BACKGROUND AND PURPOSEEpilepsy is the most prevalent neurological disease and is characterized by recurrent seizures. Here, we investigate (i) the anticonvulsant profiles of cannabis-derived botanical drug substances (BDSs) rich in cannabidivarin (CBDV) and containing cannabidiol (CBD) in acute in vivo seizure models and (ii) the binding of CBDV BDSs and their components at cannabinoid CB1 receptors. EXPERIMENTAL APPROACHThe anticonvulsant profiles of two CBDV BDSs (50-422 mg·kg −1 ) were evaluated in three animal models of acute seizure. Purified CBDV and CBD were also evaluated in an isobolographic study to evaluate potential pharmacological interactions. CBDV BDS effects on motor function were also investigated using static beam and grip strength assays. Binding of CBDV BDSs to cannabinoid CB1 receptors was evaluated using displacement binding assays. KEY RESULTSCBDV BDSs exerted significant anticonvulsant effects in the pentylenetetrazole (≥100 mg·kg ). The isobolographic study revealed that the anticonvulsant effects of purified CBDV and CBD were linearly additive when co-administered. Some motor effects of CBDV BDSs were observed on static beam performance; no effects on grip strength were found. The Δ 9 -tetrahydrocannabinol and Δ 9 -tetrahydrocannabivarin content of CBDV BDS accounted for its greater affinity for CB1 cannabinoid receptors than purified CBDV. CONCLUSIONS AND IMPLICATIONSCBDV BDSs exerted significant anticonvulsant effects in three models of seizure that were not mediated by the CB1 cannabinoid receptor and were of comparable efficacy with purified CBDV. These findings strongly support the further clinical development of CBDV BDSs for the treatment of epilepsy.

The herb Cannabis sativa (C. sativa) has been used in China and on the Indian subcontinent for thousands of years as a medicine. However, since it was brought to the UK and then the rest of the western world in the late 19th century, its use has been a source of controversy. Indeed, its psychotropic side effects are well reported but only relatively recently has scientific endeavour begun to find valuable uses for either the whole plant or its individual components. Here, we discuss evidence describing the endocannabinoid system, its endogenous and exogenous ligands and their varied effects on feeding cycles and meal patterns. Furthermore we also critically consider the mounting evidence which suggests non‐Δ9tetrahydrocannabinol phytocannabinoids play a vital role in C. sativa‐induced feeding pattern changes. Indeed, given the wide range of phytocannabinoids present in C. sativa and their equally wide range of intra‐, inter‐ and extra‐cellular mechanisms of action, we demonstrate that non‐Δ9tetrahydrocannabinol phytocannabinoids retain an important and, as yet, untapped clinical potential. Copyright © 2011 John Wiley & Sons, Ltd.

Once trained, rats are able to execute particularly difficult olfactory discrimination tasks with exceptional accuracy. Such skill acquisition, termed “rule learning”, is accompanied by a series of long‐lasting modifications to three cellular properties which modulate pyramidal neuron activity in piriform cortex; intrinsic excitability, synaptic excitation, and synaptic inhibition. Here, we explore how these changes, which are seemingly contradictory at the single‐cell level in terms of their effect on neuronal excitation, are manifested within the piriform cortical neuronal network to store the memory of the rule, while maintaining network stability. To this end, we monitored network activity via multisite extracellular recordings of field postsynaptic potentials (fPSPS) and with single‐cell recordings of miniature inhibitory and excitatory synaptic events in piriform cortex slices. We show that although 5 days after rule learning the cortical network maintains its basic activity patterns, synaptic connectivity is strengthened specifically between spatially proximal cells. Moreover, while the enhancement of inhibitory and excitatory synaptic connectivity is nearly identical, strengthening of synaptic inhibition is equally distributed between neurons while synaptic excitation is particularly strengthened within a specific subgroup of cells. We suggest that memory for the acquired rule is stored mainly by strengthening excitatory synaptic connection between close pyramidal neurons and runaway synaptic activity arising from this change is prevented by a nonspecific enhancement of synaptic inhibition.

Training rats in a complex olfactory discrimination task results in acquisition of "rule learning" (learning how to learn), a term describing the capability to perform the task superbly. Such rule learning results in strengthening of both excitatory and inhibitory synaptic connections between neurons in the piriform cortex. Moreover, intrinsic excitability is also enhanced throughout the pyramidal neuron population. Surprisingly, the cortical network retains its stability under these long-term modifications. In particular, the susceptibility for long-term potentiation (LTP) induction, while decreased for a short time window, returns to almost its pretraining value, although significant strengthening of AMPA receptor-mediated glutamatergic transmission remains. Such network balance is essential for maintaining the single-cell modifications that underlie long-term memory while preventing hyperexcitability that would result in runaway synaptic activity. However, the mechanisms underlying the long-term maintenance of such balance have yet to be described. In this study, we explored the role of astrocyte-mediated gliotransmission in long-term maintenance of learning-induced modifications in susceptibility for LTP induction and control of the strength of synaptic inhibition. We show that blocking connexin 43 hemichannels, which form gap junctions between astrocytes, decreases significantly the ability to induce LTP by stimulating the excitatory connections between piriform cortex pyramidal neurons after learning only. In parallel, spontaneous miniature inhibitory postsynaptic current amplitude is reduced in neurons from trained rats only, to the level of prelearning. Thus gliotransmission has a key role in maintaining learning-induced cortical stability by a wide-ranged control on synaptic transmission and plasticity. NEW & NOTEWORTHY We explore the role of astrocyte-mediated gliotransmission in maintenance of olfactory discrimination learning-induced modifications. We show that blocking gap junctions between astrocytes decreases significantly the ability to induce long-term potentiation in the piriform cortex after learning only. In parallel, synaptic inhibition is reduced in neurons from trained rats only, to the level of prelearning. Thus gliotransmission has a key role in maintaining learning-induced cortical stability by a wide-ranged control on synaptic transmission and plasticity.

Cultures of cortical neurons grown on multielectrode arrays exhibit spontaneous, robust, and recurrent patterns of highly synchronous activity called bursts. These bursts play a crucial role in the development and topological self-organization of neuronal networks. Thus, understanding the evolution of synchrony within these bursts could give insight into network growth and the functional processes involved in learning and memory. Functional connectivity networks can be constructed by observing patterns of synchrony that evolve during bursts. To capture this evolution, a modeling approach is adopted using a framework of emergent evolving complex networks and, through taking advantage of the multiple time scales of the system, aims to show the importance of sequential and ordered synchronization in network function.