Long-term depression (LTD) of synaptic transmission at parallel fibre-Purkinje cell synapses is thought to be a cellular substrate of motor learning in the cerebellum. This use-dependent change in synaptic efficacy is induced by conjunctive stimulation of Parallel fibres and climbing fibres. Researchers agree that the induction of LTD requires, as an initial step, a calcium influx via voltage-gated Ca2+ channels into a Purkinje cell, together with activation of ionotropic (AMPA) and probably metabotropic subtypes of glutamate receptors of this cell. Indeed, due to the lack of specific antagonist, the final demonstration of the contribution of metabotropic receptors in the LTD induction process, under functional conditions, remains unanswered. The debate is now focused on the second-messenger processes leading to LTD of synaptic transmission at parallel fibre-Purkinje cell synapses, after the calcium influx into the cell. All researchers agree that a calcium-dependent cascade of events including activation of protein kinase C is necessary for LTD induction. In contrast, the recruitment in the LTD induction of another cascade, also triggered by Ca2+, that is, through synthesis of nitric oxide and cyclic GMP, remains controversial.

On the other hand, growing evidence suggests that these chains of reaction underlying LTD might ultimately lead to a genuine change in the functional characteristics of AMPA receptors at the parallel fibre-Purkinje cell synapses.

Desensitization of cGMP-activated channels was examined in excised, inside-out patches obtained from rod photoreceptors. Cyclic GMP was applied using a rapid-flow system in which concentration jumps are complete within 10–50 ms. In outer-segment patches containing many channels, the cGMP-dependent conductance reached a steady plateau that was maintained for tens of seconds in the presence of cGMP; thus, there was no indication of slow desensitization. However, rapid desensitization on the scale of milliseconds could not be ruled out because of limited speed of access of cGMP to the inner face of the patch membrane. To test for rapid desensitization, inner-segment patches containing only a single cGMP-activated channel were used. In these one-channel patches, there was no change in activity of the channel with time from its earliest onset after application of cGMP, indicating that rapid desensitization also did not occur.

AMPA and NMDA type glutamate receptors were studied in isolated catfish cone horizontal cells using the whole-cell and outside-out patch-recording techniques. In whole-cell recordings, cyclothiazide (CTZ) enhanced the peak current in response to glutamate (in the presence of NMDA receptor antagonists). In patch recordings, currents evoked by rapid and maintained applications of glutamate desensitized with a time constant of one millisecond. CTZ blocked this rapid desensitization. Recovery from desensitization of the AMPA receptors was rapid, having a time constant of 8.65 ms. In contrast, the whole-cell and patch responses to applications of NMDA were much smaller than the AMPA receptor responses and did not desensitize. The relative contribution of these two receptor subtypes depends critically on the condition of the synapse: if glutamate levels are tonically present, the NMDA receptors contribute significantly to the postsynaptic response. If glutamate levels fall rapidly following the release of a single quantum of glutamate, then AMPA receptor currents will dominate the postsynaptic response.

We previously reported that blood forms of Trypanosoma cruzi express alpha- and beta-adrenergic receptors and that binding of specific agonists to these receptors modifies the infective capacity of the parasite in vitro. The present study has revealed that the inhibitory effect of the beta-adrenergic agonist L-isoproterenol and the stimulatory effect of the alpha-adrenergic agonist L-phenylephrine are not produced when the parasite is subjected to prolonged exposure to otherwise effective doses of these agonists or when supraoptimal doses of these agonists are used. We refer to these phenomena as ‘desensitization’ because of their analogy with vertebrate cells becoming desensitized by prolonged exposure to, or relatively high concentrations of, adrenergic agonists. At a constant agonist concentration, T. cruzi desensitization was time-dependent and, when the time of parasite treatment with the agonists was not changed, the higher concentrations of the agonist tested were the most effective in producing desensitization. The reduced infectivity resulting from treatment with optimal doses of L-isoproterenol was accompanied by elevated levels of cyclic adenosine mono- phosphate (cAMP) which were not detectable when L-isoproterenol concentrations producing desensitization were used. This finding implicated cAMP as a likely second signal in the inhibitory mechanisms of this agonist. No significant change in cAMP was detectable in parasites treated with L-phenylephrine, leaving open the question about how optimal doses of this alpha-adrenergic agonist enhance T. cruzi infectivity. Parasite responsiveness to alpha- and beta-adrenergic agonists as well as the desensitization effects define a system which regulates infectivity and could be modified at the host tissue level by naturally occurring agonists.

Sensitization Alternating Desensitization (SADTM) is a revolutionary, Paradigm-Shifting approach for treating post-traumatic stress disorder and most other psychological and physiological problems. It has been clearly shown to be efficacious through anecdotal evidence and a complete lack of findings from controlled-outcome studies. (Satirical)

Childhood phobias are complexly determined but responsive to behavioral interventions. This review focuses on emotive imagery, a variant of systematic desensitization developed specifically for use in treatment of children’s excessive fears. Although emotive imagery appears to be a useful treatment procedure, further research is needed before it could be considered as having “well-established” empirical status. Several other important methodological and theoretical issues are emphasized.