Cannabinoid CB₁ receptor‐mediated inhibition of hippocampal acetylcholine release is preserved in aged mice

Abstract

1 The cannabinoid CB 1 receptor inverse agonist/antagonist SR 141716 increases acetylcholine release in rodent hippocampus and improves memory in some experimental paradigms. Since drugs like SR 141716 may represent a novel class of cognition-enhancing drugs, we wanted to check whether the function of the CB 1 receptor is preserved during ageing. 2 Hippocampal and striatal slices from 2-to 3-and 24-to 28-month-old C57BL/6J mice were preincubated with [ 3 H]-choline or [ 3 H]-noradrenaline ([ 3 H]-NA) and superfused. 3 The cannabinoid receptor agonist WIN 55,212-2 inhibited, and SR 141716 facilitated, the electrically (3 Hz) evoked tritium overflow in hippocampal slices (preincubated with [ 3 H]-choline) from young and aged mice to the same extent. The evoked overflow per se was less by 33% in slices from aged animals. 4 WIN 55,212-2 and SR 141716 did not affect, but the muscarinic receptor agonist oxotremorine inhibited, the evoked (3 Hz) overflow in striatal slices (preincubated with [ 3 H]-choline) from young and aged mice to the same extent. The evoked overflow per se tended to be less in slices from aged animals. 5 The evoked (0.3 Hz) overflow in hippocampal slices (preincubated with [ 3 H]-NA) was not affected by WIN 55,212-2 and SR 141716, but was inhibited by histamine (via H 3 receptors) in slices from young mice and, to a somewhat less extent, in slices from aged mice. The evoked overflow per se did not differ between age groups. 6 In conclusion, the function of the CB 1 receptor involved in the tonic inhibition of hippocampal acetylcholine release is preserved in aged mice.

The Endocannabinoid System in Ageing: A New Target for Drug Development

“…Although CB1R expression seems to be regulated in several brain areas during ageing, there is no significant difference between young adult and aged mice with respect to the cannabinoidmediated inhibition of acetylcholine release in the hippocampus, a function of the CBRs which is preserved in aged mice [126].…”

Chronic, intermittent treatment with a cannabinoid receptor agonist impairs recognition memory and brain network functional connectivity

“…One immediate consequence of cannabis consumption is an impairment in memory consolidation, seen in both humans (Ranganathan and D'Souza 2006;Borgelt et al 2013) and laboratory animals (Clarke et al 2008;Kano et al 2009;Sousa et al 2011;Mouro et al 2017). Cannabinoidmediated disruptions in learning and memory may be related to reported impairments in long-term potentiation at glutamatergic synapses (Terranova et al 1995;Stella et al 1997;Misner and Sullivan 1999;Wang et al 2016;Silva-Cruz et al 2017), detrimental modifications in fast-/slow-wave oscillations, known to be modulated by GABAergic interneurons (Freund et al 2003), and altered activity in septal-hippocampal monoaminergic and cholinergic pathways, known to regulate cortical plasticity and activity (Miller and Branconnier 1983;Gessa et al 1998;Sullivan 2000;Redmer et al 2003;Khakpai et al 2012).…”

Cannabinoid CB1 receptor‐mediated modulation of evoked dopamine release and of adenylyl cyclase activity in the human neocortex

“…The increasing effect was diminished by CP55.940, suggesting a CB 1 receptor‐mediated action. The enhanced release may be explained by the blockade of constitutively active CB 1 receptors ( Bouaboula et al , 1997 ) and/or by the disruption of an endocannabinoid tone leading to permanent depression of neurotransmitter release (Gifford & Ashby, 1996; Redmer et al , 2003 ). In our opinion, the latter alternative seems more likely, since we recently found evidence for a stimulation‐dependent endocannabinoid tone at human neocortical CB 1 receptors inhibiting ACh release ( Steffens et al , 2003b ).…”