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Sensitization of prepulse inhibition deficits by repeated administration of dizocilpine
B Schulz1, M Fendt, V Pedersen
1Tierphysiologie, Universität Tübingen, Germany.
Rationale:
Repeated administration of psychoactive drugs results in a progressive enhancement of the behavioral effects of these compounds, a phenomenon termed sensitization.
Objective:
We tested whether repeated administration of the non-competitive NMDA receptor antagonist dizocilpine (MK-801) induces sensitization of the disruptive effects of this compound on prepulse inhibition (PPI) of startle.
Methods:
Rats received nine daily i.p. injections of 0.1 mg/kg MK-801 in the startle cage and were tested for PPI, startle in the absence of prepulses and motor activity in the startle cage. Another group of rats received MK-801 in the home cage on 9 days without daily testing. Controls were injected with saline and tested daily, while a separate group of rats received saline in the home cage without daily testing. On day 10, all rats received saline injections and were tested. On day 11, all rats were injected with 0.1 mg/kg MK-801 and tested again. On day 12, all rats received 1 mg/kg dl-amphetamine i.p. and were tested for PPI, to assess a possible cross-sensitization.
Results:
MK-801 had no effect on day 1 of testing but induced a PPI deficit after 6-9 days of daily treatment and testing in those rats that received the drug in the startle cage, but not in the home cage. Motor activity was increased after repeated treatment and testing. There was also a trend towards sensitization of enhancement of the startle magnitude by MK-801 in these rats. dl-Amphetamine reduced PPI in those rats that received daily MK-801 injections in the startle cage to a similar extent as saline injections.
Conclusions:
Since PPI is considered as a measure of sensorimotor gating, our data indicate that sensorimotor gating deficits induced by MK-801 are subject to a sensitization process. These findings may be relevant for current hypotheses relating schizophrenic symptoms to sensitization.
Insights
Repeated administration of dizocilpine (MK-801) in a testing environment caused sensitization of sensorimotor gating deficits in rats. This sensitization of prepulse inhibition (PPI) deficits may relate to schizophrenia hypotheses.
Area of Science:
- Neuroscience
- Psychopharmacology
Background:
- Repeated psychoactive drug administration can enhance behavioral effects, a process known as sensitization.
- Sensitization is a key factor in understanding long-term drug effects and potential therapeutic interventions.
Purpose of the Study:
- To investigate if repeated dizocilpine (MK-801) administration sensitizes its disruptive effects on prepulse inhibition (PPI) of startle.
- To explore the relationship between MK-801-induced sensorimotor gating deficits and sensitization.
Main Methods:
- Rats received daily intraperitoneal injections of MK-801 or saline.
- Prepulse inhibition (PPI), startle magnitude, and motor activity were assessed.
- Cross-sensitization with dl-amphetamine was evaluated.
Main Results:
- Daily MK-801 administration in the startle cage, but not the home cage, led to a deficit in PPI after 6-9 days.
- Repeated treatment and testing increased motor activity.
- MK-801 showed a trend towards sensitizing startle magnitude enhancement.
Conclusions:
- Sensorimotor gating deficits induced by MK-801 are subject to sensitization.
- These findings may inform hypotheses linking schizophrenic symptoms to sensitization processes.
- The location of drug administration (testing vs. home cage) influences sensitization development.