Psychedelic drug use and schizotypy in young adults.

Despite recently resurrected scientific interest in classical psychedelics, few studies have focused on potential harms associated with abuse of these substances. In particular, the link between psychedelic use and psychotic symptoms has been debated while no conclusive evidence has been presented. Here, we studied an adult population (n = 1032) with a special focus on young (18-35 years) and healthy individuals (n = 701) to evaluate the association of psychedelic drug use with schizotypy and evidence integration impairment typically observed in psychosis-spectrum disorders. Experimental behavioural testing was performed in a subsample of the subjects (n = 39). We observed higher schizotypy scores in psychedelic users in the total sample. However, the effect size was notably small and only marginally significant when considering young and healthy subjects (Cohen's d = 0.13). Controlling for concomitant drug use, none of our analyses found significant associations between psychedelic use and schizotypal traits. Results from experimental testing showed that total exposure to psychedelics (frequency and temporal proximity of use) was associated with better evidence integration (Cohen's d = 0.13) and a higher sensitivity of fear responses (Cohen's d = 1.05) to the effects instructed knowledge in a reversal aversive learning task modelled computationally with skin conductance response and pupillometry. This effect was present even when controlling for demographics and concomitant drug use. On a group level, however, only difference in sensitivity of fear responses to instructed knowledge reached statistical significance. Taken together, our findings suggest that psychedelic drug use is only weakly associated with psychosis-like symptoms, which, in turn, is to a large extent explained by psychiatric comorbidities and use of other psychoactive substances. Our results also suggest that psychedelics may have an effect on flexibility of evidence integration and aversive learning processes, that may be linked to recently suggested therapeutic effects of psychedelic drugs in non-psychotic psychiatric populations.

Influence of the displacement out of the center of mass and nonaxiality of the dipole on the thermodynamics of liquids composed of linear dipole molecules.

We present results for organic liquids modeled as linear rods with an embedded point dipole shifted from the geometrical center. Previously, we have obtained results for the vapor-liquid equilibrium (VLE) of similar systems with centered point dipoles. Our results included both models and applications to real systems. Results presented here are based on a previous work ( Phys. Rev. E 2003, 68, 021201) on the structural properties of these systems where relevant results about the appearance of dimers were found. Now, we have also performed systematic simulations on these systems to calculate the VLE of models with different aspect ratios, dipole shifts, and dipole strengths using the Gibbs ensemble Monte Carlo (GEMC) to calculate equilibrium densities and vapor pressure at each temperature. The applications considered here include some important substances such as 1-amines, acetonitrile, and 1-alcohols whose intermolecular parameters were fitted from our model simulations. Furthermore, we have used quantum chemistry calculations to obtain a reliable charge distribution, and we have applied our model to predict the vapor pressure of alpha,omega-diols where experimental results are rather scarce. Our results show a general improvement of the agreement between experiment and models compared to centered dipole models previously used. Results for amines are particularly remarkable.

Immunoreactive substance P and calcitonin-gene-related peptide (CGRP) in rat milk and in human milk and infant formulas.

This study examined the presence of substance P and calcitonin-gene-related peptide (CGRP) immunoreactivities in various milks and infant formulas. Rat milk was obtained from lactating dams between parturition and weaning (0, 2, 5, 10, 15, and 20 d postpartum). Samples of human milk were obtained from seven multiparous, nonsmoking white women, and newborn infant formulas were purchased from local stores. Substance P and CGRP were measured by competitive enzyme immunoassay using acetylcholinesterase-peptide conjugates as tracers. In rats, substance P and CGRP were below detectable concentrations in amniotic fluid from the last day of gestation. In contrast, in milk the concentrations of substance P and CGRP-like immunoreactivities were high on the first day of lactation (3.1 +/- 0.2 and 23.1 +/- 1.5 micrograms/L, respectively), then dropped after day 2 (1.6 +/- 0.7 and 7.5 +/- 0.4 microgram/L, respectively) and remained fairly constant until weaning. Significant concentrations of substance P and CGRP were found in human milk (129.2 +/- 27 ng/L and 4.5 +/- 0.7 microgram/L, respectively, at 15 wk), but substance P or CGRP could not be detected in any of the formulas tested. These data show that milk contains high concentrations of immunoreactive substance P and CGRP. In rats the absence of peptides in amniotic fluid suggests that there is a flood of peptides into the gastrointestinal tract of neonates when suckling is initiated. Significant concentrations of substance P and CGRP in human milk but not in infant formulas may therefore have physiologic implications for neonatal nutrition.

