Two novel adamantane derivatives, adamantan-1-yl(1-pentyl-1H-indol-3-yl)methanone (AB-001) and N-(adamtan-1-yl)-1-pentyl-1H-indole-3-carboxamide (SDB-001), were recently identified as cannabimimetic indoles of abuse. Conflicting anecdotal reports of the psychoactivity of AB-001 in humans, and a complete dearth of information about the bioactivity of SDB-001, prompted the preparation of AB-001, SDB-001, and several analogues intended to explore preliminary structure−activity relationships within this class. This study sought to elucidate which structural features of AB-001, SDB-001, and their analogues govern the cannabimimetic potency of these chemotypes in vitro and in vivo. All compounds showed similar full agonist profiles at CB 1 (EC 50 = 16−43 nM) and CB 2 (EC 50 = 29−216 nM) receptors in vitro using a FLIPR membrane potential assay, with the exception of SDB-002, which demonstrated partial agonist activity at CB 2 receptors. The activity of AB-001, AB-002, and SDB-001 in rats was compared to that of Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and cannabimimetic indole JWH-018 using biotelemetry. SDB-001 dose-dependently induced hypothermia and reduced heart rate (maximal dose 10 mg/kg) with potency comparable to that of Δ 9 -tetrahydrocannabinol (Δ 9 -THC, maximal dose 10 mg/kg), and lower than that of JWH-018 (maximal dose 3 mg/kg). Additionally, the changes in body temperature and heart rate affected by SDB-001 are of longer duration than those of Δ 9 -THC or JWH-018, suggesting a different pharmacokinetic profile. In contrast, AB-001, and its homologue, AB-002, did not produce significant hypothermic and bradycardic effects, even at relatively higher doses (up to 30 mg/kg), indicating greatly reduced potency compared to Δ 9 -THC, JWH-018, and SDB-001.

Mephedrone (MMC) is a relatively new recreational drug that has rapidly increased in popularity in recent years. This study explored the characteristics of intravenous MMC self-administration in the rat, with methamphetamine (METH) used as a comparator drug. Male Sprague-Dawley rats were trained to nose poke for intravenous MMC or METH in daily 2 h sessions over a 10 d acquisition period. Dose-response functions were then established under fixed- and progressive-ratio (FR and PR) schedules over three subsequent weeks of testing. Brains were analyzed ex vivo for striatal serotonin (5-HT) and dopamine (DA) levels and metabolites, while autoradiography assessed changes in the regional density of 5-HT and serotonin transporter (SERT) and DA transporter (DAT) and induction of the inflammation marker translocator protein (TSPO). Results showed that MMC was readily and vigorously self-administered via the intravenous route. Under a FR1 schedule, peak responding for MMC was obtained at 0.1 mg/kg/infusion, versus 0.01 mg/kg/infusion for METH. Break points under a PR schedule peaked at 1 mg/kg/infusion MMC versus 0.3 mg/kg/infusion for METH. Final intakes of MMC were 31.3 mg/kg/d compared to 4 mg/kg/d for METH. Rats self-administering MMC, but not METH, gained weight at a slower rate than control rats. METH, but not MMC, self-administration elevated TSPO receptor density in the nucleus accumbens and hippocampus, while MMC, but not METH, self-administration decreased striatal 5-hydroxyindolacetic acid (5-HIAA) concentrations. In summary, MMC supported high levels of self-administration, matching or exceeding those previously reported with other drugs of abuse.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, characterized by deposition of amyloid beta, neurofibrillary tangles, astrogliosis and microgliosis, leading to neuronal dysfunction and loss in the brain. Bio- and histochemical evidence suggests a pivotal role of central and peripheral inflammation in its aetiopathology, linked to the production of free radicals. Numerous epidemiological studies support that the long-term use of non-steroidal antiinflammatory drugs is preventive against AD, but these medications do not slow down the progression of the disease in already diagnosed patients. There are a number of studies focusing on traditional herbal medicines and small molecules (usually plant secondary metabolites) as potential anti-inflammatory drugs, particulary in respect to cytokine suppression. For instance, ω-3 polyunsaturated fatty acids and a number of polyphenolic phytochemicals have been shown to be effective against inflammation in animal and cell models. Some of these plant secondary metabolites have also been shown to possess antioxidant, anti-inflammatory, anti-amyloidogenic, neuroprotective, and cognition-enhancing effects. This review will provide an overview the effects of catechins/proanthocyanidins from green tea, curcumin from turmeric, extracts enriched in bacosides from Brahmi (Bacopa monnieri), flavone glycosides from Ginkgo biloba, and ω-3 polyunsaturated fatty acids. They do not only counteract one pathophysiological aspect of AD in numerous in vitro and in vivo studies of models of AD, but also ameliorate several of the above mentioned pathologies. The evidence suggests that increased consumption of these compounds might lead to a safe strategy to delay the onset of AD. The continuing investigation of the potential of these substances is necessary as they are promising to yield a possible remedy for this pervasive disease.

