Fruit juice, organic anion transporting polypeptides, and drug interactions in psychiatry.

Organic anion transporting polypeptides (OATPs) are a group of membrane transport proteins that facilitate the influx of endogenous and exogenous substances across biological membranes. OATPs are found in enterocytes and hepatocytes and in brain, kidney, and other tissues. In enterocytes, OATPs facilitate the gastrointestinal absorption of certain orally administered drugs. Fruit juices such as grapefruit juice, orange juice, and apple juice contain substances that are OATP inhibitors. These fruit juices diminish the gastrointestinal absorption of certain antiallergen, antibiotic, antihypertensive, and ß-blocker drugs. While there is no evidence, so far, that OATP inhibition affects the absorption of psychotropic medications, there is no room for complacency because the field is still nascent and because the necessary studies have not been conducted. Patients should therefore err on the side of caution, taking their medications at least 4 hours distant from fruit juice intake. Doing so is especially desirable with grapefruit juice, orange juice, and apple juice; with commercial fruit juices in which OATP-inhibiting substances are likely to be present in higher concentrations; with calcium-fortified fruit juices; and with medications such as atenolol and fexofenadine, the absorption of which is substantially diminished by concurrent fruit juice intake.

Cocaine facilitates protein synthesis-dependent LTP: the role of metabotropic glutamate receptors.

Cocaine addiction alters synaptic plasticity in many brain areas involved in learning and memory processes, including the hippocampus. Long-term potentiation (LTP) is one of the best studied examples of hippocampal synaptic plasticity and it is considered as one of the molecular basis of learning and memory. We previously demonstrated that in the presence of cocaine, a long lasting form of hippocampal LTP is induced by a single pulse of high frequency stimulation, which in normal conditions evokes only an early form of LTP. In this study, we further explore the molecular basis of this modulation of synaptic plasticity by cocaine. By performing pharmacological experiments on hippocampal slices, we were able to show that cocaine converts early LTP to a form of LTP dependent on protein synthesis, probably through the cAMP-dependent protein kinase and extracellular signal-regulated kinase signaling cascades. We also found that metabotropic glutamate receptors are involved in this phenomenon. These studies further clarify the molecular machinery used by cocaine to alter synaptic plasticity and modulate learning and memory processes.

In vivo comparison of harmine efficacy against psychostimulants: preferential inhibition of the cocaine response through a glutamatergic mechanism.

Harmine is a ß-carboline compound that targets glutamatergic, monoaminergic, and GABAergic pathways underlying drug addiction. We compared the efficacy of harmine against different psychoactive drugs using an invertebrate (planarian) assay designed to quantify 'C-shape' responses. Harmine itself (0.01-10 µM) did not produce C-shapes. However, when applied over the same concentration range, harmine significantly inhibited C-shapes elicited by cocaine, with a concentration of 0.1 µM producing almost 90% inhibition. Consistent with its putative actions, harmine produced a similar, though less efficacious, inhibition of C-shapes elicited by the substituted amphetamines methamphetamine and mephedrone (4-methylmethcathinone) but was much less effective against nicotine. When tested in the presence of the glutamate transporter inhibitor dihydrokainate (DHK) (0.1, 1 µM), harmine (0.1 µM) efficacy against cocaine-induced C-shapes was significantly reduced. Harmine also attenuated C-shapes elicited by N-methyl-d-aspartate (NMDA) and by glutamate itself. The present data suggest that harmine displays preferential efficacy against different addictive substances (cocaine>amphetamines>nicotine) and, at least for cocaine, is dependent on the glutamate system.

Clozapine and SCH 23390 prevent the spatial working memory disruption induced by Δ9-THC administration into the medial prefrontal cortex.