Inhibition by cow's milk of histamine-induced gastric acid secretion in the rat.

The effects of a 4-day milk diet on basal and histamine-induced gastric acid secretion were examined in vivo in adult rats. Rats were fed on raw cow's milk only. Their acid secretion was measured in the perfused stomach under basal conditions or after administration of varying doses of histamine. In milk-fed rats, basal secretion rose slightly compared with control secretion (1.86 +/- 0.09 vs. 1.52 +/- 0.06 microEq H+/10 min; p less than 0.01), but maximal secretion in response to noncumulative doses of histamine (range: 7.0-20.0 mg/kg) was inhibited by 57%. The degree of this inhibition was similar to that observed in control rats with an equimolar dose of H2-antagonist cimetidine. These results indicate that in the adult rat, chronic administration of cow's milk strongly inhibits histamine-stimulated acid output.

[Hydrochloric acid secretion of fetal rat gastric mucosa]. / Sécrétion d'acide chlorhydrique par la muqueuse gastrique du foetus de rat

In Rat, spontaneous secretion of hydrochloric acid by gastric mucosa takes place before birth. From day 20 of gestation until birth, the pH of gastric content markedly decreases, reaching 3 pH-units in newborns. During this period, Cl- concentration in gastric juice increases, while p-CO2 remains constant.

Ontogenesis of gastric response to agonists and antagonists of acid secretion in fetal rat.

The responsiveness of fetal rat stomach to the main agonists and antagonists of acid secretion was examined in vivo on days 19 and 20 of gestation. Significant acidification of the gastric content was observed only in response to pentagastrin, gastrin G-17, histamine and carbamylcholine from day 20, when the fetal stomach starts secreting hydrochloric acid. Vagally-mediated stimulation of gastric acid secretion in response to 2-deoxyglucose was also demonstrated on day 20. The effects of cimetidine and atropine on stimulated acid secretion were observed to be specifically related to histamine and carbamylcholine respectively. The findings provide evidence that the fetal gastric mucosa is sensitive to the three primary stimuli of acid secretion at the point when differentiated parietal cells start secreting acid. They suggest that at the functional differentiation stage, distinct pathways exist in fetal rat stomach for the stimulation of hormonal and neural acid secretion.

Ontogenesis of gastric acid secretion in fetal rat.

The pH of gastric fluid was measured in rat fetuses during the last 3 days of gestation. On day 19, the gastric pH was close to neutral. During the night of day 20, the pH was clearly lowered (6.11 +/- 0.15 units), this decrease becoming more marked on the following day. At birth (day 22), just before the first feeding, the pH of gastric fluid reached the mean value of 2.98 +/- 0.14 units. This drop in gastric pH was concomitant with an increase in chloride concentration whereas the gastric PCO2 remained constant. These results imply that in term rat fetuses, the gastric mucosa secretes fixed acid, very likely hydrochloride acid. The administration of acetazolamide (inhibitor of carbonic anhydrase) to 20-day-old fetuses did not suppress the spontaneous acidification of gastric fluid, although the enzyme activity was reduced by approximately 80%. Moreover, the gastric pH in acetazolamide-injected fetuses was markedly lower than in the noninjected littermates. The administration of NaCl solution (acetazolamide vehicle) had no effect on the carbonic anhydrase activity but clearly decreased the pH of gastric fluid. Thus, the drop of gastric pH produced by injection of acetazolamide or saline solution alone probably results from a stress effect of puncture. In fetuses from adrenalectomized, metopirone-treated mothers, the injection of NaCl solution no longer had effect on the pH of gastric fluid whereas triamcinolone injection produced a clear decrease in the gastric pH 3 hr latter.

