Piracetam potentiates neuronal and behavioral effects of ketamine

Introduction: Ketamine has a fast, but short-term antidepressant effect. To support the therapeutic effect, repeated administrations of the drug are needed, which causes cognitive disorders. The drugs with cerebroprotective action can potentially intensify the main and weaken the side effects of drugs. Materials and methods: The impact of ketamine (5 and 20 μM), piracetam (100 μM), and their combinations on the synaptic transmission was studied on hippocampal slices in the CA1 area of rat hippocampus by means of electrophysiological methods. In behavioral experiments were aimed at studying an impact of the used drugs on the predictors which mark depressant behavior of rats: the duration of immobilization in a forced swimming test and preference for the consumption of sucrose solution (comparably with water). The behavioral experiments were performed on intact rats and rats with behavioral depression induced by chronic swimming stress. Results and discussion: Ketamine (5 and 20 μM) potentiates synaptic transmission in the radial layer of the CA1 hippocampal area. At a smaller concentration, ketamine potentiates synaptic transmission only due to the postsynaptic action, and at a greater concentration – with help of post- and presynaptic action. Piracetam (100 µM), like ketamine at a concentration of 5 μM stimulated synaptic transmission, but to a lesser degree. Ketamine at a concentration 5 μM under combined effect with piracetam induced the same effect as that at a concentration of 20 μM without piracetam, only due to a postsynaptic action. Ketamine at doses of 5 and 20 mg/kg one hour after a single systemic administration resulted in the reduced immobilization duration, but not predictors of preference for consuming a sweet solution; piracetam at a dose of 100 mg/kg under these conditions had no impact on the parameters of the rats’ behavior. The studied behavior parameters in cases of behavioral depression also changed after a single administration of ketamine at the doses of 5 and 20 mg/kg. Piracetam significantly stimulated an antidepressant action of ketamine under these circumstances. Conclusion: Piracetam potentiates a ketamine-induced enhancement of the synaptic transmission at the radial layer of the CA1 hippocampal area when investigating at the brain slices. Piracetam stimulates an antidepressant action of a single dose of ketamine in cases of behavioral depression, though it has no antidepressant effect when administered at a single dose.

Single synapses control mossy cell firing

The function of mossy cells (MCs) in the dentate gyrus has remained elusive. Here we determined the functional impact of single mossy fibre (MF) synapses on MC firing in mouse entorhino-hippocampal slice cultures. We stimulated single MF boutons and recorded Ca2+ transients in the postsynaptic spine and unitary excitatory postsynaptic potentials (EPSPs) at the MC soma. Synaptic responses to single presynaptic stimuli varied strongly between different MF synapses, even if they were located on the same MC dendrite. Synaptic strengths ranged from subthreshold EPSPs to direct postsynaptic action potential (AP) generation. Induction of synaptic plasticity at these individual MF synapses resulted in potentiation or depression depending on the initially encountered synaptic state, indicating that synaptic transmission at MF synapses on MCs is determined by their previous functional history. With these unique functional properties MF-MC synapses control MC firing individually thereby enabling modulation of the dentate network by single granule cells.

PKC-mediated GABAergic enhancement of dopaminergic responses: implication for short-term potentiation at a dual-transmitter synapse

Transmitter-mediated homosynaptic potentiation is generally implemented by the same transmitter that mediates the excitatory postsynaptic potentials (EPSPs), e.g., glutamate. When a presynaptic neuron contains more than one transmitter, however, potentiation can in principle be implemented by a transmitter different from that which elicits the EPSPs. Neuron B20 in Aplysia contains both dopamine and GABA. Although only dopamine acts as the fast excitatory transmitter at the B20-to-B8 synapse, GABA increases the size of these dopaminergic EPSPs. We now provide evidence that repeated stimulation of B20 potentiates B20-evoked dopaminergic EPSPs in B8 apparently via a postsynaptic mechanism, and short-term potentiation of this synapse is critical for the establishment and maintenance of an egestive network state. We show that GABA can act postsynaptically to increase dopamine currents that are elicited by direct applications of dopamine to B8 and that dopamine is acting on a 5-HT3-like receptor. This potentiation is mediated by GABAB-like receptors as GABAB-receptor agonists and antagonists, respectively, mimicked and blocked the potentiating actions of GABA. The postsynaptic actions of GABA rely on a G protein-mediated activation of PKC. Our results suggest that the postsynaptic action of cotransmitter-mediated potentiation may contribute to the maintenance of the egestive state of Aplysia feeding network and, in more general terms, may participate in the plasticity of networks that mediate complex behaviors.

Neuropeptide S: a novel regulator of pain-related amygdala plasticity and behaviors

Amygdala plasticity is an important contributor to the emotional-affective dimension of pain. Recently discovered neuropeptide S (NPS) has anxiolytic properties through actions in the amygdala. Behavioral data also suggest antinociceptive effects of centrally acting NPS, but site and mechanism of action remain to be determined. This is the first electrophysiological analysis of pain-related NPS effects in the brain. We combined whole cell patch-clamp recordings in brain slices and behavioral assays to test the hypothesis that NPS activates synaptic inhibition of amygdala output to suppress pain behavior in an arthritis pain model. Recordings of neurons in the laterocapsular division of the central nucleus (CeLC), which serves pain-related amygdala output functions, show that NPS inhibited the enhanced excitatory drive [monosynaptic excitatory postsynaptic currents (EPSCs)] from the basolateral amygdala (BLA) in the pain state. As shown by miniature EPSC analysis, the inhibitory effect of NPS did not involve direct postsynaptic action on CeLC neurons but rather a presynaptic, action potential-dependent network mechanism. Indeed, NPS increased external capsule (EC)-driven synaptic inhibition of CeLC neurons through PKA-dependent facilitatory postsynaptic action on a cluster of inhibitory intercalated (ITC) cells. NPS had no effect on BLA neurons. High-frequency stimulation (HFS) of excitatory EC inputs to ITC cells also inhibited synaptic activation of CeLC neurons, providing further evidence that ITC activation can control amygdala output. The cellular mechanisms by which EC-driven synaptic inhibition controls CeLC output remain to be determined. Administration of NPS into ITC, but not CeLC, also inhibited vocalizations and anxiety-like behavior in arthritic rats. A selective NPS receptor antagonist ([d-Cys(tBu)5]NPS) blocked electrophysiological and behavioral effects of NPS. Thus NPS is a novel tool to control amygdala output and pain-related affective behaviors through a direct action on inhibitory ITC cells.