Fall 2000

Archive of Newsletters

Invited Speaker Abstracts: SSPD Evening Paper Session at Society for Neuroscience Meeting

Can drug cues represent a context to which sensitization can be associated?

Werner J. Schmidt, Zoologisches Institut, Neuropharmakologie, Universität Tübingen, Tübingen, Germany

Behavioural sensitization refers to the intensification of a behaviour upon repeated administration of a drug. Sensitization is nearly unextinguishable and therefore is considered to play a major role in the formation of an "addiction memory". The finding that glutamate/NMDA receptor (R)-antagonists block the development of sensitization has lead to the hypothesis that repeated exposure to an addictive drug activates glutamatergic transmission and this promotes drug seeking and relapse. Many findings are in accordance with this view but not all: In several experiments the development of sensitization was not inhibited by NMDA-R-antagonists, however the expression of sensitization (which is tested only under the sensitizing drug) was abolished. This has been explained as a state-dependency effect, i. e. what has been learned in the presence of an NMDA-R-antagonist (here sensitization) can not be expressed in the absence of an NMDA-R-antagonist. State-dependent effects may have been overlooked so far since in many studies animals were treated in the home cages with the sensitizing drug plus the NMDA-R-antagonist and the development of sensitization (for example the day to day increase in locomotion) was not measured in the experimental set up. The state-dependency interpretation was criticised since most of the studies have been conducted with MK-801 and this drug produces sensitization to ist own locomotor stimulant effects. To clarify this issue, we chose haloperidol-induced catalepsy (akinesia and rigidity) of the rat that shows pronounced sensitization when repeatedly elicited (known as the "repeated measures effect"). Since acutely administrated NMDA-R-antagonists show clear cut anticataleptic effects, a possible day to day intensification of catalepsy can not be due to the effects of the NMDA-R-antagonist. We showed that haloperidol-induced catalepsy was counteracted by the NMDA-R-antagonists MK-801, CPPene, eliprodil, Ro 25-6981 as expected, but that the development of sensitization of catalepsy was not inhibited by these drugs. A challenge with haloperidol 14 days after sensitization revealed no sensitized catalepsy, haloperidol plus NMDA-R-antagonist produced the sensitized response and most interestingly, the NMDA-R-antagonist alone also elicited the sensitized response. We concluded from these findings that sensitization of catalepsy developed context dependently i. e. sensitization has been associated to the drug (NMDA-R-antagonist) cue which makes expression of sensitization dependent from the NMDA-R-antagonist state. The paradoxical finding that an anticataleptic drug can induce sensitized catalepsy shows that expression of sensitized catalepsy has been rendered completely state-dependent.

In conclusion, two forms of sensitization exist, a context-independent (non-associative) form, which can be inhibited by NMDA-R-antagonists, and a context-dependent (associative) form. It may be speculated that in the latter case NMDA-R-antagonists may disrupt the association to the environmental context but instead represent a contextual stimulus to which sensitization can become associated.

Drug sensitization, state-dependency and the activation of excitatory amino acid receptors: What are the issues?

Paul Vezina, Department of Psychiatry, Committee on Neurobiology, The University of Chicago, Chicago, IL

Both drug sensitization and state-dependency are well established phenomena that can exert powerful effects on the expression of various behaviors. Recently, a certain degree of controversy has developed over whether the latter phenomenon can provide an alternative account for the apparent ability of glutamate receptor antagonists - dizocilpine, in particular - to prevent the induction of sensitization. In a review of the results from a number of studies, it will first be addressed whether sensitized responding during induction is in fact necessary and sufficient for the subsequent later expression of sensitization. In this context, the actions of the non-competitive NMDA receptor antagonist dizocilpine on behavioral, cellular and biochemical responses during induction and expression of sensitization will be compared to those of competitive antagonists of NMDA as well as non-NMDA receptors and other manipulations impacting excitatory amino acid transmission. While the actions of dizocilpine on acute and sensitized drug-induced responding may be complex, the results of the above experiments taken together strongly support a critical need for excitatory amino acid receptor activation in the induction of drug sensitization. Supported by USPHS grants DA-9397 and DA-9860.

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