Neuroscience
-
Dysfunction of basal ganglia circuits underlies a variety of movement disorders and neuropsychiatric conditions. Selective control of the electrical activity of striatal outflow pathways by manipulation of ion channel function presents a novel therapeutic approach. Toward this end, we have constructed and studied in vitro an adenoviral gene transfer vector that employs the promoter region of the dopamine-1 receptor to drive expression of the inward rectifier K(+) channel Kir2.3. ⋯ Current clamp studies of transduced striatal neurons demonstrated an increase in the firing threshold, latency to first action potential and decrease in neuronal excitability. Neurotoxin-induced activation of c-Fos, a marker of neuronal activity, was blocked in transduced neurons indicating that the decrease in electrical excitability was physiologically significant. When used in vivo, this strategy may have the potential to positively impact movement disorders by selectively changing activity of neurons belonging to the direct striatal pathway, characterized by the expression of dopamine-1 receptors.
-
Previous investigations with 3,4-methylenedioxymethamphetamine (MDMA) have suggested that administration of this drug results in a degeneration of 5-HT nerve terminals and subsequent alterations in 5-HT neurotransmission. However, only limited investigations have examined the effects of MDMA on the dorsal raphe nucleus. The present study was designed to assess the effect of MDMA on the rate-limiting enzyme in 5-HT biosynthesis, tryptophan hydroxylase (TPH), by measuring TPH2 protein and mRNA levels in rat dorsal raphe (DR) nucleus. ⋯ MDMA treatment significantly decreased (125)I-RTI-55 labeled SERT binding sites in the striatum, nucleus accumbens and cingulate cortex demonstrating a loss of 5-HT terminals. The increase in TPH2 mRNA levels in both the mid DR and caudal DR of MDMA-treated rats may reflect a compensatory mechanism in the injured 5-HT neurons to increase TPH2 protein synthesis. Taken together, our results suggest that a serious defect occurs in the biosynthesis of TPH2 in the DR following MDMA administration.
-
The rewarding effects of cocaine have been reported to occur within seconds of administration. Extensive evidence suggests that these actions involve the ability of cocaine to inhibit the dopamine (DA) transporter. We recently showed that 1.5 mg/kg i.v. cocaine inhibits DA uptake within 5 s. ⋯ Further, the blood-brain barrier impermeant cocaine-methiodide had no effect on DA uptake or peak height, indicating that the generalized peripheral effects of cocaine do not contribute to the CNS alterations measured here. Finally, we show that GBR-12909 (0.75, 1.5, and 3.0 mg/kg) also significantly inhibited DA uptake within 5 s post-injection, although the peak effect and return to baseline were markedly delayed compared with cocaine, particularly at the highest dose. Combined, these observations indicate that the central effects of dopamine uptake inhibitors occur extremely rapidly following i.v. drug delivery.
-
Our experiments demonstrate a novel role for group I metabotropic glutamate receptor (mGluR) subtypes 1 and 5 in generating a long-lasting synaptic excitation in the substantia gelatinosa (SG) and deep dorsal horn (DH) neurons of the rat spinal cord. In the present study we have investigated a slow excitatory postsynaptic current (EPSC), elicited by a brief high intensity (at Adelta/C fiber strength) and high frequency (20 or 100 Hz) stimulation of primary afferent fibers (PAFs) using whole-cell patch-clamp recordings from neurons located in the DH (laminae II-V) in spinal cord slices of young rats and wild-type and gene-targeted mice lacking mGluR1 subtype. The results shown here suggest that the activation of both mGluR1 and mGluR5 along with NK1 receptors, may be involved in the generation of the slow EPSC in the spinal cord DH. ⋯ Therefore, we conclude, that glutamate transporters strongly influence the group I mGluR activation by PAFs possibly at sensory synapses in the DH. Overall these data indicate that stimulus trains can generate a sustained and widespread glutamate signal that can further elicit prolonged EPSCs predominantly mediated by the group I mGluRs. These slow excitatory synaptic currents may have important functional implications for DH cell firing and synaptic plasticity of sensory transmission, including nociception.
-
Long term facilitation (LTF) of C-fiber-evoked firing of wide dynamic range neurons in the spinal dorsal horn in response to conditioning stimulation (CS) of afferent fibers is a widely studied cellular model of spinal nociceptive sensitization. Although 100 Hz CS of primary afferent fibers is commonly used to induce spinal cord LTF, this frequency exceeds the physiological firing range. Here, we examined the effects of electrical stimulation of the sciatic nerve within the physiological frequency range on the magnitude and stability of the C-fiber-evoked responses of wide dynamic range neurons and the expression of immediate early genes (c-fos, zif268, and Arc) in anesthetized rats. ⋯ Three hertz stimulation induced the early phase of LTF, but the responses were decremental. Arc and zif268, two genes previously coupled to LTP of synaptic transmission in the adult brain, are upregulated at the same frequencies that give stable LTF (30 and 100 Hz). This frequency-dependence is important for understanding how the afferent firing pattern affects neuronal plasticity and nociception in the spinal dorsal horn.