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saline-to-drug changes of state, albeit not necessarily at the same dose; here, drug-to-saline transfer failure occurred at doses that were about three-fold lower than those at which saline-to-drug state changes caused transfer to fail (► ED50: 9.8 and 29 mg/kg, respectively).

State changes can produce powerful memory failure; under the conditions described above, extreme food deprivation to the point of starvation fails to overcome the inability to remember. Remarkably, studies involving agents such as ► benzodiazepines and ► opiates, to which ► tolerance is considered to readily develop, have so far failed to reveal any evidence that tolerance develops to those agents' ability to induce state dependence; training with drug followed by numerous further drug ("over-") training sessions does not prevent failures of recall when the subjects are later tested with saline.

The state-dependent memory failure is, however, surmountable. Rats trained with saline or CDP 40 mg/kg fail to remember when tested for the first time with CDP 40 mg/kg or saline, respectively; but if later provided the opportunity to learn the same response in the alternative state (i.e., after administration of saline or CDP 40 mg/kg, respectively) rats will eventually learn to recall the response in either state. It is uncertain, though, whether such recall in either state implements only one as opposed to one of two separate ► engrams (Colpaert 1990).

State Specificity

When a response is acquired with saline or with any given agent, the extent to which transfer occurs to other agents may vary widely but it can also be the case that transfer is confined to a narrow class of pharmacologically similar agents. For example, rats trained with ► morphine demonstrate transfer when tested with another m-opiate receptor agonist, but not with lower-efficacy opiates or any other drug. Recall may be further limited to a particular dose; rats trained with 5 mg/kg morphine remember well when tested with 5 mg/kg, but not with lower or higher doses of morphine (Fig. 2). Thus, ► retrieval can be confined to an exquisitely exclusive, molecularly defined magnitude of activation of a single, particular neurotransmitter receptor (sub)type; these findings highlight memory's state specificity in addition to its state dependence (Bruins Slot and Colpaert 1999).

Specificity can also extend to conditions other than the drug state. For example, a given agent may render state dependent a response that is acquired in a particular set of conditions of arousal and drive for instance, but not the same response in another set of conditions. Equally, with a given agent, a normal-to-drug change of state may impair

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