Rewarding Effects of the Hallucinogen 4-AcO-DMT Administration and Withdrawal in Rats: A Challenge to the Opponent-Process Theory.

According to the opponent-process theory of drug addiction, the intake of an addictive substance initiates two processes: a rapid primary process that results in the drug's rewarding effects, and a slower opponent process that leads to the aversive motivational state of drug aftereffects. This aversive state is integral in the desire, pursuit, and maintenance of drug use, potentially leading to dependence and addiction. However, current observational and experimental evidence suggests that the administration of a 5-hydroxytryptamine receptors-type 2A (5-HT2A) agonist, while capable of inducing a positive mental state in humans, may not generate the behavioral patterns typically associated with drugs of abuse. In this study, we found that administering the 5-HT2A agonist 4-Acetoxy-N,N-dimethyltryptamine fumarate (4-AcO-DMT) did not result in place preference in male rats compared to control saline administration 24 h later, after the drug has been cleared from the organism. However, in a modified place preference test where only the acute motivational effects of the drug were evaluated (excluding withdrawal), 4-AcO-DMT was found to be rewarding. Furthermore, in another modified place preference test where only the motivational effects of drug withdrawal were evaluated (excluding the acute effects of drug administration), the 24-hour aftereffect of 5-HT2A agonist administration also resulted in a robust place preference. Therefore, while 4-AcO-DMT administration was able to induce place preference, its 24-hour aftereffect also produced a strong reward. In the counterbalanced test, this reward from the aftereffect effectively overshadowed its acute rewarding properties, which could potentially create a false impression that 4-AcO-DMT lacks motivational properties. This suggests that 5-HT2A agonist administration follows a different dynamic than that proposed by the opponent-process theory of motivation and implies that the administration of 5-HT2A agonists may lead to behavioral patterns less typical of drugs associated with addiction.

Endocannabinoid system and aggression across animal species.

This narrative review article summarizes the current state of knowledge regarding the relationship between the endocannabinoid system (ECS) and aggression across multiple vertebrate species. Experimental evidence indicates that acute administration of phytocannabinoids, synthetic cannabinoids, and the pharmacological enhancement of endocannabinoid signaling decreases aggressive behavior in several animal models. However, research on the chronic effects of cannabinoids on animal aggression has yielded inconsistent findings, indicating a need for further investigation. Cannabinoid receptors, particularly cannabinoid receptor type 1, appear to be an important part of the endogenous mechanism involved in the dampening of aggressive behavior. Overall, this review underscores the importance of the ECS in regulating aggressive behavior and provides a foundation for future research in this area.

CB1R chronic intermittent pharmacological activation facilitates amphetamine seeking and self-administration and changes in CB1R/CRFR1 expression in the amygdala and nucleus accumbens in rats.

Patterns of drug ingestion may have a dissimilar impact on the brain, and therefore also the development of drug addiction. One pattern is binge intoxication that refers to the ingestion of a high amount of drug on a single occasion followed by an abstinence period of variable duration. In this study, our goal was to contrast the effect of continuous low amounts with intermittent higher amounts of Arachidonyl-chloro-ethylamide (ACEA), a CB1R agonist, on amphetamine seeking and ingestion, and describe the effects on the expression of CB1R and CRFR1 in the central nucleus of the amygdala (CeA) and in the nucleus accumbens shell (NAcS). Adult male Wistar rats were treated with a daily administration of vehicle or 20 µg of ACEA, or four days of vehicle followed by 100 µg of ACEA on the fifth day, for a total of 30 days. Upon completion of this treatment, the CB1R and CRFR1 expression in the CeA and NAcS was evaluated by immunofluorescence. Additional groups of rats were evaluated for their anxiety levels (elevated plus maze, EPM), amphetamine (AMPH) self-administration (ASA) and breakpoint (A-BP), as well as AMPH-induced conditioned place preference (A-CPP). Results indicated that ACEA induced changes in the CB1R and CRFR1 expression in both the NAcS and CeA. An increase in anxiety-like behavior, ASA, A-BP and A-CPP was also observed. Since the intermittent administration of 100 µg of ACEA induced the most evident changes in most of the parameters studied, we concluded that binge-like ingestion of drugs induces changes in the brain that may make the subject more vulnerable to developing drug addiction.

