We investigated the effects of 5-hydroxytryptamine (5-HT, serotonin) in striatal cholinergic interneurones with gramicidin-perforated whole-cell patch recordings. Bath-application of serotonin (30 µM) significantly and reversibly increased the spontaneous firing rate of 37/45 cholinergic interneurones tested. On average, in the presence of serotonin, firing rate was 273 ± 193% of control. Selective agonists of 5-HT 1A , 5-HT 3 , 5-HT 4 and 5-HT 7 receptors did not affect cholinergic interneurone firing, while the 5-HT 2 receptor agonist α-methyl-5-HT (30 µM) mimicked the excitatory effects of serotonin. Consistently, the 5-HT 2 receptor antagonist ketanserin (10 µM) fully blocked the excitatory effects of serotonin. Two prominent after-hyperpolarizations (AHPs), one of medium duration that was apamin-sensitive and followed individual spikes, and one that was slower and followed trains of spikes, were both strongly and reversibly reduced by serotonin; these effects were fully blocked by ketanserin. Conversely, the depolarizing sags observed during negative current injections and mediated by hyperpolarization-activated cationic currents were not affected. In the presence of apamin and tetrodotoxin, the slow AHP was strongly reduced by 5-HT, and fully abolished by the calcium channel blocker nickel. These results show that 5-HT exerts a powerful excitatory control on cholinergic interneurones via 5-HT 2 receptors, by suppressing the AHPs associated with two distinct calcium-activated potassium currents.

Excitation of accumbal D2 cells governs vital actions, including avoidance of learned risks, but the origins of this excitation and roles of D2 cells in innate risk-avoidance are unclear. Hypothalamic neurons producing orexins (also called hypocretins) enhance innate risk-avoidance via poorly understood neurocircuits. We describe a direct orexin→D2 excitatory circuit and show that D2 cell activity is necessary for orexin-dependent innate risk-avoidance in mice, thus revealing an unsuspected hypothalamus-accumbens interplay in action selection.

The striatum is the largest nucleus of the basal ganglia, and is crucially involved in motor control. Striatal projection cells are medium-size spiny neurons (MSNs) and form functional GABAergic synapses with other MSNs through their axon collaterals. A subpopulation of MSNs also release substance P (SP), but its role in MSN-MSN communication is unknown. We studied this issue in rat brain slices, in the presence of antagonists for GABA, acetylcholine, dopamine, and opioid receptors; under these conditions, whole-cell paired recordings from MSNs (located Ͻ100 m apart) revealed that, in 31/137 (23%) pairs, a burst of five spikes in a MSN caused significant facilitation (14.2 Ϯ 8.9%) of evoked glutamatergic responses in the other MSN. Reciprocal facilitation of glutamatergic responses was present in 4 of these pairs. These facilitatory effects were maximal when spikes preceded glutamatergic responses by 100 ms, and were completely blocked by the NK1 receptor antagonist L-732,138. Furthermore, in 31/57 (54%) MSNs, a burst of 5 antidromic stimuli delivered to MSN axons in the globus pallidus significantly potentiated glutamatergic responses evoked 250 or 500 ms later by stimulation of the corpus callosum. These effects were larger at 250 than 500 ms intervals, were completely blocked by L-732,138, and facilitated spike generation. These data demonstrate that MSNs facilitate glutamatergic inputs to neighboring MSNs through spike-released SP acting on NK1 receptors. The current view that MSNs form inhibitory networks characterized by competitive dynamics will have to be updated to incorporate the fact that groups of MSNs interact in an excitatory manner.

Medium spiny striatal projection neurons (MSNs) release opioid neuropeptides, but the role of these neurotransmitters is still poorly understood. While presynaptic inhibition of corticostriatal axons by opioid receptors has been demonstrated using exogenous ligands, the action of synaptically released opioids in the striatum has not been investigated. We performed single and paired whole-cell recordings from rat MSNs while corticostriatal fibers were electrically activated. In single recording experiments, we also activated antidromically the axons of a population of MSNs. Corticostriatal fibers were stimulated once every 10 s and every other stimulation was preceded by 5 antidromic spikes (at 100 Hz). This burst of antidromic spikes produced robust inhibition of evoked corticostriatal responses. This inhibition was not affected by the ␦-opioid receptor antagonist SDM25N, but was completely abolished by the -opioid receptor antagonist CTOP. Inhibitory effects were maximal (on average 29.6 Ϯ 11.4%) when the burst preceded the corticostriatal stimulation by 500 ms and became undetectable for intervals Ͼ2 s. Paired recordings from MSNs located Ͻ100 m apart revealed that, in 30 of 56 (54%) pairs, a burst of five action potentials in one of the MSNs caused significant inhibition (17.1 Ϯ 5.7%) of evoked glutamatergic responses in the other MSN. In 5 of these pairs, reciprocal inhibition of corticostriatal inputs was present. These effects were maximal 500 ms after the burst and were completely blocked by CTOP. Thus, these results reveal a novel, strong opioid-mediated communication between MSNs and provide a new cellular substrate for competitive dynamics in the striatum.

The striatum is the main basal ganglia input nucleus, receiving extensive glutamatergic inputs from cortex and thalamus. Medium spiny striatal projection neurons (MSNs) are GABAergic, and their axon collaterals synapse on other MSNs. Approximately 50% of MSNs corelease substance P (SP), but how this neurotransmitter controls MSN activity is poorly understood. We