BackgroundIn Parkinson’s disease (PD), cerebral dopamine depletion is associated with PD subtype-specific metabolic patterns of hypo- and hypermetabolism. It has been hypothesised that hypometabolism reflects impairment, while hypermetabolism may indicate compensatory activity. In order to associate metabolic patterns with pathophysiological and compensatory mechanisms, we combined resting state [18F]FDG-PET (to demonstrate brain metabolism in awake animals), [18F]FDOPA-PET (dopamine depletion severity) and gait analysis in a unilateral 6-hydroxydopamine rat model.ResultsWe found unilateral nigro-striatal dopaminergic loss to decrease swing speed of the contralesional forelimb and stride length of all paws in association with depletion severity. Depletion severity was found to correlate with compensatory changes such as increased stance time of the other three paws and diagonal weight shift to the ipsilesional hind paw. [18F]FDG-PET revealed ipsilesional hypo- and contralesional hypermetabolism; metabolic deactivation of the ipsilesional network needed for sensorimotor integration (hippocampus/retrosplenial cortex/lateral posterior thalamus) was solely associated with bradykinesia, but hypometabolism of the ipsilesional rostral forelimb area was related to both pathological and compensatory gait changes. Mixed effects were also found for hypermetabolism of the contralesional midbrain locomotor region, while contralesional striatal hyperactivation was linked to motor impairments rather than compensation.ConclusionsOur results indicate that ipsilesional hypo- and contralesional hypermetabolism contribute to both motor impairment and compensation. This is the first time when energy metabolism, dopamine depletion and gait analysis were combined in a hemiparkinsonian model. By experimentally increasing or decreasing compensational brain activity, its potential and limits can be further investigated.

Deep brain stimulation (DBS) in the subthalamic nucleus (STN) has been successfully used for the treatment of advanced Parkinson's disease, although the underlying mechanisms are complex and not well understood. There are conflicting results about the effects of STN-DBS on neuronal activity of the striatum, and its impact on functional striatal connectivity is entirely unknown. We therefore investigated how STN-DBS changes cerebral metabolic activity in general and striatal connectivity in particular. We used ipsilesional STN stimulation in a hemiparkinsonian rat model in combination with [ 18 F]FDOPA-PET, [ 18 F]FDG-PET and metabolic connectivity analysis. STN-DBS reversed ipsilesional hypometabolism and contralesional hypermetabolism in hemiparkinsonian rats by increasing metabolic activity in the ipsilesional ventrolateral striatum and by decreasing it in the contralesional hippocampus and brainstem. Other STN-DBS effects were subject to the magnitude of dopaminergic lesion severity measured with [ 18 F]FDOPA-PET, e.g. activation of the infralimbic cortex was negatively correlated to lesion severity. Connectivity analysis revealed that, in healthy control animals, left and right striatum formed a bilateral functional unit connected by shared cortical afferents, which was less pronounced in hemiparkinsonian rats. The healthy striatum was metabolically connected to the ipsilesional substantia nigra in hemiparkinsonian rats only (OFF condition). STN-DBS (ON condition) established a new functional striatal network, in which interhemispheric striatal connectivity was strengthened, and both the dopamine-depleted and the healthy striatum were functionally connected to the healthy substantia nigra. We conclude that both unilateral dopamine depletion and STN-DBS affect the whole brain and alter complex interhemispheric networks.