Psychopharmacology

Ayahuasca is a psychotropic plant tea from South America used for religious purposes by indigenous people of the Amazon. Increasing evidence indicates that ayahuasca may have therapeutic potential in the treatment of mental health disorders and can enhance mindfulness-related capacities. Most research so far has focused on acute and sub-acute effects of ayahuasca on mental health-related parameters and less on long-term effects. The present study aimed to assess sub-acute and long-term effects of ayahuasca on well-being and cognitive thinking style. The second objective was to assess whether sub-acute and long-term effects of ayahuasca depend on the degree of ego dissolution that was experienced after consumption of ayahuasca. Ayahuasca ceremony attendants (N = 57) in the Netherlands and Colombia were assessed before, the day after, and 4 weeks following the ritual. Relative to baseline, ratings of depression and stress significantly decreased after the ayahuasca ceremony and these changes persisted for 4 weeks. Likewise, convergent thinking improved post-ayahuasca ceremony up until the 4 weeks follow-up. Satisfaction with life and several aspects of mindfulness increased the day after the ceremony, but these changes failed to reach significance 4 weeks after. Changes in affect, satisfaction with life, and mindfulness were significantly correlated to the level of ego dissolution experienced during the ayahuasca ceremony and were unrelated to previous experience with ayahuasca. It is concluded that ayahuasca produces sub-acute and long-term improvements in affect and cognitive thinking style in non-pathological users. These data highlight the therapeutic potential of ayahuasca in the treatment of mental health disorders, such as depression.

Cues associated with rewards bias attention towards them and can motivate drug-seeking and drug-taking behavior. There is, however, considerable individual variation in the extent to which cues associated with rewards acquire motivational properties. For example, only in some rats does a localizable food cue become attractive, eliciting approach towards it, and “wanted”, in the sense that it serves as an effective conditioned reinforcer. We asked whether the propensity of animals to attribute incentive salience to a food cue predicts the extent to which a classically conditioned cocaine cue acquires incentive motivational properties. First, a Pavlovian conditioned approach procedure was used to identify rats prone to attribute incentive salience to a food cue. We then measured the extent to which a classically conditioned cocaine cue acquired two properties of an incentive stimulus: (1) the ability to elicit approach towards it, and (2) the ability to reinstate drug-seeking behavior, using an extinction-reinstatement procedure (i.e., to act as a conditioned reinforcer). We found that a classically conditioned cocaine cue became more attractive, in that it elicited greater approach toward it, and more desired, in that it supported more drug-seeking behavior under extinction conditions, in individuals prone to attribute incentive salience to a food cue. We conclude that rats vary in their propensity to attribute incentive salience to both food and cocaine cues, and it is possible to predict, prior to any drug experience, in which rats a cocaine cue will acquire the strongest motivational control over behavior.

It has been found that citalopram (Lu 10-171) has profound effects on serotonin (5-HT) metabolism by increasing the 5-HT levels in the cerebellum, medulla, and the whole brain with a corresponding decrease of the 5-HIAA levels in all parts of the brain except the brain stem. On the other hand, the drug does not appear to have any influence on the wet-dog shakes response induced by the combination of a monoamine oxidase inhibitor (MAOI) and l-tryptophan. It is suggested that by increasing the neuronal levels of 5-HT, citalopram decreases the turnover of 5-HT and firing rate of serotonin neurons. It has also been observed that citalopram could be an agonist of a certain type of 5-HT receptor which does not respond to the behavioral screening model proposed by Bedard and Pycock (1977).

