Mol Neurobiol DOI 10.1007/s12035-016-0313-5 Endocannabinoid System: the Direct and Indirect Involvement in the Memory and Learning Processes—a Short Review Marta Kruk-Slomka1 & Agnieszka Dzik1 & Barbara Budzynska1 & Grazyna Biala1 Received: 30 September 2016 /Accepted: 21 November 2016 # The Author(s) 2016. This article is published with open access at Springerlink.com Abstract The endocannabinoid system via cannabinoid Ca 2+ Calcium ions (CB: CB1 and CB2) receptors and their endogenous ligands CB Cannabinoid is directly and indirectly involved in many physiological func- CB1KOS CB1 receptor genetic knockout mice tions, especially in memory and learning processes. Extensive CB2KOS CB2 receptor genetic knockout mice studies reported that this system strictly modulates cognition- CFC Contextual fear conditioning related processes evaluated in various animal models. CNS Central nervous system However, the effects of cannabinoids on the cognition have ECS Endocannabinoid system been contradictory. The cannabinoid compounds were able to ETM Elevated T-maze both impair or improve different phases of memory processes FAAH Fattyacidamidhydrolase through direct (receptor related) or indirect (non-receptor GABA Gamma-aminobutyric acid related) mechanism. The memory-related effects induced by IA Inhibitory avoidance the cannabinoids can be depended on the kind of cannabinoid Intra-BLA Intra-basolateral amygdala compound used, dosage, and route of administration as well as Intra-PLC Intra-prelimbic on the memory task chosen. Therefore, the objectives of this i.p. Intra-peritoneally paper are to review and summarize the results describing the MAGL Monoacylglycerol lipase role of endocannabinoid system in cognition, including NADA N-arachidonoyl dopamine various stages of memory. NAGly N-arachidonylglycine OEA Oleoylethanolamine Keywords Endocannabinoid system . Cannabinoid OF Open field receptors . Memory and learning . Cognition . Animal models ORT Object recognition task of memory PA Passive avoidance PCR Polymerase chain reaction PEA Palmitoylethanolamide RAM Radial arm maze Abbreviations VTA Ventral tegmental area 2-AG 2-Arachidonoylglycerol WMT Water maze test Δ-9-THC Δ-9-Tetrahydrokannabinol AEA Anandamide Pharmacology of the Endocannabinoid System * Marta Kruk-Slomka The endocannabinoid system (ECS) is a lipid signaling [email protected] system, which is functionally active since the early stages of brain development and remains active during both prenatal 1 Department of Pharmacology and Pharmacodynamics, Medical and post-natal life [1–3]. This system consists of the cannabi- University of Lublin, Chodzki 4a Street, 20-093 Lublin, Poland noid (CB) receptors, their endogenous ligands, the enzymes Mol Neurobiol for the synthesis and degradation of endocannabinoids, and schizophrenia [20, 21], depression [22], and bipolar disorders the reuptake transport system [4]. [23]. Moreover, in CB2-knockout mice, schizophrenia-like The discovery of specific CB receptors, followed by iden- symptoms were observed [24]. Additionally, the CB2 receptors tification of their endogenous ligands, gave an opportunity to modulate both excitatory [25, 26] and inhibitory synaptic trans- the extensive research on the significance of this system for missions in the hippocampus [27–29]. It has been reported that the proper functioning of the organism. CB receptors were the activation of CB2 receptors reduces pain [30], impulsive discovered in late 1980s and then were divided into two dif- behavior [31], locomotor activity of rodents [22, 32, 33], and ferent subtypes of G protein-coupled receptors [5]. Currently, vomiting of ferrets [34]. Stimulation of CB2 receptors also two types of CB receptors are known. The pharmacological decreases the excitability of peripheral sensory neurons [30], effects are mainly exerted through the activation of Gi/o cortical pyramidal neurons [35], and dopaminergic neurons in protein-coupled membrane receptors CB1 and CB2. Despite the ventral tegmental area (VTA) [36](Fig.1). the fact that both CB1 and CB2 receptors belong to the group As mentioned earlier, endocannabinoids are synthesized on of G protein-coupled receptors and are characterized by sig- demand from lipid precursors derived from the enzymatic nificant homology, they differ in their function and specificity cleavage of cell membrane constituents in response to neuronal of cellular expression [6]. membrane depolarization or immune cell activation and are CB1 receptors are located mainly in the central nervous released from post-synaptic membranes as retrograde messen- system (CNS), and they are one of the most abundantly gers onto presynaptic terminals of excitatory or inhibitory char- expressed neuronal receptors in the CNS, which suggests their acter, thus