Amapola, lindísima amapola: de los opiáceos y los opioides, utilidad y riesgos / Poppy, beautiful poppy: opiates and opioids, utility and risks

Resumen El opio y sus derivados, y recientemente los opioides, han acompañado a la humanidad desde las civilizaciones más antiguas hasta la actualidad. Sus efectos analgésicos, hipnóticos y placenteros no pasaron desapercibidos para los antiguos, los consideraron de utilidad médica y beneficiosa para el estado de ánimo. Hoy en día no existe otro tipo de medicamentos que puedan tratar el dolor más intenso tan eficientemente como estos potentes analgésicos. Sin embargo, el uso médico y recreativo de los opiáceos y los opioides conlleva riesgos para la salud, como la tolerancia, la hiperalgesia y la adicción. Actualmente, además de ser indiscutiblemente el tratamiento médico más poderoso para mitigar el sufrimiento ocasionado por el dolor, se ha convertido también en un problema de salud pública debido a la alta cantidad de personas con trastorno por uso de opioides y por las muertes ocasionadas por sobredosis. En esta revisión se hará mención de las bondades de los opiáceos y opioides, y también de los efectos no deseados que estos producen.

Abstract Opium and its derivatives, and recently the opioids have accompanied the humankind since the ancient civilizations to the present day. Its analgesic, hypnotic and pleasant effects did not go unnoticed by ancient people, which considered most of these effects of medical utility and noticed that they had remarkable mood benefits. Currently, there are no other kind of drugs that can palliate intense pain as efficiently as these powerful analgesics. However, the medical and recreational use of opiates and opioids may carry health risks such as tolerance, hyperalgesia, and addiction. Nowadays, in addition to being indisputably the most powerful medical treatment to alleviate the suffering caused by pain, it has also become a public health problem due to the high number of people with opioid use disorder that have facilitated deaths caused by opioids overdose. In this review we will discuss the medical benefits of opiates and opioids, as much as the unwanted effects they produce.

GPR55 activation prevents amphetamine-induced conditioned place preference and decrease the amphetamine-stimulated inflammatory response in the ventral hippocampus in male rats.

Inflammatory response in the Central Nervous System (CNS) induced by psychostimulants seems to be a crucial factor in the development and maintenance of drug addiction. The ventral hippocampus (vHp) is part of the reward system involved in substance addiction and expresses abundant G protein-coupled receptor 55 (GPR55). This receptor modulates the inflammatory response in vitro and in vivo, but there is no information regarding its anti-inflammatory effects and its impact on psychostimulant consumption. The aim of the present study was to investigate whether vHp GPR55 activation prevents both the inflammatory response induced by amphetamine (AMPH) in the vHp and the AMPH-induced conditioned place preference (A-CPP). Wistar adult male rats with a bilateral cannula into the vHp or intact males were subjected to A-CPP (5 mg/kg). Upon the completion of A-CPP, the vHp was dissected to evaluate IL-1ß and IL-6 expression through RT-PCR, Western blot and immunofluorescence. Our results reveal that AMPH induces both A-CPP and an increase of IL-1ß and IL-6 in the vHp. The GPR55 agonist lysophosphatidylinositol (LPI, 10 µM) infused into the vHp prevented A-CPP and the AMPH-induced IL-1ß increase. CID 16020046 (CID, 10 µM), a selective GPR55 antagonist, abolished LPI effects. To evaluate the effect of the inflammatory response, lipopolysaccharide (LPS, 5 µg/µl) was infused bilaterally into the vHp during A-CPP acquisition. LPS strengthened A-CPP and increased IL-1ß/IL-6 mRNA and protein levels in the vHp. LPS also increased CD68, Iba1, GFAP and vimentin expression. All LPS-induced effects were blocked by LPI. Our results suggest that GPR55 activation in the vHp prevents A-CPP while decreasing the local neuro-inflammatory response. These findings indicate that vHp GPR55 is a crucial factor in preventing the rewarding effects of AMPH due to its capacity to interfere with proinflammatory responses in the vHp.

Dominance status is associated with a variation in cannabinoid receptor 1 expression and amphetamine reward.

The rewarding effects of psychostimulants appear to be distinct between dominant and subordinate individuals. In turn, the endocannabinoid system is an important modulator of drug reward in the nucleus accumbens and medial prefrontal cortex, however the connection with social dominance is yet to be established. Male rats were classified as dominant or subordinate on the basis of their spontaneous agonistic interactions and drug reward was assessed by means of conditioned place preference with amphetamine (AMPH). In addition, the expression of CB1R, CB2R, FAAH1, and DAGLa was quantified from accumbal and cortical tissue samples. Our findings demonstrate that dominant rats required a lesser dose of AMPH to acquire a preference for the drug-associated compartment, thereby suggesting a higher sensitivity to the rewarding effects of AMPH. Furthermore, dominants exhibited a lower expression of CB1R in the medial prefrontal cortex and nucleus accumbens. This study illustrates how CBR1 expression could differentiate the behavioral phenotypes associated to social dominance.

Brain electrophysiological responses associated with the retrieval of temporal and spatial contexts in episodic memory.

