Serotonin-dependent maintenance of spatial performance and electroencephalography activation after cholinergic blockade: effects of serotonergic receptor antagonists.

The interaction between acetylcholine (ACh) and serotonin (5-hydroxytryptamine, 5-HT) in the control of behavior such as spatial navigation has received considerable attention over the last years. Previous research indicates that while a selective reduction in cholinergic transmission often produces only mild impairments in spatial and other behavioral tests, additional serotonergic blockade results in the appearance of severe behavioral deficits. Consequently, it has been argued that 5-HT plays a role in the maintenance of behavioral capacities in the face of reduced cholinergic transmission. Here, we examined the effects of 5-HT depletion and receptor blockade, alone and in combination with cholinergic-muscarinic antagonism, on spatial navigation of rats in the Morris water maze. Further, electroencephalographic (EEG) recordings were taken to test the hypothesis that a loss of neocortical activation is related to the behavioral deficits apparent after cholinergic-serotonergic blockade. The muscarinic antagonist, scopolamine (1 mg/kg) produced a moderate impairment in navigational performance. The 5-HT depletor, p-chlorophenylalanine (PCPA; 500 mg kg(-1) day(-1)x2) did not impair performance when given alone but strongly potentiated the scopolamine-induced deficit and completely blocked the acquisition of an escape response in the water maze. This effect was mimicked by the non-selective serotonin(1-2) receptor antagonist, methiothepin (0.3 mg/kg), but not by the selective serotonin(1A) antagonist, WAY 100635 (0.1-0.5 mg/kg) or the serotonin(2) antagonist, ketanserin (2-4 mg/kg). None of the 5-HT antagonists impaired performance when given alone. Electrocorticographic recordings in rats treated with scopolamine and serotonergic receptor antagonists showed that during behavioral immobility, scopolamine (1 mg/kg) increased spectral power in all frequency bands between 0.5 and 20 Hz without significantly affecting cortical activity during movement. None of the 5-HT antagonists affected cortical activity when given alone. However, methiothepin, at the same dose that produced behavioral impairments, increased spectral power between 0.5 and 4 Hz and between 8 and 12 Hz during movement when co-administered with scopolamine. The results suggest that a concurrent blockade of multiple 5-HT receptors, but not selective blockade of serotonin(1A) or serotonin(2) receptors alone, mimics the ability of global 5-HT depletion to abolish behavioral capacities that are resistant to muscarinic receptor blockade. The behavioral deficits observed here are accompanied by a reduction in neocortical activation, suggesting that disturbances of processing in cortical networks can contribute to the behavioral disorganization apparent after cholinergic and serotonergic blockade. A focus on concurrent serotonergic-cholinergic deficits may provide a useful framework for the development of novel pharmacological treatments to counteract the behavioral disorganization and loss of EEG activation present in senile dementia and Alzheimer's disease.