Marijuana (Cannabis sativa) is one of the most widely used illicit drugs in the world. Its use is associated with impairments in cognitive function. We previously reported that Δ(9)-tetrahydrocannabinol (Δ(9)-THC), the primary psychoactive component of marijuana, impaired spatial working memory in the radial maze task when injected intracortically (IC) into the medial prefrontal cortex (mPFC) of rats. Here, we used this paradigm to evaluate the involvement of prefrontal dopamine receptors in working memory disruption induced by Δ(9)-THC. Intracortical pre-treatment of animals with either the D(1)- or D(2)-like dopamine receptor antagonists SCH 23390 or clozapine, respectively, significantly reduced the number of errors rats made in the radial maze following treatment with Δ(9)-THC also administered intracortically. These results were obtained in the absence of locomotor impairment, as evidenced by the time spent in each arm a rat visited. Our findings suggest that prefrontal dopamine receptors are involved in Δ(9)-THC-induced disruption of spatial working memory. This interaction between the cannabinoid system and dopamine release in the PFC contributes to new directions in research and to treatments for cognitive dysfunctions associated with drug abuse and dependence.

[Effect of psychotropic drugs on activity of anticonvulsants in maximal electroshock test].

The effect ofpsychotropic drugs on the pharmacological properties of anticonvulsants was studied on white mice under maximal electroshock (ME) test conditions. Changes in the anticonvulsant effect of phenobarbital, diphenin, carbamazepine, hexamidine were traced upon their joint administration with psychotropic drugs, including piracetam, aminalon, amitriptyline, imizine, levomepromazine, and lithium oxybutyrate. An important result of research is the fact, that in no one of combinations the basic pharmacological effect of anticonvulsants was decreased. Based on the results of experiments, the most rational combinations of anticonvulsants with psychotropic preparations were revealed as manifested in the ME test. As criterion of rational combination was the increase in the activity of anticonvulsants and reduction of their toxicity in combination or at least invariance of this parameter. Rational combinations include (i) phenobarbital with piracetam, amitriptyline, levomepromazine, and lithium oxybutyrate; (ii) carbamazepine with piracetam; and (iii) hexamidine with amitriptyline, levomepromazine and imizine.

Does cannabidiol protect against the negative effects of THC?

A recent study by Morgan and colleagues found that cannabidiol attenuates the acute cognitive effects of delta-9-tetrahydrocannabinol (THC). This is of interest as THC has been associated with the detrimental effects of cannabis on mental health in at-risk users, and the potency of cannabis is increasing across Europe.

[GABAergic mechanism of cerebrovasculareffect of mexidol].

Experiments on rats showed that mexidol significantly increases local cerebral blood flow in animals under conditions of global transient brain ischemia, whereas in intact rats this drug initially causes a decrease in the blood flow, followed by its recovery. Mechanism of the cerebrovascular effect of mexidol is determined by its action on GABA receptors of cerebral vessels, which confirmed the fact that the cerebrovascular effect of mexidol is absent in the presence of bicuculline.

Cannabinoid receptor type 1- and 2-mediated increase in cyclic AMP inhibits T cell receptor-triggered signaling.

The aim of this study was to characterize inhibitory mechanisms on T cell receptor signaling mediated by the cannabinoid receptors CB1 and CB2. Both receptors are coupled to G(i/o) proteins, which are associated with inhibition of cyclic AMP formation. In human primary and Jurkat T lymphocytes, activation of CB1 by R(+)-methanandamide, CB2 by JWH015, and both by Delta9-tetrahydrocannabinol induced a short decrease in cyclic AMP lasting less than 1 h. However, this decrease was followed by a massive (up to 10-fold) and sustained (at least up to 48 h) increase in cyclic AMP. Mediated by the cyclic AMP-activated protein kinase A and C-terminal Src kinase, the cannabinoids induced a stable phosphorylation of the inhibitory Tyr-505 of the leukocyte-specific protein tyrosine kinase (Lck). By thus arresting Lck in its inhibited form, the cannabinoids prevented the dephosphorylation of Lck at Tyr-505 in response to T cell receptor activation, which is necessary for the subsequent initiation of T cell receptor signaling. In this way the cannabinoids inhibited the T cell receptor-triggered signaling, i.e. the activation of the zeta-chain-associated protein kinase of 70 kDa, the linker for activation of T cells, MAPK, the induction of interleukin-2, and T cell proliferation. All of the effects of the cannabinoids were blocked by the CB1 and CB2 antagonists AM281 and AM630. These findings help to better understand the immunosuppressive effects of cannabinoids and explain the beneficial effects of these drugs in the treatment of T cell-mediated autoimmune disorders like multiple sclerosis.

