original state does appear to underlie opiate addiction, in effect constituting its very ''system'' mechanism. This implies that the signal transductions that are involved in pain processing and opiate actions thereon are currently thought to proceed in a bidirectional manner; any input
State Dependence of Memory. Fig. 4. Regressive, temporally graded retrograde amnesia induced by a normal-to-scopolamine state changes. Rats were in the normal state trained in a complex task in which learning was assessed from five parameters that characterize the newly acquired behavior (Fig. 3). The acute injection of different doses (ordinate) of scopolamine caused the parameters to assume values that resembled those observed at one or another point in the course of training. The abscissa indicates the remoteness in time (relative to day 0, the last day of training) of such corresponding points (mean ±SEM of the five parameters; day - 165 corresponds to the beginning of training). Increasing doses resulted in a behavior similar to that observed at increasingly remote stages of the acquisition that preceded the drug test. (Redrawn from Colpaert et al. 2001.)
to such systems induces not a single but two dual effects that are opposite in sign. Thus, morphine causes not only analgesia as a ''first-order'' effect, but also a ''second-order'' hyperalgesia or frank pain that outlasts the analgesia for some time. With chronic opiate exposure, the second-order pain grows and masks the first-order analgesia, resulting in analgesic tolerance. In a parallel manner, opiates also induce two distinct memory states that coincide temporally with their first and second-order effects on pain processing. The first-order opiate memory state is one in which analgesia is encoded, but the second-order state is one in which the individual experiences a possibly excruciating, opiate-induced pain and is enabled to learn and remember that the next opiate administration powerfully relieves that pain, however temporarily. Thus emerges the view that opiate addiction represents the self-medication of compelling opiate pain, with both that pain and the pain-relieving instrumental behavior being encoded in the second-order (withdrawal) state of memory (Colpaert etal. 2006).
Clearly, an organism's memory can operate in any one of a decidedly large number of different states in which engrams can be specifically stored. Such state dependence of memory challenges the common view that an individual possesses a single, unified memory that integrates all past experience and can be acted upon at any time. Rather, at any point of time, memory appears to be locked into, limited to, but also enabled with the unique capabilities of one particular state. As time moves from one to another point, so memory comprises another, equally unique set of retrievable capabilities based on current state.
The state dependence of memory invites the question as to whether ► forgetting occurs at all; it is unclear
State Dependence of Memory. Fig. 3. Studies examining the effects of saline-to-scopolamine changes of mnemonic state on the recall of five aspects of learned behavior. (a) Rats were trained for in all 165 days in a complex task in which the different independent measures (e.g., total responding) reflect different aspects (e.g., performance) of what was learned. (b) The acquisition data in panel A are here plotted as the % of animals satisfying the learning criterion that was applied to each of the five measures. These % data were fit by best-fitting functions to generate the five learning curves shown in panel B. (c) Over the 8-month period that followed training, rats were tested for retrieval after injection of different doses of scopolamine;data from these tests are shown here and expressed as in panel A. (d) The scopolamine test data in panel C are here plotted as the % of animals satisfying the criteria used to generate panel B and expressed as in the same manner. These % data were fit with the dose-response functions shown. At 0.01 mg/kg scopolamine, the outcome for each of the parameters was similar (i.e., about 100%) to that at the end of acquisition. Higher doses decreased each parameter value, such that the outcomes resembled those observed earlier in training. Projections are plotted (dashed lines) to identify the point in time-since-the-end-of-acquisition ("past time'') with which the test data corresponded. These retrograde projections yielded outcomes that differed among the five parameters, the mean (M along past time) being - 136 days for the 0.16 mg/kg dose. In this manner, the mean was found for all doses, generating the function relating scopolamine dose to past time shown in Fig. 4. (Redrawn from Colpaert et al. 2001.)
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