Air-breathing behaviour of the Colombian catfish Eremophilus mutisii (Trichomycteridae, Siluriformes).

Eremophilus mutisii uses the vascularized central portion of its stomach for aerial respiration, and is a frequent but not obligatory air breather. Air ventilation takes place during a rapid dash to the surface with the expiration of old air preceding inspiration. The frequency of air breathing is affected by aquatic O2 concentration. E. mutisii can survive at least 10 days without air breathing in normoxic water but cannot survive without air access in water containing less than 2.0 ppm O2.

Development of sodium and chloride transport across fetal and newborn rat stomach in vitro.

1. Unidirectional and net Na+ and Cl- fluxes were determined across isolated fetal rat stomach 19-21 days post-coitum, and across the stomach of newborn rats aged 5 or 12 days. 2. On fetal day 19, absorption of both Na+ and Cl- was greater than the short-circuit current, Isc (net Na+ flux, JnetNa = 4.7 +/- 1.0 and net Cl- flux, JnetCl = 5.4 +/- 1.4 mu equiv cm-2 h-1 vs. Isc = 0.9 +/- 0.1 mu equiv cm-2 h-1). Mucosal addition of 10 microM-amiloride did not significantly alter JnetNa, JnetCl, Isc or total conductance. 3. However, on fetal day 20, neutral absorption of NaCl was no longer observed but amiloride had inhibited electrogenic absorption of Na+, and significant active secretion of Cl- was observed (JnetCl = -1.3 +/- 0.6 mu equiv cm-2 h-1). On day 21 (i.e. 24 h before birth), values for JnetNa, JnetCl, and Isc were not different from those determined on adult gastric mucosa. 4. After birth, NaCl transport continued to exhibit its prenatal characteristics on day 5 but not on day 12, when Na+ and Cl- were both absorbed; on that day, JnetNa-Isc was equal to both JnetCl and to the amiloride-insensitive component of Isc, indicating that neutral NaCl absorption had resumed. 5. These data show that in rat stomach, NaCl transport differentiates on fetal day 20, when H+ secretion is first observed, and thereafter undergoes biphasic development. 6. The significant Cl- absorption observed on post-natal day 12 was concomitant with the inhibition of net H+ secretion.

Development of acid secretory function in the rat stomach: sensitivity to secretagogues and corticosterone.

Gastric acid secretion was studied in anesthetized rats from day 6 of the postnatal period up to the time of weaning. Basal H+ secretion was detected from day 6 in the first group studied (2.4 +/- 0.2 muEq of H+/10 min/100 g of body weight, BW) and remained constant up to the time of weaning (day 18: 2.5 +/- 0.2 muEq of H+/10 min/100 g of body weight) except for the period between days 10 and 12, when it fell significantly (1.5 +/- 0.06 muEq H+/10 min/100 g of BW on day 12). Both histamine H2 receptor sensitivity and intracellular transduction mechanism activities were evaluated by studying the secretory responses to histamine, impromidine (an H2 receptor agonist), cimetidine (an H2 receptor antagonist), forskolin (a direct adenylate cyclase activator), and dibutyryl (db) cAMP (an analogue of cAMP, the intracellular messenger mediating the response to histamine). The effects of pentagastrin and carbachol were also determined. The secretory responses obtained on days 6, 8, and 18 were similar and represented about threefold increases over basal secretion for all the secretagogues used. After weaning on day 20, both the basal secretion and the response to secretagogues were significantly increased compared with those of unweaned animals. On day 12, the responses were always weaker than on both days 8 and 18. Injection of 1 mg/kg of corticosterone 21 acetate daily from day 8 resulted on day 12 in a basal secretion and a response to histamine equivalent to those measured in 18-day-old pups not injected.(ABSTRACT TRUNCATED AT 250 WORDS)

Milk-stimulated PGE2 production by isolated gastric cells: a possible role in the inhibition of histamine-induced acid secretion.

