Combined β-Adrenergic and Cholinergic Antagonism Produces Behavioral and Cognitive Impairments in the Water Maze: Implications for Alzheimer Disease and Pharmacotherapy with β-Adrenergic Antagonists

Abstract

This study examined the effects of b-adrenergic and muscarinic blockade on spatial learning and strategy use in the water maze. Male Long-Evans rats received systemic injections of propranolol (PRO; 10 or 20 mg/kg) or scopolamine (SCO; 0.3 or 1.0 mg/kg) either singly or in combination. To separate strategies learning from spatial learning approximately half of the rats underwent water maze strategies pretraining prior to drug administration and spatial training. PRO did not impair performance in any group. SCO impaired naive but not pretrained rats. PRO and SCO given together in high doses impaired all aspects of behavior in both naive and pretrained rats, and caused sensorimotor disturbances in some groups. PRO (10 mg/kg) and SCO (0.3 mg/kg) together caused a specific spatial reversal learning impairment in pretrained rats without causing strategies impairments or sensorimotor disturbances. Nadolol administered with SCO failed to produce the same impairments as PRO, suggesting that PRO produced its effects by acting on central nervous system sites. These results point to a greater than additive impairing effect of PRO and SCO on adaptive behavior, and a specific role for b-adrenergic and cholinergic systems working in conjunction in spatial learning. They also suggest that some of the behavioral and cognitive impairments seen in Alzheimer patients or patients receiving pharmacotherapy with b-adrenergic antagonists in which cholinergic activity is also compromised may result from the combined impairment of b-adrenergic and cholinergic systems.

Combined but not Individual Administration of β-Adrenergic and Serotonergic Antagonists Impairs Water Maze Acquisition in the Rat

“…The findings also suggest a link between the cognitive and behavioral impairments that occur in Alzheimer disease and the fact that multiple neurotransmitter systems such as cholinergic, noradrenergic, and serotonergic systems are typically impaired in the brain of Alzheimer patients (Chen et al, 2000;Davis et al, 1999;Dringenberg, 2000;Francis et al, 1999;Lai et al, 2002;Reinikainen et al, 1990). Our previous studies confirmed that neither PRO nor pCPA given individually impaired WM performance, and that scopolamine impaired naive but not WM strategiespretrained rats (Beiko et al, 1997;Saber and Cain, 2003). We also found that combinations of either PRO and scopolamine, or pCPA and scopolamine impaired all aspects of WM performance in both naive and strategiespretrained rats, and also caused sensorimotor impairments (Beiko et al, 1997;Saber and Cain, 2003).…”

“…Our previous studies confirmed that neither PRO nor pCPA given individually impaired WM performance, and that scopolamine impaired naive but not WM strategiespretrained rats (Beiko et al, 1997;Saber and Cain, 2003). We also found that combinations of either PRO and scopolamine, or pCPA and scopolamine impaired all aspects of WM performance in both naive and strategiespretrained rats, and also caused sensorimotor impairments (Beiko et al, 1997;Saber and Cain, 2003). These 'global' cognitive/behavioral impairments due to combined antagonism of neurotransmitter systems known to be impaired in Alzheimer disease are consistent with the cognitive/ behavioral impairments seen in Alzheimer patients.…”

“…A spatial navigation task was chosen because Alzheimer patients often are unable to make use of landmarks in a familiar environment, wander away from their living quarters, and display repetitive behaviors that appear purposeless (De Deyn et al, 1999;Fairburn and Hope, 1988;Teri et al, 1988). These symptoms appear to be similar to the spatial navigation impairments and repetitive thigmotaxic swimming behaviors seen in previous studies that used combined administration of agents relevant to the brain neurotransmitter impairments seen in Alzheimer disease (Beiko et al, 1997;Cain et al, 2000;Saber and Cain, 2003).…”

Limited efficacy of propranolol on the reconsolidation of fear memories

“…with either 10 mg/kg of propranolol or saline and tested again 48 h later (Test 2). This dosage of propranolol is one of the highest previously used in several studies to interfere with the consolidation or reconsolidation in several different types of memories, including both aversive and appetitive (e.g., Sara et al 1995;Przybyslawski et al 1999;Saber and Cain 2003;Debiec and LeDoux 2004;Diergaarde et al 2006;Abrari et al 2007;Milton et al 2008;Rodriguez-Romaguera et al 2009). All groups of rats had similar retention latencies at Test 1 and Test 2.…”

“…Whereas we cannot exclude that intracerebral administration of propranolol might affect IA reconsolidation, in the present study we chose to focus on systemic administrations, because our goal was to test for effects potentially relevant for clinical applications. Furthermore, the dose used in our studies is the same used in the majority of investigations that reported an effect of propranolol on memory consolidation and reconsolidation (e.g., Sara et al 1995;Przybyslawski et al 1999;Saber and Cain 2003;Debiec and LeDoux 2004;Diergaarde et al 2006;Abrari et al 2007;Milton et al 2008;Rodriguez-Romaguera et al 2009). A total of 10 mg/kg appears to be the highest dose that can be utilized systemically in rat without causing a toxic effect.…”