It has been proposed that dopamine (DA) sustains up states in striatal medium spiny neurons (MSN). Testing this hypothesis requires an in vitro preparation, but up states are typically only observed in vivo. In this study, we used corticostriatal organotypic cocultures, a preparation in which up states have been previously observed, to test the DA control of cortically-driven plateau depolarizations. After 7–21 days in vitro in serum-free conditions, plateau depolarizations resembling up states were only observed in cultures with a critical extent of striatal DA innervation. These plateaus were completely blocked by the non-NMDA antagonist CNQX and significantly shortened by the NMDA antagonist APV or the D1 antagonist SCH23390. Intracellular interruption of Ca++ or protein-kinase A (PKA) signaling also eliminated the plateaus. The D2 antagonist eticlopride failed to disrupt the plateaus, but significantly increased MSN excitability. These results suggest that coincident activation of corticostriatal glutamatergic and mesostriatal DA transmission may set ensembles of MSN into prolonged depolarizations through a D1 enhancement of striatal NMDA function in a Ca++ and PKA-dependent manner.

Twenty milligram diazepam (DZ) was compared with 20 mg of its main metabolite N-desmethyldiazepam (NDDZ) as single dose, oral premedication in a genuine stressfull situation. Fifty patients participated in the randomized, double-blind controlled study. Anxiety and sedation were measured the day before an operation and one hour after premedication, just before the operation. NDDZ was significantly less sedative while the degree of anxiety was rated equal in the two groups. The results may support the hypothesis that a competition between DZ and NDDZ can explain the shift in the effect profile of DZ during long term treatment.

Rationale: Corticotropin-releasing factor (CRF) and urocortin (Ucn) belong to the CRF-related family, share a high degree of structural homology and bind to CRF receptors. However, compared with CRF, Ucn was shown to display either weaker or similar anxiogenic-like effects in vivo. Objective: To compare the anxiogenic-like responses of rats injected intracerebroventricularly (ICV) with different doses of either rat/human CRF (r/hCRF) or rat Ucn (rUcn) at different intervals after injection. Methods: Rats were tested on three validated paradigms of emotional behavior [i.e. elevated plus-maze (EPM), defensive withdrawal (DW) and conflict test (CT)] 5 and 30 min after treatment. Results: In the EPM test only r/hCRF, but not rUcn, produced anxiogenic-like effects at the dose of 1.0 µg, when the peptides were injected 5 min before testing. At 30 min after injection, both peptides caused a significant reduction of open arms exploration, rUcn being effective at 0.01 µg. In the DW test both peptides were equally potent in decreasing the exploratory behavior and increasing the time spent in the chamber at the dose of 1.0 µg when tested 30 min after injection. In the CT both rUcn (0.25–1.0 µg) and r/hCRF (0.75–1.0 µg) decreased significantly the responding in the punished component. However, rUcn reduced food responding also in the unpunished component possibly due to its powerful anorectic activity. Conclusions: Comparison of anxiogenic-like activities of r/hCRF and rUcn at doses up to 1.0 µg revealed striking differential effects that depended on the time of testing after ICV peptide injection, and on the paradigm of anxiety used. These results suggest that the onset of r/hCRF and rUcn actions related to behavioral responses to anxiety is likely to depend on brain peptide-specific mechanisms including binding properties to CRF-receptors, differential distribution to specific functional brain sites and the distribution and effectiveness of binding-protein interactions.

 Recent evidence suggests that the dopamine D4 receptor may play a role in schizophrenia, and that the atypical properties of the antipsychotic clozapine may be attributable in part to its antagonistic actions at this receptor. In the present study, clozapine and three other compounds having D4 dopamine receptor antagonist properties were examined for their effectiveness in reducing losses in prepulse inhibition (PPI) induced in rats by the dopamine receptor agonist apomorphine. Previously, activity in the PPI model has been shown to correlate highly with the antipsychotic potency of a number of neuroleptics. As previously reported, clozapine (1–5.6 mg/kg) significantly reduced apomorphine-induced PPI deficits. The three D4-selective compounds, CP-293,019 (5.6–17.8 mg/kg), U-101,387 (3–30 mg/kg) and L-745,870 (1–10 mg/kg), also significantly blocked the losses in PPI produced by apomorphine. Taken together, these results suggest that dopamine receptor antagonists with selectivity for the D4 dopamine receptor subtype may be effective in the treatment of schizophrenia, while being less likely to produce dyskinesias associated with D2 receptor antagonists.