The effects of a milk diet on gastric acid secretion of rats fed raw bovine milk for 4 days were examined using dispersed gastric cells. Parietal cell acid secretion was estimated by the accumulation of 14C-aminopyrine (AP), an index of secretory function. Basal AP accumulation was significantly increased (60%) by the milk diet. There was a marked upward shift in the dose-response curve of histamine (HA; 10(-8) to 10(-3) M) in milk-fed rats, indicating enhanced sensitivity of parietal cell-H2 receptor to exogenous HA. In contrast, the dose-dependent inhibition of HA-induced AP accumulation by prostaglandin (PG) E2 was significantly reduced, indicating that the parietal cells of milk-fed rats were less sensitive to exogenous PGE2. The PGE2 content of bovine milk was low (less than 20 pg/ml), but the production of endogenous PGE2 by the gastric cells was dramatically increased by the milk diet and exhibited maximal control production rate in the presence of 10 microM arachidonic acid. The increased responsiveness to histamine and the decreased responsiveness to PGE2 indicated that the milk diet induced low histamine and high PGE2 availability in the vicinity of the parietal cell basolateral membrane. This regulation, which involves stimulation of PGE2 production in the gastric mucosa, may underly the inhibition of acid secretion observed in vivo in chronically milk-fed adult rats.

Effect of a milk diet on rat gastric mucosa: receptor activity, histamine metabolism and ultrastructural analyses.

A bovine milk diet (BM) resulted in remarkable changes in histamine H2 receptor activity (sensitization) and PGE2 receptor activity (desensitization) in gastric glands isolated from adult rats. In contrast, the receptor-cAMP systems sensitive to glucagon(s) and secretin in parietal cells and muco-peptic cells were unaffected. In the two experimental groups, cimetidine produced a parallel displacement of the histamine dose-response curve suggesting competitive inhibition between this classical H2 receptor antagonist and histamine. The BM diet reduced the histidine decarboxylase activity in rat gastric mucosa; the histamine content was not significantly different in control and BM-fed rats. There was no alteration of the circadian rhythm of the parietal cell (ultrastructural changes: microvilli, tubulo-vesicles) determined at intervals of 6 hours in milk-fed rats. Prostaglandins and other components in milk (EGF, somatostatin, etc.) might therefore protect gastric mucosa by a differential control of PGE2 and histamine H2 receptor activity, either directly (PGE2 and EGF in milk) or indirectly (inhibition of endogeneous histamine synthesis/release and stimulation of prostaglandin synthesis/release).

Biphasic development of pentagastrin sensitivity in rat stomach.

Rat stomach sensitivity to pentagastrin was examined in fetal (days 19--21) and newborn (5--day-old) preparations in vivo and in vitro. Gastric acidification in vivo was expressed as the gastric content pH and in vitro as the net transepithelial H+ fluxes determined in an Ussing chamber. In both preparations, fetal stomach first responded to pentagastrin on day 20. Dose-dependent H+ secretion was demonstrated in vitro for pentagastrin concentrations of 10(-8) to 10(-6) M, with half-maximal stimulations at 1.9 x 10(-7) and 4 x 10(-7) M on days 20 and 21, respectively. In contrast, isolated fundic mucosa of 5-day-old rat pups exhibited very low H+ secretion rates, and pentagastrin did not significantly stimulate acid output. Fetal serum immunoreactive gastrin was detected as early as day 16 in fairly constant concentrations (about 77.5 pg eq synthetic human gastrin/ml). These results indicate that, although immunoreactive gastrin is present in serum as early as day 165, pentagastrin does nt stimulate acid secretion until day 20 when fetal stomach exhibits active H+ secretion and decreased passive permeability. Pentagastrin sensitivity disappears during the 1st days of extrauterine life. These findings strongly suggest that the development of pentagastrin sensitivity in rat stomach is biphasic.