The psychoactive plant cannabinoid, Delta9-tetrahydrocannabinol, is antagonized by Delta8- and Delta9-tetrahydrocannabivarin in mice in vivo.

BACKGROUND AND PURPOSE: To follow up in vitro evidence that Delta(9)-tetrahydrocannabivarin extracted from cannabis (eDelta(9)-THCV) is a CB(1) receptor antagonist by establishing whether synthetic Delta(9)-tetrahydrocannabivarin (O-4394) and Delta(8)-tetrahydrocannabivarin (O-4395) behave as CB(1) antagonists in vivo. EXPERIMENTAL APPROACH: O-4394 and O-4395 were compared with eDelta(9)-THCV as displacers of [(3)H]-CP55940 from specific CB(1) binding sites on mouse brain membranes and as antagonists of CP55940 in [(35)S]GTPgammaS binding assays performed with mouse brain membranes and of R-(+)-WIN55212 in mouse isolated vasa deferentia. Their ability to antagonize in vivo effects of 3 or 10 mg kg(-1) (i.v.) Delta(9)-tetrahydrocannabinol in mice was then investigated. KEY RESULTS: O-4394 and O-4395 exhibited similar potencies to eDelta(9)-THCV as displacers of [(3)H]-CP55940 (K (i)=46.6 and 64.4 nM, respectively) and as antagonists of CP55940 in the [(35)S]GTPgammaS binding assay (apparent K (B)=82.1 and 125.9 nM, respectively) and R-(+)-WIN55212 in the vas deferens (apparent K (B)=4.8 and 3.9 nM respectively). At i.v. doses of 0.1, 0.3, 1.0 and/or 3 mg kg(-1) O-4394 and O-4395 attenuated Delta(9)-tetrahydrocannabinol-induced anti-nociception (tail-flick test) and hypothermia (rectal temperature). O-4395 but not O-4394 also antagonized Delta(9)-tetrahydrocannabinol-induced ring immobility. By themselves, O-4395 and O-4394 induced ring immobility at 3 or 10 mg kg(-1) (i.v.) and antinociception at doses above 10 mg kg(-1) (i.v.). O-4395 also induced hypothermia at 3 mg kg(-1) (i.v.) and above. CONCLUSIONS AND IMPLICATIONS: O-4394 and O-4395 exhibit similar in vitro potencies to eDelta(9)-THCV as CB(1) receptor ligands and as antagonists of cannabinoid receptor agonists and can antagonize Delta(9)-tetrahydrocannabinol in vivo.

Motivational effects of cannabinoids are mediated by mu-opioid and kappa-opioid receptors.

Repeated THC administration produces motivational and somatic adaptive changes leading to dependence in rodents. To investigate the molecular basis for cannabinoid dependence and its possible relationship with the endogenous opioid system, we explored delta9-tetrahydrocannabinol (THC) activity in mice lacking mu-, delta- or kappa-opioid receptor genes. Acute THC-induced hypothermia, antinociception, and hypolocomotion remained unaffected in these mice, whereas THC tolerance and withdrawal were minimally modified in mutant animals. In contrast, profound phenotypic changes are observed in several place conditioning protocols that reveal both THC rewarding and aversive properties. Absence of microreceptors abolishes THC place preference. Deletion of kappa receptors ablates THC place aversion and furthermore unmasks THC place preference. Thus, an opposing activity of mu- and kappa-opioid receptors in modulating reward pathways forms the basis for the dual euphoric-dysphoric activity of THC.

