Muscarinic toxin selective for m4 receptors impairs memory in the rat

Abstract

The selectivity of the muscarinic toxin MT3 from green mamba snake venom was corroborated by inhibition of the binding of [3H]NMS, a classical muscarinic radioligand, to native and cloned muscarinic receptors, showing 214-fold higher affinity for m4 than for m1 subtype, without significant binding to the others. The highest concentrations of MT3 sites (putative m4 receptors) in the rat brain were found in striatum and olfactory tubercle, intermediate concentration in dentate gyrus and CA1, and lower but still conspicuous levels in CA3 and frontal cortex. MT3 caused retrograde amnesia of an inhibitory avoidance task, when injected into the dorsal hippocampus of rats after training, suggesting a positive role of these MT3 sensitive sites, which are probably m4 muscarinic receptors, in memory consolidation of this task.

Differential involvement of M1-type and M4-type muscarinic cholinergic receptors in the dorsomedial striatum in task switching

“…In contrast, MT-7 has a high selectivity for the M1-type muscarinic receptor with no or minimal affinity for the other muscarinic receptor subtypes, including the M4-type receptor (Karlsson, Jolkkonen, Mulugeta, Onali & Adem, 2000). MT-3 has a high selectivity for the M4-type receptor which is 100 to 200-fold greater than for the M1-type receptor (Jolkkonen et al, 1994;Max et al, 1993;Jerusalinsky et al, 1998). Because these different muscarinic toxins are highly selective for specific muscarinic receptor subtypes the present findings more definitely indicate that M1-type muscarinic receptors in the dorsomedial striatum are important for a shift in response patterns.…”

“…The doses were chosen based on previous experiments using similar concentrations to examine learning and memory effects following intracranial infusions (Diehl, Furstenau de Oliveira, Sanchez, Camboim, de Oliveira Alvares, Lanziotti, Cervenansky, Kornisiuk, Jerusalinky & Quillfeldt, 2007;Ferreira, Furstenau, Blanco, Kornisiuk, Sanchez, Daroit, Castro e Silva, Cervenansky, Jerusalinsky & Quillfeldt, 2003;Jerusalinsky et al,1998). Ten minutes prior to each test session a rat received an intracranial injection.…”

“…Ten minutes prior to each test session a rat received an intracranial injection. A 10-minute post-injection test time was chosen based on previous experiments demonstrating that a comparable post-injection time with MT-3 affected learning and memory (Diehl et al, 2007;Ferreira et al, 2003;Jerusalinsky et al, 1998). Group assignment was determined by the treatment administered during each test phase with the final sample size for each group represented in brackets: 1) acquisition -saline and reversal learning -saline (n = 7); 2) acquisition -MT-3 2 μg and reversal learning -saline (n = 5); 3) acquisition -saline and reversal learning -MT-3 0.05 μg (n = 7); 4) acquisition -saline and reversal learning -MT-3 1 μg (n = 6); 5) acquisition -saline and reversal learning -MT-3 2 μg (n = 9).…”

“…For example, Karlsson and colleagues (2000) report that muscarinic toxin 7 (MT-7) has more than 20,000 times higher selectivity for the M1 muscarinic cholinergic receptor than for any other muscarinic receptor subtype. In a comparable manner, muscarinic toxin 3 (MT-3) has more than 200 times higher selectivity for the M4 muscarinic cholinergic receptor than for the M1 muscarinic cholinergic receptor subtype with negligible activity at the other muscarinic cholinergic receptor subtypes (Jerusalinsky, Kornisiuk, Alfaro, Quillfeldt., Alonso, Verde, Cervenansky & Harvey, 1998). Thus, the use of specific muscarinic toxins, e.g.…”

Amnesia of inhibitory avoidance by scopolamine is overcome by previous open-field exposure

“…Learning of an IA task depends on the activation of the cholinergic system (Baratti et al 1979;Izquierdo et al 1998;Jerusalinsky et al 1998;Giovannini et al 1999;Barros et al 2002, for reviews, see Jerusalinsky et al 1997;McGaugh 2000). Low doses of i.p.…”