Effects of Exogenous and Endogenous Cannabinoids on GABAergic Neurotransmission between the Caudate-Putamen and the Globus Pallidus in the Mouse

Abstract

Globus pallidus neurons receive GABAergic input from the caudate-putamen via the striatopallidal pathway. Anatomical studies indicate that many CB 1 cannabinoid receptors are localized on terminals of striatopallidal axons. Accordingly, the hypothesis of the present work was that activation of CB 1 receptors presynaptically inhibits neurotransmission between striatopallidal axons and globus pallidus neurons. In sagittal mouse brain slices, striatopallidal axons were electrically stimulated in the caudate-putamen, and the resulting GABAergic inhibitory postsynaptic currents (IPSCs) were recorded in globus pallidus neurons. The synthetic cannabinoid receptor agonists R(ϩ)- [2,3-dihydro-5-methyl-3-[(morpholinyl) Prevention of DSI by rimonabant indicates that endocannabinoids released from the postsynaptic neurons acted on CB 1 receptors to suppress synaptic transmission. WIN55212-2 did not modify currents in globus pallidus neurons elicited by GABA released from its chemically bound ("caged") form by a flash pulse, suggesting that WIN55212-2 depressed neurotransmission presynaptically. For studying the mechanism of the inhibition of GABA release, terminals of striatopallidal axons were labeled with a calcium-sensitive fluorescent dye. WIN55212-2 depressed the action potentialevoked increase in axon terminal calcium concentration. The results show that activation of CB 1 receptors by exogenous and endogenous cannabinoids leads to presynaptic inhibition of neurotransmission between striatopallidal axons and globus pallidus neurons. Depression of the action potential-evoked calcium influx into axon terminals is the probable mechanism of this inhibition.The G␣ i/o protein-coupled CB 1 cannabinoid receptor is the primary neuronal target of the phytocannabinoid ⌬ 9 -tetrahydrocannabinol and of the endogenous cannabinoids (endocannabinoids) anandamide and 2-arachidonylglycerol (Howlett et al., 2002;Abood, 2005). The CB 1 receptor is widely distributed in the central and the peripheral nervous system (Herkenham et al., 1991b;Mailleux and Vanderhaeghen, 1992;Tsou et al., 1998). Activation of CB 1 receptors leads to presynaptic inhibition of synaptic transmission in many regions of the central and peripheral nervous system (Freund et al., 2003;Szabo and Schlicker, 2005).The present work focuses on the neuronal connection between the caudate putamen and the globus pallidus (also called external or lateral globus pallidus). Globus pallidus neurons receive strong GABAergic input from medium spiny neurons of the caudate-putamen (striatopallidal projection neurons; Gerfen, 2004). The concentration of CB 1 receptor protein in the globus pallidus is very high (Herkenham et al., 1991b;Mailleux and Vanderhaeghen, 1992;Tsou et al., 1998). Two kinds of observations support the idea that the majority of CB 1 receptors in the globus pallidus is localized This work was supported by the Deutsche Forschungsgemeinschaft (Sz 72/5-1).Article, publication date, and citation information can be found at

Abnormal Neurotransmitter Release Underlying Behavioral and Cognitive Disorders: Toward Concepts of Dynamic and Function-Specific Dysregulation

“…For example, electrically-evoked ACh release from human neocortical slices was demonstrated to decrease with age (Feuerstein and Seeger, 1997). Although the nature of the stimuli used in these studies potentially allow the dissociation of effects of different modes of neuronal activity, the available evidence indicates that overflow data obtained from brain tissues from patients, animals modeling disorders and/or treated with drugs, typically have been interpreted as indicating aberrant tonic levels of neurotransmission (eg, Engler et al, 2006;Roberts et al, 2005).…”

Endocannabinoid-Mediated Control of Synaptic Transmission

“…Therefore, it is reasonable to assume that, in these forms of eCB-STD, endocannabinoid release is induced by Ca 2ϩ elevation itself, which we proposed to term CaER (210,315 (180). In globus pallidus neurons, postsynaptic depolarization (from Ϫ60 to ϩ30 mV, 5 s) induced Ca 2ϩ transients with peak values of 14.5 M in the soma and 9.9 M in dendrites, which induced prominent DSI (147). From these studies, it is conceivable that Ca 2ϩ elevation to micromolar level is required for CaER.…”

“…Engler et al (147) showed that this pathway is cannabinoid sensitive and exhibits DSI in a CB 1 -dependent manner (147). The authors recorded IPSCs from globus pallidus neurons in slice preparations in response to stimulation in the caudata-putamen.…”

Gene expression of opioid and dopamine systems in mouse striatum: effects of CB1 receptors, age and sex

“…CB 1 -deficient mice lack normal dopamine-mediated suppression of PKA activity, mediated by postsynaptic D 4 receptors, which blocks GABA A currents in the globus pallidus (Engler et al 2006;Shin et al 2003). Selective genes in striata, including those for opioid peptides, are influenced by increased cAMP and PKA activation via a cAMP response element binding protein (CREB)-mediated mechanism.…”