[Pharmacological and physiological effects of ginseng on actions induced by opioids and psychostimulants].

Pharmacological and physiological effects of ginseng on actions induced by opioids and psychostimulants were summarized. Analgesic effects of opioids, such as morphine and U-50,488H, were blocked by ginseng in a non-opioid dependent manner. Furthermore, ginseng inhibited the tolerance to and dependence on morphine, and prevented the suppressive effect on the development of morphine tolerance caused by co-exposure to foot-shock stress, but not psychological stress. On the other hand, behavioral sensitization (reverse tolerance to ambulation-accelerating effect) to morphine, methamphetamine (MAP) and cocaine was also inhibited by ginseng. Interestingly, ginseng also inhibited the appearance of the recurrent phenomenon (reappearance of the sensitized state was observed at the time of readministration of MAP and cocaine even after a 30-day discontinuation of drug administration) of the effect of MAP and cocaine. The conditioned place preference of MAP and cocaine was completely blocked by ginseng. These findings provide evidence that ginseng may be useful clinically for the prevention of abuse and dependence of opioids and psychostimulants.

Modification of behavioral effects of drugs in mice by neuroactive steroids.

RATIONALE: Neuroactive steroids represent a novel class of potential therapeutic agents (epilepsy, anxiety, migraine, drug dependence) thought to act through positive allosteric modulation of the GABA(A) receptor. A synthetically derived neuroactive steroid, ganaxolone (3alphahydroxy-3beta-methyl-5alpha-pregnan-20-one), is in phase-II clinical trials for epilepsy. Unlike traditional anticonvulsants such as diazepam and phenobarbital, ganaxolone shows equipotent suppression of both the seizure activity and the behavioral effects of pentylenetetrazol (PTZ) administration. OBJECTIVES: The present study explored possible reversal by ganaxolone and related neuroactive steroids of some behavioral effects of additional pharmacological challenges. METHODS: Direct behavioral observation and photocell-counted locomotor activity of male, Swiss-Webster mice were made with various compounds alone and in conjunction with ganaxolone. RESULTS: Ganaxolone both prevented and reversed PTZ-induced locomotor depression in mice. Further, ganaxolone reversed the locomotor depression induced by other convulsant/anxiogenic stimuli: bicuculline, picrotoxin and, to a lesser extent, yohimbine. Ganaxolone failed to reverse the locomotor stimulation induced by cocaine, methamphetamine, dizocilpine, and phencyclidine. In addition to ganaxolone, the endogenous neuroactive steroids allopregnanolone and pregnanolone and the synthetic neuroactive steroid Co 2-1068 also reversed observed behaviors and locomotor depression induced by PTZ. CONCLUSIONS: The present findings support the unique pharmacological effects of neuroactive steroids as a novel class of positive allosteric modulators of GABA.

[Extracorporeal blood correction in the therapy of drug-resistant mental disorders]. / Ekstrakorporal'naia gemokorrektsiia v terapii farmakorezistentnykh psikhicheskikh rasstroistv.

544 patients resistant to pharmacotherapy were treated by different methods of extracorporal hemocorrection (EH). Positive changes in mental state were achieved in more than half of the patients by means of EH without any psychopharmacologic drugs. These changes were caused by antipsychotic and antidepressive effects of EH as well as by its ability to normalize biochemical, immunological and rheological blood indices

Antagonism by CPP (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, of beta-phenylethylamine (PEA)-induced hypermotility in mice of different strains.

