Search

Summary: Endocannabinoid (eCB)-mediated long-term depression (LTD) requires dopamine (DA) D2 receptors (D2Rs) for eCB mobilization. The cellular locus of the D2Rs involved in LTD induction remains highly debated. We directly examined the role in LTD induction of D2Rs expressed by striatal cholinergic interneurons (Chls) and indirect pathway medium spiny neurons (iMSNs) using neuron-specific targeted deletion of D2Rs. Deletion of Chl-D2Rs (Chl-Drd2KO) impaired LTD induction in both subtypes of MSNs. LTD induction was restored in the Chl-Drd2KO mice by an M1-selective muscarinic acetylcholine receptor antagonist. In contrast, after the deletion of iMSN-D2Rs (iMSN-Drd2KO), LTD induction was intact in MSNs. Separate interrogation of direct pathway and iMSNs revealed a deficit in LTD induction only at synapses onto iMSNs that lack D2Rs. LTD induction in iMSNs was restored by D2R agonist application. Our findings suggest that Chl D2Rs strongly modulate LTD induction in MSNs, with iMSN-D2Rs having a weaker, iMSN-specific, modulatory effect. : The cellular location of dopamine D2 receptors (D2Rs) involved in corticostriatal long-term synaptic depression (LTD) is controversial. Augustin et al. show that D2Rs on cholinergic interneurons strongly modulate LTD induction at synapses onto all medium spiny neurons (MSNs), while D2Rs on iMSNs weakly modulate induction at synapses onto iMSNs. Keywords: D2 receptors, cholinergic interneurons, iMSNs, dMSNs, long-term depression

Metabotropic glutamate (mGlu) receptors are family C G protein-coupled receptors (GPCRs) that modulate neuronal excitability and synaptic transmission throughout the nervous system. Owing to recent advances in development of subtype-selective allosteric modulators of mGlu receptors, individual members of the mGlu receptor family have been proposed as targets for treating a variety of neurological and psychiatric disorders, including substance use disorders. In this chapter, we highlight preclinical evidence that allosteric modulators of mGlu receptors could be useful for reducing alcohol consumption and preventing relapse in alcohol use disorder (AUD). We begin with an overview of the preclinical models that are used to study mGlu receptor involvement in alcohol-related behaviors. Alcohol exposure causes adaptations in both expression and function of various mGlu receptor subtypes, and pharmacotherapies aimed at reversing these adaptations have the potential to reduce alcohol consumption and seeking. Positive allosteric modulators (PAMs) of mGlu2 and negative allosteric modulators of mGlu5 show particular promise for reducing alcohol intake and/or preventing relapse. Finally, this chapter discusses important considerations for translating preclinical findings toward the development of clinically useful drugs, including the potential for PAMs to avoid tolerance issues that are frequently observed with repeated administration of GPCR agonists.

Ethanol and preparations of cannabis sativa (cannabinoid drugs) are among the most widely used and abused psychoactive substances. Research over the last few decades has revealed that cannabinoid drugs produce most of their effects via actions on receptors that are normally activated by endogenous lipid metabolites (endocannabinoids) that have juxtracrine signaling actions and act as neuromodulators. Investigation of ethanol interactions with cannabinoid drugs has been ongoing for some time. In this chapter, we summarize and critique the available information about these interactions when drugs are administered acutely, and we also discuss evidence for cross-tolerance between ethanol and cannabinoid drugs when given repeatedly. In addition, we discuss areas in which more information is needed about drug interactions. For example, relatively little is known about the effects of combined ethanol and cannabinoid drug exposure on learning and memory. There is now considerable interest in ethanol effects on brain endocannabinoid signaling, stimulated by the finding that ethanol consumption is decreased by blockade or genetic knockout of the cannabinoid type-1 receptor (CB1, the major endocannabinoid-activated receptor in the brain). In this context, we summarize findings regarding effects of acute and chronic ethanol actions on the molecules involved in endocannabinoid signaling. We also review the fast-growing literature exploring how ethanol consumption and other ethanol-related behaviors are altered by manipulation of endocannabinoid signaling. Finally, we review the existing literature on genetic polymorphisms and haplotypes in endocannabinoid-related proteins, and their association with alcohol-related phenotypes. There is clear evidence for multiple effects of ethanol on the endocannabinoid system, and it also clear that altering endocannabinoid signaling affects a variety of alcohol-related behaviors. Thus there is interest in targeting this system for treatment of alcohol use disorders. This effort may be aided by identification of genetically encoded differences in endocannabinoid-related proteins that increase the likelihood of a person developing an alcohol use disorder, but this line of research is still at an early stage. It is our hope that this chapter will stimulate additional investigation of ethanol–cannabinoid interactions that will result in useful advances in the understanding and treatment of alcohol abuse and alcoholism.