Episodic memory allows us to remember three main elements regarding an event: what (it is), where (it is in space), and when (it appears). The brain's electrical activity signaling the occurrence of these processes has been studied separately, revealing different patterns of ERP components and changes in the EEG theta band amplitude. However, how these patterns signal the retrieval of the temporal and spatial contexts of the same episode is unknown. The objective of this study was to evaluate the ERP components and the EEG theta band in association to the retrieval of the what, where, and when of the same episode through a source memory task. Three types of trials were identified here: total retrieval (what, where, and when), spatial retrieval (what and where), and correct rejections (correctly identified as new items). Attentional components, N200 and P300, and theta band were sensitive to the amount of information retrieved from episodic memory. Total retrieval and spatial trials elicited higher mean amplitude of FN400 and LPC, familiarity and recollection markers, respectively, than correct rejections. Our results suggest that early attention mechanisms can discern the strength of retrieval; in turn, familiarity and recollection mechanisms participate in the retrieval of the main contexts of episodic memory, but not in a cumulative way.

Irreversible hippocampal changes induced by high fructose diet in rats.

Some reports have described that a high fructose diet is associated with a deficit of hippocampus-dependent cognitive functions. In this study, we have evaluated the effects of fructose on spatial memory and molecular markers in the hippocampus and prefrontal cortex and analyzed whether those alterations are reversible. Male Wistar rats (n = 60) began their treatment during adolescence. A group was forced to drink a solution of 10% fructose for twelve weeks. Another group was subjected to the same fructose intake schedule, but later fructose was removed, and tap water was provided for four weeks. After treatments, spatial memory was evaluated with Barnes maze. Different neurogenesis, inflammation, astrocyte, and energy homeostasis markers were evaluated with immunofluorescence, ELISA, and Western blot. Changes were analyzed using two-way repeated-measures ANOVA, one-way ANOVA, and Tukeýs posthoc test (p < 0.05). Results showed that after long-term consumption of fructose, there was an impairment of spatial memory. This deficit was concomitant with the abolition of hippocampal neurogenesis and significant increases of IL-1b in the hippocampus and prefrontal cortex. Levels of COX-2 were decreased in the hippocampus. Besides, fructose induced a significant increase in GFAP and a decrease of glutamine synthetase. Likewise, energy homeostasis-associated neuropeptide orexin-A and their receptors (ORX R1 and ORX R2) were significantly increased. The spatial memory deficit, neuroinflammation, and changes in some proteins expression were permanent one month after the fructose elimination from the diet. These results suggest that fructose induces substantial hippocampal and cortical changes, and those are irreversible after a shift in the diet.

The Alerting and Orienting Systems of Attention Are Modified by Cannabis Dependence.

Attention allows us to select relevant information from the background. Although several studies have described that cannabis use induces deleterious effects on attention, it remains unclear if cannabis dependence affects the attention network systems differently. OBJECTIVES: To evaluate whether customary consumption of cannabis or cannabis dependence impacts the alerting, orienting, and executive control systems in young adults; to find out whether it is related to tobacco or alcohol dependence and if cannabis use characteristics are associated with the attention network systems. METHOD: One-hundred and fifty-four healthy adults and 102 cannabis users performed the Attention Network Test (ANT) to evaluate the alerting, orienting, and executive control systems. RESULTS: Cannabis use enhanced the alerting system but decreased the orienting system. Moreover, those effects seem to be associated with cannabis dependence. Out of all the cannabis-using variables, only the age of onset of cannabis use significantly predicted the efficiency of the orienting and executive control systems. CONCLUSION: Cannabis dependence favors tonic alertness but reduces selective attention ability; earlier use of cannabis worsens the efficiency of selective attention and resolution of conflicts.

Función de la impulsividad en el trastorno por consumo de sustancias / Impulsivity`s role in substance use disorder

Resumen La proporción de usuarios de una sustancia de abuso que desarrolla problemas con su consumo (abuso o dependencia) representa solo una parte de esta población. En México, el 63.8 % de la población consume alcohol, y de ellos, el 15 % desarrolla algún trastorno por consumo de alcohol (TCA). Se ha observado una relación causal entre el trastorno por consumo de sustancias (TCS) y la falta de autocontrol. Es decir, satisfacer necesidades de manera impulsiva, v. gr., consumir una droga sin evaluar las consecuencias. La corteza prefrontal (CPF) es el principal sustrato neuroanatómico del autocontrol y característicamente la CPF alcanza la madurez alrededor de los 30 años, sugieriendo que el autocontrol se alcanza despues de esta edad. Se ha propuesto que todos los grupos etarios que no han consolidado el uso del autocontrol son vulnerables al TCS. Similarmente ocurre con aquellos sujetos que por algún trastorno psiquiátrico tienen como característica una limitada función prefrontal. La CPF coordina una red subcortical cuya interacción depende de distintos sistemas de neurotransmisión, entre ellos, endocanabinoides. En este trabajo se revisó la función de la CPF y del sistema de endocanabinoides (sECB) y su relación con la vulnerabilidad a la adicción y otros trastornos psiquiátricos.