In male C57BL/6, BALB/c, and SHR (bred from Swiss) mice, pretreatment with (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), a competitive antagonist of N-methyl-D-aspartate (NMDA) receptor, attenuated the hyperlocomotion induced by beta-phenylethylamine (PEA). This effect of CPP was blocked by intracerebroventricularly (ICV) administered NMDA (0.2 nM). CPP did not alter the hyperlocomotion induced by d-amphetamine. PEA rarely inhibited spontaneous motor activity in those strains. Two other competitive antagonists of NMDA, 2-amino-5-phosphonopentanoic acid (AP-5) and 2-amino-7-phosphonoheptanoic acid (AP-7), ICV at doses of 0.01-0.1 microgram, were ineffective. The noncompetitive antagonists of NMDA, dizocilpine (MK-801) and phencyclidine, at subthreshold doses of 0.1-0.5 mg/kg, potentiated the stimulant effect of PEA. In earlier studies we also observed antagonism between CPP and PEA in NIH-Swiss mice, a strain in which PEA inhibits locomotion. Relationships between the stimulant and the anxiogenic effects of PEA are discussed.

[The use of hyperbaric oxygenation in treating mental patients resistant to psychopharmacotherapy]. / Primenenie giperbaricheskoi oksigenatsii v lechenii rezistentnykh k psikhofarmakoterapii psikhicheski bol'nykh.

127 patients were observed: 65 schizophrenic patients and 62 patients with vascular mental disorders. The treatment by hyperbaric oxygenation (HBO) was applied in such patients to overcome resistance to psychopharmacotherapy. A positive clinical effect was marked in 72.5% of cases (in 67.4% of schizophrenic patients and in 77.4% of patients with vascular diseases). The conclusion was made that HBO enabled to shorten the time of hospital treatment as well as to improve both clinical and social prognosis.

Antisense oligodeoxynucleotides to the kappa-1 receptor block the antinociceptive effects of delta 9-THC in the spinal cord.

Intrathecal pretreatment of mice with an antisense oligodeoxynucleotide directed against the kappa-1 receptor significantly reduced the antinociceptive effects of the kappa receptor agonist U50,488 as well as delta 9-THC, the major psychoactive ingredient found in cannabis. A mismatched oligodeoxynucleotide which contained four switched bases did not block the antinociception produced by U50,488 or delta 9-THC. Furthermore, kappa-1 antisense did not alter the antinociceptive effects of either the mu receptor-selective opioid DAMGO, or the delta receptor-selective opioid DPDPE. By using kappa-1 antisense, we were able to demonstrate that an interaction occurs between the cannabinoids and opioids in the spinal cord.

Effects of BMY-21502 on anoxia in mice.

The protective effects of BMY-21502 (1-[[1-[2-(trifluoromethyl)-4-pyrimidinyl]-4-piperidinyl]methyl]-2- pyrrolidinone) against cerebral anoxia were investigated using various models in mice, in comparison with those of other cerebroactive drugs. Oral administration of BMY-21502 (10-100 mg/kg) significantly prolonged the survival time in KCN (2.4 mg/kg, i.v.)-induced anoxia. Oxiracetam and idebenone exerted similar but weak protection at doses above 100 mg/kg, p.o. and only at a dose of 100 mg/kg, p.o., respectively. Significant protection by BMY-21502 against moderate hypobaric hypoxia was observed at doses of 30 and 100 mg/kg, p.o. Idebenone (100 and 300 mg/kg, p.o.) significantly prolonged the survival time of mice in this model, but oxiracetam (30-300 mg/kg, p.o.) did not. Oral administration of all of these drugs (BMY-21502, 3-300 mg/kg; Oxiracetam, 100-1000 mg/kg; Idebenone, 100-1000 mg/kg) failed to increase the number of gasps and the duration of gasping in the decapitated head of mice as a complete ischemic model. The anti-anoxic effect of BMY-21502 in the KCN-anoxia model was blocked by pretreatment with scopolamine. These findings suggest that BMY-21502 has an anti-anoxic action superior to those of the other cerebroactive drugs used, and activation of the CNS cholinergic system is involved as one of the causative mechanisms for the anti-anoxic effect of BMY-21502.