Differential drug-drug interactions of the synthetic Cannabinoids JWH-018 and JWH-073: implications for drug abuse liability and pain therapy.

Marijuana substitutes often contain blends of multiple psychoactive synthetic cannabinoids (SCBs), including the prevalent SCBs (1-pentyl-1H-indole-3-yl)-1-naphthalenyl-methanone (JWH-018) and (1-butyl-1H-indole-3-yl)-1-naphthalenyl-methanone (JWH-073). Because SCBs are frequently used in combinations, we hypothesized that coadministering multiple SCBs induces synergistic drug-drug interactions. Drug-drug interactions between JWH-018 and JWH-073 were investigated in vivo for Δ(9)-tetrahydrocannabinol (Δ(9)-THC)-like discriminative stimulus effects, analgesia, task disruption, and hypothermia. Combinations (JWH-018:JWH-073) of these drugs were administered to mice in assays of Δ(9)-THC discrimination, tail-immersion, and food-maintained responding, and rectal temperatures were measured. Synergism occurred in the Δ(9)-THC discrimination assay for two constant dose ratio combinations (1:3 and 1:1). A 1:1 and 2:3 dose ratio induced additivity and synergy, respectively, in the tail-immersion assay. Both 1:1 and 2:3 dose ratios were additive for hypothermia, whereas a 1:3 dose ratio induced subadditive suppression of food-maintained responding. In vitro drug-drug interactions were assessed using competition receptor-binding assays employing mouse brain homogenates and cannabinoid 1 receptor (CB1R)-mediated inhibition of adenylyl cyclase activity in Neuro2A wild-type cells. Interestingly, synergy occurred in the competition receptor-binding assay for two dose ratios (1:5 and 1:10), but not in the adenylyl cyclase activity assay (1:5). Altogether, these data indicate that drug-drug interactions between JWH-018 and JWH-073 are effect- and ratio-dependent and may increase the relative potency of marijuana substitutes for subjective Δ(9)-THC-like effects. Combinations may improve the therapeutic profile of cannabinoids, considering that analgesia but not hypothermia or task disruption was potentiated. Importantly, synergy in the competition receptor-binding assay suggests multiple CB1R-SCB binding sites.

Contribution of different taste cells and signaling pathways to the discrimination of "bitter" taste stimuli by an insect.

Animals can discriminate among many different types of foods. This discrimination process involves multiple sensory systems, but the sense of taste is known to play a central role. We asked how the taste system contributes to the discrimination of different "bitter" taste stimuli in Manduca sexta caterpillars. This insect has approximately eight bilateral pairs of taste cells that respond selectively to bitter taste stimuli. Each bilateral pair of bitter-sensitive taste cells has a different molecular receptive range (MRR); some of these taste cells also contain two signaling pathways with distinctive MRRs and temporal patterns of spiking. To test for discrimination, we habituated the caterpillar's taste-mediated aversive response to one bitter taste stimulus (salicin) and then asked whether this habituation phenomenon generalized to four other bitter taste stimuli (caffeine, aristolochic acid, Grindelia extract, and Canna extract). We inferred that the two compounds were discriminable if the habituation phenomenon failed to generalize (e.g., from salicin to aristolochic acid). We found that M. sexta could discriminate between salicin and those bitter taste stimuli that activate (1) different populations of bitter-sensitive taste cells (Grindelia extract and Canna extract) or (2) different signaling pathways within the same bitter-sensitive taste cell (aristolochic acid). M. sexta could not discriminate between salicin and a bitter taste stimulus that activates the same signaling pathway within the same bitter-sensitive taste cell (caffeine). We propose that the heterogeneous population of bitter-sensitive taste cells and signaling pathways within this insect facilitates the discrimination of bitter taste stimuli.

[Discriminative stimulus properties of ephedra herb (Ephedra sinica) in rats].

The stimulus properties of ephedra herb (drug of Chinese medicine) were demonstrated in rats trained to discriminate between 2.5 ml/kg extract of ephedra herb and same volume of distilled water (p.o.). On the discrimination training, animals were shaped on an FR20 schedule to respond to one of two levers for food reinforcement when they were administrated ephedra herb extract, and to respond to the other lever when they were treated with distilled water. Cumulative dosing tests for the discriminative stimulus properties consisted of two to five trials of FR20 schedule; responses for both levers were reinforced. d-Methamphetamine 1.43 mg/kg p.o. indicated complete generalization to the ephedra herb. Nicotine and caffeine indicated modest generalization, but some animals generalized completely. These results suggest that the ephedra herb has d-methamphetamine-like, but unique discriminative stimulus properties.

Tolerance to the analgesic, but not discriminative stimulus effects of morphine after brief social defeat in rats.

One of the most prominent consequences of defeat in a social confrontation is a long-lasting tolerance-like insensitivity to the analgesic effects of opiates, even when only small short-lived changes in nociception are detectable during the acute social stress. The present experiments examined (1) which kinds of social experiences lead to morphine tolerance, (2) whether or not the morphine tolerance in defeat-experienced rats extends from the analgesic effects to the discriminative stimulus and rate-decreasing effects of morphine, and (3) how long morphine tolerance lasts after a defeat experience. After five brief social confrontations including attack and threat by a resident rat leading to submission or defeat of the intruder, the latter exhibits marked tolerance to the analgesic effects of morphine, but not to the discriminative stimulus or behaviorally suppressive effects. Changes in social housing did not alter morphine's behavioral effects. Tolerance to the analgesic morphine effects was detected for 2 months after the defeat experience, whereas the discriminative stimulus and rate-decreasing effects were closely similar to those before defeat. This pattern was seen in animals for whom discriminative stimulus training with morphine was suspended after defeat as well as in those for whom it continued. In additional defeated and non-defeated animals, morphine's effects on the acoustic startle reflex was assessed. In contrast to the tail flick reflex to a noxious heat stimulus, the acoustic startle response remained unaffected by defeat experience or by morphine (up to 30 mg/kg). The long-lasting and large degree of tolerance after brief social defeat experiences appears to be limited to the analgesic effects of morphine.(ABSTRACT TRUNCATED AT 250 WORDS)

[A neuropharmacological analysis of the compensatory-recovery processes in organic failure of the parafascicular complex of the thalamus]. / Neirofarmakologicheskii analiz kompensatorno-vosstanovitel'nykh protsessov pri organicheskoi nedostatochnosti parafastsikuliarnogo kompleksa talamusa.

On the model of biological precursors of thinking in animals (cats), in conditions of free behaviour it has been shown that after neurosurgical lesion of various parts of the parafascicular complex restoration is possible of the disturbed functions of generalization and abstraction by neuropharmacological drugs acting on cholinergic, dopaminergic and GABA-ergic systems. Complex interactions are observed between transmitter structures.

Screening hallucinogenic drugs II. Systematic study of two behavioral tests.

The effects of hallucinogenic and nonhallucinogenic drugs were studied on two behavioral tests: (1) discriminated Sidman avoidance, using modified Bovet-Gatti profiles, which have been proposed as specific in detecting hallucinogenic activity and (2) a drug discrimination experiment. By the first method, the "hallucinogenic profile" was obtained with both hallucinogenic and nonhallucinogenic drugs and, at least as used here, was not a suitable screening method. In the drug discrimination experiment, data from the present study along with other available evidence suggest the potential value of this method for drug screening procedures.