suppressing both inhibitory and excitatory signaling important role in the function of the CNS. These receptors are within specific neuronal area. Endocannabinoids control syn- widely expressed in multiple brain areas with the highest con- aptic plasticity by an influence on neurotransmitter release [5, centration in the regions associated with cognition and move- 6, 18]. They have affinity for both CB1 and CB2 receptors [6]. ment like amygdala, hippocampus, septum, brain cortex, Henceforth, two endogenous cannabinoids (endocannabinoids) globus pallidus, substantia nigra, cerebellum, and lateral cau- were discovered: arachidonoylethanolamide (anandamide date putamen [4]. Additionally, they are also present at lower (AEA)) and 2-arachidonoylglycerol (2-AG) [5]. They remain concentration in a variety of peripheral tissues, both on sen- the two most studied endogenous substances from the others sory nerve fibers and in the autonomic nervous system [6–8]. known so far, including virodhamine, noladin ether, CB1 receptors are localized presynaptically on glutamatergic palmitoylethanolamide (PEA), N-arachidonoyl dopamine and gamma-aminobutyric (GABA) acid axon terminals [9]. In (NADA), N-arachidonylglycine (NAGly), oleamide, and the hippocampus, CB1 receptors are located mainly in oleoylethanolamine (OEA) [37](Table1). GABA-ergic, inhibitory interneurons. They are also present 2-AG is mainly produced in the CNS, and AEA is produced in the hippocampal glutamatergic axon terminals, but their at low levels in the periphery and the CNS [38]. Production of concentration is at least 20 times lower than in the presynaptic endogenous cannabinoids is increased in response to patho- areas of this brain structure. Activation of CB1 receptors is genic stimulus. Particularly important to immune modulation connected with inhibition of adenyl cyclase as well as calcium is a fact that the production of endocannabinoids is stimulated channels and leads to activation of potassium channels; thus, it by activation of immune cells (macrophages) and dendritic contributes to short-term depression of neurotransmitter re- cells, and stimulated immune cells have reduced the expres- lease in corticostriatal GABA-ergic and glutamatergic neurons sion of endocannabinoid-degrading enzymes [39]. [5]. CB1 receptors are also present on noradrenergic termi- Endocannabinoids are metabolized by degradative enzymes nals, and their blockade increases release of norepinephrine like fatty acid amid hydrolase (FAAH), which metabolizes in limbic regions [10, 11]. Owing to their localization, CB1 AEA as well as 2-AG, and monoacylglycerol lipase receptors control both cognitive process and emotional behav- (MAGL), which metabolizes 2-AG [8]. ior, including stress, fear, or anxiety [12–17]bymodulating It should be also noted that there are two novel G protein- neuronal signaling and synaptic plasticity [18]. coupled orphan receptors GPR55 and GPR119, which have In turn, CB2 receptors are present mainly peripherally and been recently defined as CB receptors [40]. Though showing are the most abundant in the immune system in a variety of virtuallynoapparenthomologytoeitheroftheclassicalCB immune cells including B lymphocytes, natural killer cells, receptors, GPR55 was identified as a novel CB receptor [41]. monocytes, macrophages, polymorphonuclear neutrophils, The CB-sensitive receptor GPR55 was identified and cloned by and T cells [4, 6]. Thus, they are mainly involved in immune Sawzdargo et al. [42]. Its presence in the brain, including the system functions [6, 19]. However, the CB2 receptors have also hippocampus, has been proved by using quantitative polymer- been found in microglial cells in the CNS. The gathered data ase chain reaction (PCR) [43, 44]. GPR55 activity can be mod- suggests that CB2 receptors modulate neuronal function and ulated by phytocannabinoids and endocannabinoids [38, 44]. play a role in psychiatric disorders. Polymorphism of CB2 The endocannabinoids that have affinity for GPR55 receptors receptor gene encoding CB2 receptors in humans is related to probably include AEA, 2-AG, PEA, and others [45]. Moreover, Mol Neurobiol Fig. 1 The distribution of CB receptors in the CNS and periphery Table 1 The chemical structure of endocannabinoids Anandamide (5Z,8Z,11Z,14Z)-N-(2- HO NH hydroxyethyl)icosa-5,8,11,14- O tetraenamide HC3 2-arachidonoylglycerol 1,3-dihydroxypropan-2-yl HO HO O (5Z,8Z,11Z,14Z)-icosa- O 5,8,11,14-tetraenoate HC3 Virodhamine 2-aminoethyl HN2 (5Z,8Z,11Z,14Z)-icosa- O O 5,8,11,14-tetraenoate HC3 Noladin ether 2-[(5Z,8Z,11Z,14Z)-icosa- HO O OH 5,8,11,14-tetraenoxy]propane- 1,3-diol HC3 Mol Neurobiol Table 1 (continued) Palmitoylethanolamide N-(2- OH hydroxyethyl)hexadecanamide NH O 3CH N-Arachidonoyl (5Z,8Z,11Z,14Z)-N-[2-(3,4-