Publisher Summary This chapter presents that endocannabinoid juxtacrine and paracrine signaling is widespread throughout the brain and body, representing one of the most prevalent lipid/fatty acid-based intercellular communication systems in mammals. The cannabinoid part of the name is derived from the cannabis sativa plant and the drugs, marijuana and hashish among others, made from this plant. It discusses that the receptors for these drugs are the major targets of a group of lipid derived signaling molecules known as the eCBs. Two arachidonoyl-containing fatty acids, arachidonoylethanolamide (AEA or anandamide) and 2-arachydonoyl glycerol (2-AG) are thought to produce the majority of eCB signaling. These two compounds are synthesized from arachidonate-containing membrane lipids via separate pathways consisting of several enzyme-catalyzed steps. The chapter also reviews that the CB1 receptor is the main mediator of eCB actions in the brain, and is responsible for the majority of the intoxicating effects of natural and synthetic cannabinoid drugs. Endocannabinoids can also activate the CB2 receptor that is mainly found in the periphery but is apparently also present in the central nervous system (CNS).

Publisher Summary α 2 -Adrenergic receptors ( α 2 ARs) are broadly associated with inhibitory actions of norepinephrine and epinephrine. Studies with drugs designed as α 2 AR agonists and antagonists have shown that α 2 ARs participate in a wide range of central nervous system activities, including central regulation of blood pressure, sedation and analgesia, control of affect, and modulation of pituitary hormone release. In the periphery, α 2 ARs inhibit neurotransmitter release from peripheral nervous system neuronal terminals, inhibit insulin secretion by pancreatic β cells, and participate in the regulation of water and electrolyte balance in the kidney. The α 2 ARs that elicit these varied responses represent a structural and functional family of receptor subtypes defined by pharmacological measurements and molecular cloning. Interest of studies has been to establish a mouse line that expressed a mutant α 2A AR receptor with selectively altered signal transduction capabilities. Studies have shown that mutation of the highly conserved aspartate residue at position 79 in the α 2A AR to asparagine (D79N) results in a receptor that is uncoupled from a single signaling pathway. In this purpose the two-step “hit and run” gene-targeting approach is successfully used in mouse embryonic stem cells to establish a mouse line with this D79N α 2A AR mutation. Such studies reveal that the α 2A AR subtype has a role central to several of the clinically desirable effects of α 2A R agonists, suggesting that these functions cannot be separated by administering subtype-specific drugs. Null mutation of the α 2B AR subtype has revealed that this subtype mediates the increase in blood pressure immediately following α 2A R agonist administration. Thus, drugs that are selective for the α 2A AR subtype relative to the α 2B AR subtype may hold promise as improved antihypertensive agents. Sedative side effects might be eliminated if high-affinity partial agonists are developed, especially if higher receptor occupancy is needed to evoke sedation in contrast to hypotension.

Publisher Summary This chapter focuses on those mechanisms that operate in the neostriatum (caudate and putamen nuclei) and attempts to integrate this information into existing models of the function of striatal circuitry. The neostriatum is the entryway into the basal ganglia and is the site of many of the neurological defects involving functions of the basal ganglia. Thus, it is important to understand the regulation of synaptic transmission at afferent synapses innervating the neostriatum. Cortical glutamatergic and nigral dopaminergic afferent inputs impinge on neurons in the neostriatum, providing the most significant afferent inputs to this structure. The corticostriatal glutamatergic inputs produce a rapid depolarization of striatal neurons via the activation of ionotropic AMPA-type glutamate receptors. In addition, transmission is modulated by a number of presynaptic, G protein-coupled receptors, but surprisingly, relatively little evidence of postsynaptic modulation has been observed. Corticostriatal synapses also express certain forms of plasticity, most notably short- and long-term synaptic depression. It appears that long-term depression (LTD) may involve the convergent actions of glutamate and dopamine. Striatal LTD may have important roles in information storage and motor set selection in the striatum. However, some aspects of synaptic transmission in the striatum remain unclear. In particular, the physiological roles of dopaminergic nigrostriatal input and the role of N-methyl-D-aspartate (NMDA)-type glutamate receptors are not well understood. In addition, intrastriatal synaptic connections have received relatively little attention compared to extrinsic input to the neostriatum.