Effects of metabotropic glutamate receptor 2/3 agonism and antagonism on schizophrenia-like cognitive deficits induced by phencyclidine in rats

Abstract

Dysregulation of glutamate neurotransmission may play a role in cognitive deficits in schizophrenia. Manipulation of glutamate signaling using drugs acting at metabotropic glutamate receptors has been suggested as a novel approach to treating schizophrenia-related cognitive dysfunction. We examined how the metabotropic glutamate receptor 2/3 agonist LY379268 and the metabotropic glutamate receptor 2/3 antagonist LY341495 altered phencyclidine-induced disruptions in performance in the 5-choice serial reaction time task. This test assesses multiple cognitive modalities characteristically impaired in schizophrenia that are disrupted by phencyclidine administration. Acute LY379268 alone did not affect 5-choice serial reaction time task performance, except for nonspecific response suppression at high doses. Acute LY379268 administration exacerbated phencyclidine-induced disruption of attentional performance in this task, while acute LY341495 did not alter 5-choice serial reaction time task performance during phencyclidine exposure. Chronic LY341495 impaired attentional performance in the 5-choice serial reaction time task by itself, but attenuated phencyclidine-induced excessive timeout responding. The mixed effects of metabotropic glutamate receptor 2/3 agonism and antagonism on cognitive performance under baseline conditions and after disruption with phencyclidine demonstrate that different aspects of cognition may respond differently to a given pharmacological manipulation, indicating that potential antipsychotic or pro-cognitive medications need to be tested for their effects on a range of cognitive modalities. Our findings also suggest that additional mechanisms, besides cortical glutamatergic transmission, may be involved in certain cognitive dysfunctions in schizophrenia.

Figure 1. Diagrams of experimental designs

Injections and procedures in Experiments 2 and 3 (A) and Experiment 4 (B) are schematically represented; dark line denotes period of pump treatment. PCP: phencyclidine.

Figure 2. Effects of acute administration of the metabotropic glutamate receptor 2/3 agonist LY379268 on performance in the 5-choice serial reaction time task under baseline conditions

Accuracy (A), percent correct responses (B), premature responses (C), timeout responses (D), latency to correct response (E), and total trials (F) are expressed as mean ± SEM. Asterisks (*P < 0.05; **P < 0.01; ***P < 0.001) denote statistically significant differences after LY379268 administration compared with performance after vehicle administration; ampersand (^&P < 0.05) denotes significant main effect detected by ANOVA.

Figure 3. Effects of acute administration of the metabotropic glutamate receptor 2/3 agonist LY379268 on performance in the 5-choice serial reaction time task during repeated phencyclidine administration

Accuracy (A), percent correct responses (B), premature responses (C), timeout responses (D), latency to correct response (E), and total trials (F) are expressed as mean ± SEM. Pound signs (^##P < 0.01; ^###P < 0.001) denote statistically significant difference during phencyclidine administration compared with baseline performance; asterisks (*P < 0.05; **P < 0.01) denote statistically significantly difference between the LY379268-treated group compared with the vehicle-treated group; closed arrow (↑) denotes a phencyclidine injection; open arrow (⇧) denotes an LY379268 injection.

Figure 4. Effects of acute administration of the metabotropic glutamate receptor 2/3 antagonist LY341495 on performance in the 5-choice serial reaction time task during repeated phencyclidine administration

Accuracy (A), percent correct responses (B), premature responses (C), timeout responses (D), latency to correct response (E), and total trials (F) are expressed as mean ± SEM. Pound signs (^##P < 0.01; ^###P < 0.001) denote statistically significant difference during phencyclidine administration compared with baseline performance; dollar signs (^$P < 0.08) denote a trend toward differences during phencyclidine administration compared with baseline performance; closed arrow (↑) denotes a phencyclidine injection; open arrow (⇧) denotes an LY341495 injection.

Figure 5. Effects of chronic administration of the metabotropic glutamate receptor 2/3 antagonist LY341495 on performance in the 5-choice serial reaction time task during repeated phencyclidine administration

Accuracy (A), percent correct responses (B), premature responses (C), timeout responses (D), latency to correct response (E), and total trials (F) are expressed as mean ± SEM. Pound signs (^##P < 0.01) denote statistically significant differences during phencyclidine administration compared with baseline performance; dagger signs (^††P < 0.01; ^†††P < 0.001) denote statistically significant differences during phencyclidine administration compared with performance after saline injections; asterisks (*P < 0.05; ***P < 0.001) denote statistically significantly differences between the LY341495-treated group compared with the vehicle-treated group; “at” signs (^@P < 0.05; ^@@P < 0.01; ^@@@P < 0.001) denote a statistically significant Presence of Pump × Pump Content interaction (see section 2.6 “Data analyses” for a definition of the factors analyzed); gray field denotes the period of pump treatment; closed arrow (↑) in the graphs denotes a phencyclidine injection; closed arrows (↑) below the abscissa denote pump implantation and removal.