Effects of the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine on phencyclidine-induced behavior and expression of the immediate-early genes in the discrete brain regions of rats.

Because of the possible interaction between adenosine receptors and dopaminergic functions, the compound acting on the specific adenosine receptor subtype may be a candidate for novel antipsychotic drugs. To elucidate the antipsychotic potential of the selective adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA), we examined herein the effects of CPA on phencyclidine (PCP)-induced behavior and expression of the immediate-early genes (IEGs), arc, c-fos and jun B, in the discrete brain regions of rats. PCP (7.5 mg/kg, s.c.) increased locomotor activity and head weaving in rats and this effect was significantly attenuated by pretreatment with CPA (0.5 mg/kg, s.c.). PCP increased the mRNA levels of c-fos and jun B in the medial prefrontal cortex, nucleus accumbens and posterior cingulate cortex, while leaving the striatum and hippocampus unaffected. CPA pretreatment significantly attenuated the PCP-induced increase in c-fos mRNA levels in the medial prefrontal cortex and nucleus accumbens. CPA also significantly attenuated the PCP-induced arc expression in the medial prefrontal cortex and posterior cingulate cortex. When administered alone, CPA decreased the mRNA levels of all IEGs examined in the nucleus accumbens, but not in other brain regions. Based on the ability of CPA to inhibit PCP-induced hyperlocomotion and its interaction with neural systems in the medial prefrontal cortex, posterior cingulate cortex and nucleus accumbens, the present results provide further evidence for a significant antipsychotic effect of the adenosine A(1) receptor agonist.

Small-conductance Ca2+-dependent K+ channels are the target of spike-induced Ca2+ release in a feedback regulation of pyramidal cell excitability.

Cooperative regulation of inosiol-1,4,5-trisphosphate receptors (IP(3)Rs) by Ca(2+) and IP(3) has been increasingly recognized, although its functional significance is not clear. The present experiments first confirmed that depolarization-induced Ca(2+) influx triggers an outward current in visual cortex pyramidal cells in normal medium, which was mediated by apamin-sensitive, small-conductance Ca(2+)-dependent K(+) channels (SK channels). With IP(3)-mobilizing neurotransmitters bath-applied, a delayed outward current was evoked in addition to the initial outward current and was mediated again by SK channels. Calcium turnover underlying this biphasic SK channel activation was investigated. By voltage-clamp recording, Ca(2+) influx through voltage-dependent Ca(2+) channels (VDCCs) was shown to be responsible for activating the initial SK current, whereas the IP(3)R blocker heparin abolished the delayed component. High-speed Ca(2+) imaging revealed that a biphasic Ca(2+) elevation indeed underlays this dual activation of SK channels. The first Ca(2+) elevation originated from VDCCs, whereas the delayed phase was attributed to calcium release from IP(3)Rs. Such enhanced SK currents, activated dually by incoming and released calcium, were shown to intensify spike-frequency adaptation. We propose that spike-induced calcium release from IP(3)Rs leads to SK channel activation, thereby fine tuning membrane excitability in central neurons.