1 The electroencephalographic (EEG) eects of drugs interacting with dopaminergic and noradrenergic systems were studied in conscious rats. Power spectra (0 ± 30 Hz) were recorded from electrodes implanted bilaterally in the prefrontal cortex. Drug eects on EEG power were calculated as the spectral power following drug administration divided by the spectral power after vehicle administration. were dose-dependently antagonized by coadministration with moda®nil and cirazoline, but not by apomorphine. 4 In conclusion, pharmacological modulation of dopaminergic and noradrenergic transmission may result in consistent EEG changes: decreased dopaminergic or noradrenergic activity induces an increase of EEG spectral power; while increased dopaminergic or noradrenergic activity decreases EEG spectral power.

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1 The electroencephalographic (EEG) e ects of the propsychotic agent phencyclidine (PCP), were studied in conscious rats using power spectra (0 ± 30 Hz), from the prefrontal cortex or sensorimotor cortex. PCP (0.1 ± 3 mg kg 71 s.c.) caused a marked dose-dependent increase in EEG power in the frontal cortex at 1 ± 3 Hz with decreases in power at higher frequencies (9 ± 30 Hz). At high doses (3 mg kg 71 s.c.) the entire spectrum shifted to more positive values, indicating an increase in cortical synchronization. MK 801 (0.05 ± 0.1 mg kg 71 i.p.) caused similar e ects but with lesser changes in power. 2 In contrast, the non-competitive AMPA antagonists GYKI 52466 and GYKI 53655 increased EEG power over the whole power spectrum (1 ± 10 mg kg 71 i.p.). The atypical antipsychotic clozapine (0.2 mg kg 71 s.c.) synchronized the EEG (peak 8 Hz). The 5-HT 2A -antagonist, M100907, speci®cally increased EEG power at 2 ± 3 Hz at low doses (10 and 50 mg kg 71 s.c.), whereas at higher doses (0.1 mg kg 71 s.c.) the pro®le resembled that of clozapine.

1 Power spectra (0 ± 30 Hz) were recorded from transcortical electrodes implanted in prefrontal and sensorimotor cortex in conscious rats. For each animal, the spectra in the presence of a drug were divided by the spectra in the presence of vehicle to give a drug-related di erential display of the power spectra, the pro®le of EEG e ects. 2 The pro®les of a range of antipsychotic agents of di erent classes were compared. Haloperidol (0.5 mg kg 71 and 1 mg kg 71 s.c., peak 8 ± 12 Hz), chlorpromazine (0.5 mg kg 71 , i.p., peak 8 Hz), levomepromazine (1 mg kg 71 , i.p., peak 8 Hz), quetiapine (2.5 mg kg 71 , s.c., peak 9 ± 12 Hz), sertindole (2.5 mg kg 71 , s.c., peak 6 ± 14 Hz), risperidone (0.5 and 1 mg kg 71 i.p., peak 9 Hz), clozapine (0.1, 0.2, 0.3 and 5 mg kg 71 , s.c., peak 8 Hz) and MDL100907 (0.01 mg kg 71 s.c. peak 2 Hz) synchronized the EEG, increasing the power spectra between 2 and 30 Hz, although there were marked di erences between the individual pro®le of EEG e ects for each drug. 3 In contrast, the benzamides, sulpiride (7.5 and 15 mg kg 71 i.p.), and amisulpiride (1 and 15 mg kg 71 i.p.) caused marked asynchronous changes in the EEG. Raclopride (2.5 mg kg 71 i.p.), caused an initial peak at 9 Hz, but the e ects of raclopride desynchronized over a 3 h time period. 4 Moda®nil and apomorphine, administered alone, decreased the power spectra at frequencies higher than 4 Hz. Moda®nil (62.4 mg kg 71 , i.p.) selectively antagonized the e ects of clozapine, but did not antagonize the e ects of raclopride. 5 Di erent pharmacological classes of antipsychotic show synchronization or desynchronization of the EEG in the prefrontal cortex, with the benzamides showing a distinctive spectrum. There appears to be a speci®c interaction between moda®nil and clozapine. Thus, modulation of prefrontal cortical function, perhaps by thalamic gating, may be important for antipsychotic activity.

Dysfunction in the hippocampus-prefrontal cortex (H-PFC) circuit is a critical determinant of schizophrenia. Screening of pyridazinone-risperidone hybrids on this circuit revealed EGIS 11150 (S 36549). EGIS 11150 induced theta rhythm in hippocampal slice preparations in the stratum lacunosum molecular area of CA1, which was resistant to atropine and prazosin. EGIS 11150 enhanced H-PFC coherence, and increased the 8–9 Hz theta band of the EEG power spectrum (from 0.002 mg/kg i.p, at >30× lower doses than clozapine, and >100× for olanzapine, risperidone, or haloperidol). EGIS 11150 fully blocked the effects of phencyclidine (PCP) or ketamine on EEG. Inhibition of long-term potentiation (LTP) in H-PFC was blocked by platform stress, but was fully restored by EGIS 11150 (0.01 mg/kg i.p.), whereas clozapine (0.3 mg/kg ip) only partially restored LTP. EGIS 11150 has a unique electrophysiological profile, so phenotypical screening on H-PFC connectivity can reveal novel antipsychotics.