An On-Demand Drug Delivery System for Control of Epileptiform Seizures.

Drug delivery systems have the potential to deliver high concentrations of drug to target areas on demand, while elsewhere and at other times encapsulating the drug, to limit unwanted actions. Here we show proof of concept in vivo and ex vivo tests of a novel drug delivery system based on hollow-gold nanoparticles tethered to liposomes (HGN-liposomes), which become transiently permeable when activated by optical or acoustic stimulation. We show that laser or ultrasound simulation of HGN-liposomes loaded with the GABAA receptor agonist, muscimol, triggers rapid and repeatable release in a sufficient concentration to inhibit neurons and suppress seizure activity. In particular, laser-stimulated release of muscimol from previously injected HGN-liposomes caused subsecond hyperpolarizations of the membrane potential of hippocampal pyramidal neurons, measured by whole cell intracellular recordings with patch electrodes. In hippocampal slices and hippocampal-entorhinal cortical wedges, seizure activity was immediately suppressed by muscimol release from HGN-liposomes triggered by laser or ultrasound pulses. After intravenous injection of HGN-liposomes in whole anesthetized rats, ultrasound stimulation applied to the brain through the dura attenuated the seizure activity induced by pentylenetetrazol. Ultrasound alone, or HGN-liposomes without ultrasound stimulation, had no effect. Intracerebrally-injected HGN-liposomes containing kainic acid retained their contents for at least one week, without damage to surrounding tissue. Thus, we demonstrate the feasibility of precise temporal control over exposure of neurons to the drug, potentially enabling therapeutic effects without continuous exposure. For future application, studies on the pharmacokinetics, pharmacodynamics, and toxicity of HGN-liposomes and their constituents, together with improved methods of targeting, are needed, to determine the utility and safety of the technology in humans.

Responses of putative medium spiny neurons and fast-spiking interneurons to reward-related sensory signals in Wistar and genetically hypertensive rats.

Medium spiny neurons (MSN) are the primary output neurons of the striatum. Their activity is modulated by exogenous afferents and local circuit inputs, including fast-spiking interneurons (FSI). Altered responses of MSN and FSI may account for altered reward-driven behaviour in hyperactive rat strains, such as the genetically hypertensive (GH) rat. To investigate whether striatal neuron responses differ between GH and Wistar rats, we recorded putative MSNs (pMSN) and FSI (pFSI) from freely moving GH and Wistar rats in a classically conditioned (Pavlovian) cue-reward association paradigm. Here, the same auditory cue signal predicted reward delivery in one block of trials, but was not followed by reward in another. The significance of the cue as a reward predictor was indicated during each block by an environmental context provided by the house light. The results showed that pMSN in GH rats, but not Wistar rats, were more sensitive to the auditory signal in the context indicating no-reward, than in the reward context. Such enhanced sensitivity to cues in a no-reward context may contribute to a specific deficit in instrumental behaviour seen in GH rats, which maintain higher levels of instrumental responding in a context that indicates responding will not be rewarded. In addition, pFSI also responded to auditory signals, but there was no significant effect of reward context. Surprisingly, given their known feed-forward role, pFSI responded at longer latency than pMSN, suggesting that relative timing of activity in the two populations may be task specific.

Dopamine modulation of honey bee (Apis mellifera) antennal-lobe neurons.

Primary olfactory centers [antennal lobes (ALs)] of the honey bee brain are invaded by dopamine (DA)-immunoreactive neurons early in development (pupal stage 3), immediately before a period of rapid growth and compartmentalization of the AL neuropil. Here we examine the modulatory actions of DA on honey bee AL neurons during this period. Voltage-clamp recordings in whole cell configuration were used to determine the effects of DA on ionic currents in AL neurons in vitro from pupal bees at stages 4-6 of the nine stages of metamorphic adult development. In approximately 45% of the neurons tested, DA (5-50 x 10(-5) M) reduced the amplitude of outward currents in the cells. In addition to a slowly activating, sustained outward current, DA reduced the amplitude of a rapidly activating, transient outward conductance in some cells. Both of the currents modulated by DA could be abolished by the removal of Ca2+ from the external medium or by treatment of cells with charybdotoxin (2 x 10(-8) M), a blocker of Ca2+-dependent K+ currents in the cells. Ca2+ currents were not affected by DA, nor were A-type K+ currents (I(A)). Results suggest that the delayed rectifier-like current (I(KV)) also remains intact in the presence of DA. Taken together, our data indicate that Ca2+-dependent K+ currents are targets of DA modulation in honey bee AL neurons. This study lends support to the hypothesis that DA plays a role in the developing brain of the bee.