Vascular Action as the Primary Mechanism of Cognitive Effects of Cholinergic, CNS-Acting Drugs, a Rat phMRI BOLD Study

Abstract

Concordant results of functional magnetic resonance imaging (fMRI) and behavioral tests prove that some non-blood-brain barrier-penetrating drugs produce robust central nervous system (CNS) effects. The anticholinergic scopolamine interferes with learning when tested in rats, which coincides with a negative blood-oxygen-level-dependent (BOLD) change in the prefrontal cortex (PFC) as demonstrated by fMRI. The peripherally acting butylscopolamine also evokes a learning deficit in a water-labyrinth test and provokes a negative BOLD signal in the PFC. Donepezil-a highly CNS-penetrating cholinesterase inhibitor-prevents the negative BOLD and cognitive deficits regardless whether the provoking agent is scopolamine or butylscopolamine. Interestingly, the non-BBB-penetrating cholinesterase inhibitor neostigmine also prevents or substantially inhibits those cognitive and fMRI changes. Intact cerebral blood flow and optimal metabolism are crucial for the normal functioning of neurons and other cells in the brain. Drugs that are not BBB penetrating yet act on the CNS highlight the importance of unimpaired circulation, and point to the cerebral vasculature as a primary target for drug action in diseases where impaired circulation and consequently suboptimal energy metabolism are followed by upstream pathologic events.

Acute modulation of the cholinergic system in the mouse brain detected by pharmacological resting-state functional MRI

“…This allows us to assume that the peripheral effects of scopolamine on cardiovascular function and vasoconstriction can be excluded, and that the observed effects are of a central nature. In contrast with the results of this study, recent work showed that butyl-scopolamine, which is also a derivative of scopolamine with poor blood-brain-barrier permeability, induced similar fMRI brain activation changes in the rat brain as scopolamine (Kocsis et al, 2014). That study concluded that the effects of scopolamine are probably mainly due to vascular responses.…”

“…Despite these differences, Wink et al still show that altering cholinergic neurotransmission affects FC in the brain. Although rsfMRI studies targeting the cholinergic system in rodents are very limited, there are fMRI studies in rats showing altered brain activity in frontal regions after the administration of scopolamine (Kocsis et al, 2014). The cholinergic network is known to be involved in learning and memory and the functional connections that are affected by scopolamine are involved in higher cognitive functions such as spatial memory, episodic memory, contextual memory, attention etc.…”

“…RsfMRI studies targeting the cholinergic system in rodents are still quite limited. However, an fMRI study in rats showed altered brain activity in frontal brain regions after diminishing cholinergic neurotransmission (Kocsis et al, 2014).…”

The role of fMRI in drug development

“…The ketamine response can be blocked by antiglutamatergic compounds [88,89] and can reverse the phMRI signal evoked by some (but not all) antipsychotic agents and compounds designed to attenuate glutamate release [95,96]. Additional drug classes that induce phMRI signals include analgesics [97–101], antipsychotics [102], cognitive enhancers [103], drugs of abuse [104,105], calcium channel blockers [106,107], cyclooxygenase-2 (COX-2) inhibitors [108], muscarinic acetylcholine receptor modulators [109–111], and therapies traditionally thought to impact solely immune system activity [112]. In addition to traditional phMRI studies, pharmacological modulation of functional connectivity in animal models and humans has also been reported [113–118].…”

Deciphering the scopolamine challenge rat model by preclinical functional MRI

“…In contrast on the basis of its peripheral vascular action as a primary mechanism, a SCO provocation-based pharmaco-MRI model was proposed as a test for procognitive agents [5,10]. Indeed, non-blood-brain barrier-penetrating anticholinergic drug, butylscopolamine (BSCO) also evoked learning deficit similarly to SCO and both compounds induced negative blood oxygen-level-dependent (BOLD) changes in the prefrontal cortex in a pharmaco-MRI study, in isoflurane anesthesia [10]. However, in α-chloralose anesthesia in a similar preclinical pharmaco-MRI study, the SCO i.v.…”