Acid secretion in fetal rat stomach in vitro.

In vivo fetal rat stomach produces HCl 48 h before birth. This study examines the mechanisms of H+ secretion from days 19 to 21 before birth. Isolated fetal stomachs were mounted as flat sheets in Ussing chambers for measurement of the transepithelial H+ fluxes (JH+) and short-circuit current (Isc), as indexes of the active ionic fluxes, and for measurement of total ionic conductance (G) and unidirectional mannitol fluxes from serosa to mucosa (JMans leads to m), as indexes of passive permeability. The results indicate that JH+ was absent at day 19 but reached 0.75 +/- 0.1 and 0.75 +/- 0.09 mueq . h-1 . cm-2 at days 20 and 21, respectively. Concomitantly, Isc increased significantly (56%) between days 19 and 20 in the direction of anion secretion or cation absorption. Parallel reductions in G (45%) and in JMans leads to m (66%) were observed between days 19 and 20. In conclusion, the simultaneous appearance of active H+ secretion and decreased passive transepithelial permeability strongly suggests that both processes are involved in the mechanism of acidification of the fetal rat stomach before birth.

Relationship between maternal milk PGE2 and gastric acid secretion in newborn rats.

We previously demonstrated that in rats gastric acid secretion declines after birth and drops steeply on day 12 of life. In the present study, we investigated the part played in this decline by prostaglandin E2 (PGE2) from maternal milk. PGE2 content was first measured in the milk of untreated dams 0, 1, 5, 10, 12, 15, and 18 days after parturition. PGE2 levels were high during the first 5 days (123.5-200.5 pg/ml), declined significantly between days 10 and 15 (56.6-85.4 pg/ml; P less than 0.05), and dropped to 18.4 pg/ml on day 18. We also found that depleting milk of PGE2 prevented drop of acid secretion in 12-day-old suckling rats. Injecting lactating dams with indomethacin significantly reduced milk PGE2 content by 65% vs. milk of untreated dams. Surprisingly, administration of sesame oil, the indomethacin vehicle to the dams, increased milk PGE2 content by 182%. In the pups of the indomethacin-treated dams, acid secretion did not drop. On the contrary, in vivo basal and histamine-induced acid output rose markedly by 40 and 50%, respectively, and in vitro the net movements of 36Cl and 22Na measured in the isolated stomach indicated that active Cl- secretion had resumed. Mucosal PGE2 did not appear to be significantly involved in early development of acid secretion because administration of indomethacin to pups from untreated dams did not significantly modify the secretion measured on day 12. Data indicate that maternal milk depletion of PGE2 prevents the drop of gastric acid secretion previously observed in 12-day-old pups and suggest that in infant rats maternal PGE2 plays a physiological part in regulating acid secretion.

Development of gastric histidine decarboxylase in the rat: sensitivity to fasting and secretagogues.

Gastric mucosal histidine decarboxylase (HDase) was measured in fetal rats between days 16 and 21 of gestation, and in newborn rats up to weaning. HDase was not detected in fetal stomach. Its activity developed from day 1 after birth (29 +/- 2 pmol CO2/mg protein/h) and increased up to day 18 when it reached the fed adult level (894 +/- 174 pmol CO2/mg protein/h). Weaning increased HDase activity significantly (weaned versus unweaned rats: 1,664 +/- 150 and 1,036 +/- 170 pmol CO2/mg protein/h; p less than 0.005). Up to day 18, HDase activity was not altered by 16 h to 24 h of fasting. From that day on, HDase became sensitive to both pentagastrin and carbachol. These results indicate that complete functional maturation of histamine-producing cells is only reached at day 18, just before weaning. This developmental pattern may explain the differences observed between fetal and adult regulation of gastric acid secretion.