These data provide important information on the brain and plasma exposure of new phytocannabinoids and guidance for the most efficacious administration route and time points for determination of drug effects under in vivo conditions.

No abstract

Because opioid and cannabinoid systems have been reported to interact in the modulation of addictive behaviour, this study was aimed at investigating the ability of cannabinoid agents to reinstate or prevent heroin-seeking behaviour after a prolonged period of extinction. In rats previously trained to self-administer heroin intravenously, non-contingent non-reinforced priming administrations of heroin and cannabinoids were presented after long-term extinction, and lever pressing following injections was observed. Results showed that: (i) intravenous priming infusions of heroin (0.1 and 0.2 mg/kg) lead to reinstatement of drug-seeking behaviour; (ii) intraperitoneal priming injections of the central cannabinoid receptor agonists R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2,3-de]-1,4-benzoxazinyl) (1-naphthalenyl)methanonemesylate (WIN 55,212-2, 0.15 and 0.3 mg/kg) and (-)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP 55,940, 0.05 and 0.1 mg/kg), but not delta9-tetrahydrocannabinol (delta9-THC, 0.1-1.0 mg/kg), effectively restored heroin-seeking behaviour; (iii) intraperitoneal priming injection of the central cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)4-methyl-1H-pyrazole-3-carboxamide (SR 141716A, 0.3 mg/kg) did not reinstate responding, but (iv) completely prevented heroin-induced reinstatement of drug-seeking behaviour. Moreover, heroin-seeking behaviour was still present for a few days following cannabinoid primings, indicating a long-lasting effect of cannabinoids on responding for heroin. These findings indicate that relapse to heroin after an extended drug-free period is triggered by cannabinoid agonists and that SR 141716A prevents drug-seeking behaviour, suggesting that the use of the cannabinoid antagonist could have some therapeutic benefits in heroin-induced relapse.

A poorly understood feature of the tauopathies is their very different clinical presentations. The frontotemporal lobar degeneration (FTLD) spectrum is dominated by motor and emotional/psychiatric abnormalities, whereas cognitive and memory deficits are prominent in the early stages of Alzheimer’s disease (AD). We report two novel mouse models overexpressing different human tau protein constructs. One is a full-length tau carrying a double mutation [P301S/G335D; line 66 (L66)] and the second is a truncated 3-repeat tau fragment which constitutes the bulk of the PHF core in AD corresponding to residues 296–390 fused with a signal sequence targeting it to the endoplasmic reticulum membrane (line 1; L1). L66 has abundant tau pathology widely distributed throughout the brain, with particularly high counts of affected neurons in hippocampus and entorhinal cortex. The pathology is neuroanatomically static and declines with age. Behaviourally, the model is devoid of a higher cognitive phenotype but presents with sensorimotor impairments and motor learning phenotypes. L1 displays a much weaker histopathological phenotype, but shows evidence of neuroanatomical spread and amplification with age that resembles the Braak staging of AD. Behaviourally, the model has minimal motor deficits but shows severe cognitive impairments affecting particularly the rodent equivalent of episodic memory which progresses with advancing age. In both models, tau aggregation can be dissociated from abnormal phosphorylation. The two models make possible the demonstration of two distinct but nevertheless convergent pathways of tau molecular pathogenesis. L1 appears to be useful for modelling the cognitive impairment of AD, whereas L66 appears to be more useful for modelling the motor features of the FTLD spectrum. Differences in clinical presentation of AD-like and FTLD syndromes are therefore likely to be inherent to the respective underlying tauopathy, and are not dependent on presence or absence of concomitant APP pathology.