Adenosinergic System: Therapeutics for Drug Addiction
Adenosinergic System: Therapeutics for Drug Addiction
Exposure to various drugs of abuse deregulates synaptic plasticity in different parts of the CNS involved in the phenomenon of addiction. Several experimental reports implicate both the endocannabinoids and other ligands of cannabinoid CB1 receptors in the motivational and rewarding effects of drugs of abuse. The endocannabinoids act as retrograde messengers at various synaptic junctions in the brain and thus contribute to synaptic plasticity. The endocannabinoids released from the postsynaptic cells activate presynaptic CB1 receptors to induce a long-lasting decrease in neurotransmitter release. This attenuation in the release of neurotransmitters and the phenomenon of long-term depression has been reported in several brain regions such as the dorsal striatum, nucleus accumbens, hippocampus, prefrontal cortex and ventral tegmental area, involved in the etiology of drug addiction.
DA, adenosine and endocannabinoids mutually interact in the synaptic junctions of the dorsolateral striatum and thus any imbalance in the neuromodulatory effects of these three neuromodulators affects synaptic plasticity in several neuronal disorders. Excessive glutamatergic release during excitatory neurotransmission leads to an increase in adenosine levels in the synaptic junctions, which via adenosine A2A receptors further augments the glutamate release, and, through adenosine A1 receptors, inhibits the DA discharge in the nigrostriatal pathways. DA and glutamate, acting through respective postsynaptic receptors, stimulate the release of endocannabinoids, which further activate cannabinoid CB1 receptors, resulting in the suppression of corticostriatal glutamate release. Therefore, adenosine was hypothesized to be a functional antagonist of dopaminergic and endocannabinoid neurotransmission in the dorsolateral striatum. The studies reported so far on the interaction of adenosine with endocannabinoid receptors are based on chronic exposure with the receptor ligands in vivo. For example, chronic exposure with tetrahydrocannabinol was shown to reduce the adenosine A1 and GABAB receptor-induced inhibition of adenylate cyclase. The outcome of the interaction between adenosine and cannabinoid receptors is still a matter of debate. It was reported that activation or blockade of adenosine A1 receptors did not influence the inhibitory neurotransmission of a cannabinoid CB1 receptor agonist on synaptic transmission in the CA1 area of the hippocampus. Furthermore, cannabinoid CB1 receptor activation or blockade did not influence the inhibitory action of an adenosine A1 receptor agonist on hippocampal synaptic transmission. In addition, the respective inhibitions induced by the agonists of adenosine or cannabinoid receptors were additive. Thus the absence of cross-talk between adenosine A1 and cannabinoid CB1 receptors was put forward in the hippocampus after single agonist exposure. On the other hand, some recent studies have focused on the effects of synthetic and endogenous cannabinoids on the intricate uptake mechanisms of adenosine, DA and glutamate occurring at the synaptic level. In experimental studies involving two rodent species, Pandolfo et al. have shown that anandamide and 2-arachidonoyl-glycerol are capable of inhibiting adenosine uptake while N-arachidonyl-DA and N-oleoyl-DA inhibit only DA uptake in the synaptic junctions of striatum. Moreover, other synthetic cannabinoid CB1 receptor ligands were also shown to hamper the synaptic removal of adenosine and DA, with similar efficacy as that of classical uptake inhibitors.
Adenosine & Cannabinoids
Exposure to various drugs of abuse deregulates synaptic plasticity in different parts of the CNS involved in the phenomenon of addiction. Several experimental reports implicate both the endocannabinoids and other ligands of cannabinoid CB1 receptors in the motivational and rewarding effects of drugs of abuse. The endocannabinoids act as retrograde messengers at various synaptic junctions in the brain and thus contribute to synaptic plasticity. The endocannabinoids released from the postsynaptic cells activate presynaptic CB1 receptors to induce a long-lasting decrease in neurotransmitter release. This attenuation in the release of neurotransmitters and the phenomenon of long-term depression has been reported in several brain regions such as the dorsal striatum, nucleus accumbens, hippocampus, prefrontal cortex and ventral tegmental area, involved in the etiology of drug addiction.
DA, adenosine and endocannabinoids mutually interact in the synaptic junctions of the dorsolateral striatum and thus any imbalance in the neuromodulatory effects of these three neuromodulators affects synaptic plasticity in several neuronal disorders. Excessive glutamatergic release during excitatory neurotransmission leads to an increase in adenosine levels in the synaptic junctions, which via adenosine A2A receptors further augments the glutamate release, and, through adenosine A1 receptors, inhibits the DA discharge in the nigrostriatal pathways. DA and glutamate, acting through respective postsynaptic receptors, stimulate the release of endocannabinoids, which further activate cannabinoid CB1 receptors, resulting in the suppression of corticostriatal glutamate release. Therefore, adenosine was hypothesized to be a functional antagonist of dopaminergic and endocannabinoid neurotransmission in the dorsolateral striatum. The studies reported so far on the interaction of adenosine with endocannabinoid receptors are based on chronic exposure with the receptor ligands in vivo. For example, chronic exposure with tetrahydrocannabinol was shown to reduce the adenosine A1 and GABAB receptor-induced inhibition of adenylate cyclase. The outcome of the interaction between adenosine and cannabinoid receptors is still a matter of debate. It was reported that activation or blockade of adenosine A1 receptors did not influence the inhibitory neurotransmission of a cannabinoid CB1 receptor agonist on synaptic transmission in the CA1 area of the hippocampus. Furthermore, cannabinoid CB1 receptor activation or blockade did not influence the inhibitory action of an adenosine A1 receptor agonist on hippocampal synaptic transmission. In addition, the respective inhibitions induced by the agonists of adenosine or cannabinoid receptors were additive. Thus the absence of cross-talk between adenosine A1 and cannabinoid CB1 receptors was put forward in the hippocampus after single agonist exposure. On the other hand, some recent studies have focused on the effects of synthetic and endogenous cannabinoids on the intricate uptake mechanisms of adenosine, DA and glutamate occurring at the synaptic level. In experimental studies involving two rodent species, Pandolfo et al. have shown that anandamide and 2-arachidonoyl-glycerol are capable of inhibiting adenosine uptake while N-arachidonyl-DA and N-oleoyl-DA inhibit only DA uptake in the synaptic junctions of striatum. Moreover, other synthetic cannabinoid CB1 receptor ligands were also shown to hamper the synaptic removal of adenosine and DA, with similar efficacy as that of classical uptake inhibitors.
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