changes of the sham rats' neurochemistry might rather be unspecific and (temporally) unrelated to the processes involved in avoidance learning. In summary, our data demonstrate that in bulbectomised rats, repeated LSD treatment reverses depressive-like avoidance learning deficits, possibly engaging a re-balance of hippocampal 5-HT 2 (vs 5-HT 1A ) signalling. Given the postulated interrelation between the reversal of mood-relevant cognitive biases and 5-HT (2A) receptor regulation, our findings might have implications for the understanding of how hallucinogens alleviate emotional distress, such as that seen in advanced-stage cancer.
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