WIN55,212-2 impairs non-associative recognition and spatial memory in rats via CB1 receptor stimulation.

Endogenous and exogenous cannabinoids modulate learning and memory primarily via the cannabinoid type 1 receptor (CB1R). A variety of experimental procedures has focused on the role of CB1R in various aspects of learning and memory processes. However, the picture still remains unclear as there is a lack of information on the effects of relatively low doses of CB1R agonists in relation to their effects on locomotion. The present study sought to investigate CB1R activation, using a range of relatively low doses of the CB1R agonist WIN55,212-2, on multiple aspects of learning and memory in rats. For this purpose, non-associative learning was examined using the habituation of locomotion paradigm, recognition memory was evaluated with the novel object recognition task, and the radial water maze test was selected to assess rats' spatial memory. The ability of the CB1R antagonist, SR141716A, to counteract WIN55,212-2-induced behavioral effects was also tested. WIN55,212-2 (0.3, but not 0.03 or 0.1mg/kg) disrupted non-associative learning, different aspects of short- and long-term recognition memory (storage and retrieval) and retention of spatial memory. The 0.3mg/kg dose of WIN55,212-2 also decreased ambulatory, but not vertical (rearing), activity in non-habituated rats. These effects appeared to be CB1R dependent since pretreatment with SR141716A (0.03 mg/kg) prevented the WIN55,212-2-induced behavioral effects. The present findings further support and extend the complex impact of exogenous cannabinoids on learning and memory in relation to their effects on locomotion.

Cannabinoids negatively modulate striatal glutamate and dopamine release and behavioural output of acute D-amphetamine.

The cannabinoid system plays a regulatory role in neurotransmission and is involved in the central actions of psychostimulants. This complex interaction between the cannabinoid system and psychostimulants represents a potential pharmacological target for psychosis and addiction. However, most studies have focused on cocaine, therefore, it is unclear whether these findings can be extended to other psychostimulants such as the amphetamines. The present study investigated the effects of WIN55,212-2, a synthetic cannabinoid and SR141716A, a CB1 receptor antagonist, on D-amphetamine-induced locomotor activity and extracellular dopamine and glutamate release in the striatum. Rats were either observed for locomotor activity or glutamate and dopamine neurotransmitter release in the striatum using in vivo microdialysis following intraperitoneal co-administration of D-amphetamine with WIN55,212-2 or SR141716A. Our results demonstrated that d-amphetamine per se induced hyperlocomotion and enhanced dopamine and glutamate release, as expected. WIN55,212-2 dampened these effects when co-administered with d-amphetamine, while alone it displayed its characteristic biphasic motor profile coupled with increases in dopamine and decreases in glutamate release. SR141716A at high doses reduced D-amphetamine-induced hyperlocomotion and completely reversed enhanced dopamine and glutamate release but alone had no effect. These findings validate the capacity of the cannabinoid system to modulate amphetamine-induced behaviour and its neurochemical output, in a state-dependent manner, providing insight into aspects of the neurobiological substrate that underlies amphetamines' psychotogenic and addictive properties.

Δ(9)-THC and WIN55,212-2 affect brain tissue levels of excitatory amino acids in a phenotype-, compound-, dose-, and region-specific manner.

Endocannabinoids are involved in excitatory neurotransmission initiated by glutamate and aspartate. The aim of the present study was to investigate the effects of the cannabinoid agonists, Δ(9)-THC and WIN55,212-2, on tissue (prefrontal cortex, dorsal striatum, nucleus accumbens, hippocampus, amygdala and hypothalamus) levels of glutamate and aspartate in two rat phenotypes, high responders (HR) and low responders (LR), differentiated according to their response to a novel environment. HR displayed increased motor activity but no difference in basal levels of glutamate and aspartate as compared to LR. Both cannabinoids increased ambulatory activity at the low doses, this effect was observed only in HR following Δ(9)-THC, but in both HR and LR following WIN55,212-2. The cannabinoids primarily increased glutamate levels in the prefrontal cortex, dorsal striatum, nucleus accumbens and hippocampus, while the high dose of WIN55,212-2 decreased glutamate levels in the amygdala and both doses in the hypothalamus; these effects appeared overall more pronounced in HR. In contrast, the cannabinoids primarily decreased aspartate levels in all brain regions, except in the dorsal striatum, where an increase was seen after both doses of Δ(9)-THC and WIN55,212-2 as well as in the nucleus accumbens after the low dose of Δ(9)-THC in HR; these effects also appeared overall more pronounced in HR. Present results show that exogenous cannabinoids affect tissue levels of glutamate and aspartate in a phenotype-, compound-, dose-, and brain region-dependent manner.

Glutamate levels and activity of the T cell voltage-gated potassium Kv1.3 channel in patients with systemic lupus erythematosus.

OBJECTIVE: Alterations in glutamate homeostasis and Kv1.3 voltage-gated potassium channel function have been independently associated with T cell dysfunction, whereas selective blockade of Kv1.3 channels inhibits T cell activation and improves T cell-mediated manifestations in animal models of autoimmunity. Because low extracellular glutamate concentrations enhance the activity of this channel in normal T cells ex vivo, we undertook this study to examine serum glutamate concentrations and Kv1.3 channel activity in patients with systemic lupus erythematosus (SLE). METHODS: We used high-performance liquid chromatography for glutamate measurements, and we used the whole-cell patch-clamp technique for electrophysiologic studies performed in freshly isolated, noncultured peripheral T cells. RESULTS: Mean +/- SD serum concentrations of glutamate were lower in patients with either clinically quiescent SLE (77 +/- 27 microM [n = 18]) or active SLE (61 +/- 36 microM [n = 16]) than in healthy controls (166 +/- 64 microM [n = 24]) (both P < 0.0001). The intrinsic gating properties of the Kv1.3 channels in lupus T cells were found to be comparable with those in healthy control-derived T cells. Notably, electrophysiologic data from SLE patient-derived T cells exposed to extracellular glutamate concentrations similar to their respective serum levels (50 microM) demonstrated Kv1.3 current responses enhanced by almost 20% (P < 0.01) compared with those subsequently obtained from the same cell in the presence of glutamate concentrations within control serum levels (200 microM). CONCLUSION: Based on the key role of Kv1.3 channel activity in lymphocyte physiology, an enhancing in vivo effect of low serum glutamate concentrations on the functional activity of this channel may contribute to lupus T cell hyperactivity. Studies to further elucidate Kv1.3 responses in SLE, as well as the possible pathogenetic role of this unsuspected metabolic abnormality, may have therapeutic implications for SLE patients.