A Potential Cholinergic Mechanism of Procaine's Limbic Activation

Abstract

The local anesthetic procaine, when administered to humans intravenously (i.v.), yields brief intense emotional and sensory experiences, and concomitant increases in anterior paralimbic cerebral blood flow, as measured by positron emission tomography (PET). Procaine's high muscarinic affinity, together with the distribution of muscarinic receptors that overlaps with brain regions activated by procaine, suggests a muscarinic contribution to procaine's emotional and sensory effects. This study evaluates the effects of procaine on cerebral muscarinic cholinergic receptors in the anesthetized rhesus monkey. Whole brain and regional muscarinic receptor binding was measured before and after procaine administration on the same day in three anesthetized rhesus monkeys with PET and the radiotracer 3-(3-(3[ 18 F]fluoropropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine ([ 18 F]FP-TZTP), a cholinergic ligand that has preferential binding to muscarinic (M 2 ) receptors. On separate days each animal received six different doses of i.v. procaine in a randomized fashion. Procaine blocked up to B90% of [ 18 F]FP-TZTP specific binding globally in a dose-related manner. There were no regional differences in procaine's inhibitory concentration for 50% blockade (IC 50 ) for [ 18 F]FP-TZTP. Tracer delivery, which was highly correlated to cerebral blood flow in previous monkey studies, was significantly increased at all doses of procaine with the greatest increases occurring near procaine's IC 50 for average cortex. Furthermore, anterior limbic regions showed greater increases in tracer delivery than nonlimbic regions. Procaine has high affinity to muscarinic M 2 receptors in vivo in the rhesus monkey. This, as well as a preferential increase of tracer delivery to paralimbic regions, suggests that action at these receptors could contribute to i.v. procaine's emotional and sensory effects in man. These findings are consistent with other evidence of cholinergic modulation of mood and emotion.

Towards the development of new subtype-specific muscarinic receptor radiopharmaceuticals — Radiosynthesis and ex vivo biodistribution of [18F]3-(4-(2-(2-(2-fluoroethoxy)ethoxy)ethylthio)-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,5,6-tetrahydropyridine

“…17,18 Fluorine-18-labelled FP-TZTP has been used to study risk factors of ageing [19][20][21] and mood disorders. 22,23 Driven largely by the theory that M 1 receptor density is altered in the brain of patients with Alzheimer's disease in response to the degeneration of the cholinergic pathway, another TZTP derivative, 3-(4-(hexyloxy)-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,5,6-tetrahydropyridine (xanomeline), was found to exhibit M 1 /M 4 selectivity. 24 While it was found that xanomeline increased cognitive function of patients with Alzheimer's disease, several side effects precluded its therapeutic use.…”

Local Anesthetic Procaine Protects Rat Pheochromocytoma PC12 Cells against β-Amyloid-Induced Neurotoxicity

“…Although the IC 50 seems modest (6.3 Ìmol/l), this result does not take into consideration the possibility of a much higher affinity of procaine towards specific subtypes of muscarinic receptors. Moreover, procaine has been recently reported to bind in vivo with a high affinity the M2 receptor located in the paralimbic area of the monkey brain [49]. This affinity for the muscarinic M2 receptor has been presented by these authors to have a role in the emotions and mood modulation which, therefore, could have an interest to treat the non-cognitive conditions which occur during AD.…”

Intravenous lidocaine for neuropathic pain: Diagnostic utility and therapeutic efficacy

“…Furthermore, lidocaine infused for pain management has been reported to result in dramatic behavioral changes [5]. Procaine, another local anesthetic, is known to have profound selective limbic system activation when administered systemically, which correlates with specific regional blood flow changes in the anterior paralimbic area of the brain [6,7]. As demonstrated on positron emission tomography scan, selective activation of an anterior limbic and paralimbic network in the absence of significant cortical activation is achieved by intravenous procaine infusion and induces "powerful emotional and visceral experiences in healthy subjects" [8].…”