Adenosine and the adenine nucleotides have a potent depressant action on cerebral cortical neurons, including identified corticospinal cells. Other purine and pyrimidine nucleotides were either weakly depressant (inosine and guanosine derivatives) or largely inactive (xanthine, cytidine, thymidine, uridine derivatives). The 5'-triphosphates and to a lesser extent the 5'-diphosphates of all the purine and pyrimidines tested had excitant actions on cortical neurons. Adenosine transport blockers and deaminase inhibitors depressed the firing of cortical neurons and potentiated the depressant actions of adenosine and the adenine nucleotides. Methylxanthines (theophylline, caffeine, and isobutylmethylxanthine) antagonized the depressant effects of adenosine and the adenine nucleotides and enhanced the spontaneous firing rate of cerebral cortical neurons. Intracellular recordings showed that adenosine 5'-monophosphate hyperpolarizes cerebral cortical neurons and suppresses spontaneous and evoked excitatory postsynaptic potentials in the absence of any pronounced alterations in membrane resistance or of the threshold for action potential generation. It is suggested that adenosine depresses spontaneous and evoked activity by inhibiting the release of transmitter from presynaptic nerve terminals. Furthermore, the depressant effects of potentiators and excitant effects of antagonists of adenosine on neuronal firing are consistent with the hypothesis that cortical neurons are subject to control by endogenously released purines.

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Creutzfeldt–Jakob disease (CJD) is the prototypic human prion disease that occurs most commonly in sporadic and genetic forms, but it is also transmissible and can be acquired through medical procedures, resulting in iatrogenic CJD (iCJD). The largest numbers of iCJD cases that have occurred worldwide have resulted from contaminated cadaveric pituitary-derived human growth hormone (hGH) and its use to treat primary and secondary growth hormone deficiency. We report a comprehensive, tissue-based and molecular genetic analysis of the largest series of UK hGH-iCJD cases reported to date, including in vitro kinetic molecular modelling of genotypic factors influencing prion transmission. The results show the interplay of prion strain and host genotype in governing the molecular, pathological and temporal characteristics of the UK hGH-iCJD epidemic and provide insights into the adaptive mechanisms involved when prions cross genotypic barriers. We conclude that all of the available evidence is consistent with the hypothesis that the UK hGH-iCJD epidemic resulted from transmission of the V2 human prion strain, which is associated with the second most common form of sporadic CJD.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1638-x) contains supplementary material, which is available to authorized users.

Vasoactive intestinal polypeptide (VIP) was tested on neurons in the rat sensory motor cerebral cortex and on the isolated hemisected toad spinal cord. Iontophoretically applied VIP excited deep, spontaneously active cortical neurons, including identified corticospinal neurons. The excitation had a latency of onset varying from several seconds to over 1 min and often lasted for a minute or longer after cessation of the application. Desensitization of the effect occurred with repeated applications. VIP caused a depolarization of motoneurons and dorsal root terminals in the isolated amphibian spinal cord. Threshold for this effect was about 10(-6) M. The effects of VIP on both preparations were comparable with those of another peptide, substance P.

The effects of a number of neuronally localized peptides have been ascertained on corticospinal and other unidentified neurons in the rat cerebral cortex. Motilin, somatostatin, and luteinizing hormone releasing hormone excited most of the corticospinal neurons on which they were tested. Cholecystokinin. Met-enkephalin, vasoactive intestinal peptide, and neurotensin also excited some corticospinal neurons. Many nonidentified neurons were excited by all of these peptides. Met-enkephalin had a depressant action on some (14%) corticospinal neurons. Leu-enkaphalin depressed many identified and nonidentified neurons and had an excitatory action on a few neurons. Both excitatory and inhibitory actions of the enkephalins were antagonized by naloxone. Thyrotropin-releasing hormone had predominantly depressant actions on the spontaneous firing of corticospinal and nonidentified neurons but did excite some unidentified cortical neurons. Secretin had no effect on the firing of most of the neurons tested.