Abstract The proportion of users of a substance of abuse who develop problems with its use (abuse or dependence) represents only a part of this population. In Mexico, 63.8% of the population consumes alcohol and only 15% of them develop an alcohol use disorder (AUD). A causal relation has been observed between substance use disorder (SUD) and the lack of self-control. Which means, satisfying needs in an impulsive way, v.gr. using a drug, without considering the consequences. The prefrontal cortex (PFC) is the main neuroanatomical substrate of self-control and characteristically reaches maturity around the age of 30, suggesting that self-control is reached after this age. We suggest that all age groups that have not consolidated the use of self-control are vulnerable to SUD. The same occurs with those who, due to a psychiatric disorder, have the characteristic of a limited prefrontal function. The PFC coordinates a subcortical network whose interaction depends on different neurotransmission systems among them, the endocannabinoids system (ECBs). In this work we will review the function of the PFC, the ECBs and its relationship with vulnerability to addiction and other psychiatric disorders.

Allele-dosage genetic polymorphisms of cannabinoid receptor 1 predict attention, but not working memory performance in humans.

Attention and working memory (WM) are under high genetic regulation. Single nucleotide polymorphisms (SNPs) of the CNR1 gene, that encode for CB1R, have previously been shown to be related with individual differences in attentional control and WM. However, it remains unclear whether there is an allele-dosage or a dominant contribution of polymorphisms of CNR1 affecting attention and WM performance. This study evaluated the associations between attention and WM performance and three SNPs of CNR1: rs1406977, rs2180619, and rs1049353, previously associated with both processes. Healthy volunteers (n = 127) were asked to perform the Attention Network Task (ANT) to evaluate their overall attention and alerting, orienting, and executive systems, and the n-back task for evaluating their WM. All subjects were genotyped using qPCR with TaqMan assays; and dominant and additive models were assessed using the risk alleles of each SNP as the predictor variable. Results showed an individual association of the three SNPs with attention performance, but the composite genotype by the three alleles had the greatest contribution. Moreover, the additive-dosage model showed that for each G-allele added to the genotypic configuration, there was an increase in the percentage of correct responses respect to carriers who have no risk alleles in their genotypic configuration. The number of risk alleles in the genotypic configurations did not predict efficiency in any of the attention systems, nor in WM performance. Our model showed a contribution of three single nucleotide polymorphisms of the CNR1 gene to explain 9% of the variance of attention in an additive manner.

Fragility of reward vs antifragility of defense brain systems in drug dependence.

Drug dependence is a debilitating disorder, affecting 30 million people worldwide. In this short review we discuss about the plasticity changes in the reward and defense brain systems induced by early-life psychosocial stressful experiences. Such changes may render persons more vulnerable to illicit drugs use, facilitating behaviors of abuse and development of addiction. We propose that underlying plasticity changes render brain reward system as increasingly fragile because of tolerance and other physiological effects that reduce responsiveness with repeated use. In contrast, we propose that brain defense system makes maintain antifragile mechanisms that generate more robust responses with the prolonged consumption of drugs. Investigating the underlying mechanisms of these brain plasticity changes may advance the development of more efficacious pharmacologic and psychotherapeutic approaches to rehabilitate patients and more efficacious prevention policies to protect children from stressful experiences.

Cannabinoids and Sleep/Wake Control.

The sleep-wake cycle is a complex process that includes wake (W), non-rapid-eye-movement (NREM) and rapid-eye-movement (REM) sleep. Each phase is regulated by specialized brain structures that, by means of different neurotransmitters, maintain the constant expression of the sleep-wake cycle. Molecules like orexin, serotonin, noradrenaline, histamine, for waking; GABA, adenosine, prostaglandins, for NREM sleep and acetylcholine and glutamate for REM sleep, among other molecules are responsible for the expression and maintenance of each phase. When the endocannabinoid system was being described for the first time, almost three decades ago, oleamide's sleep promoting properties were highlighted. Nowadays, enough evidence has been cumulated to support the endocannabinoid system role in the sleep-wake cycle regulation. The endocannabinoids oleamide anandamide, and 2-arachidonylglycerol promote NREM and/or REM sleep via the CB1R, thereby making this system a target to treat sleep disorders, such as insomnia.

Maternal separation plus social isolation during adolescence reprogram brain dopamine and endocannabinoid systems and facilitate alcohol intake in rats.

Adverse early life experiences, i.e. abusive parenting, during postnatal development, induce long-lasting effects on the stress response systems and behavior. Such changes persist throughout an individual's life, making him/her vulnerable to suffer psychiatric disorders, including anxiety disorders and drug addiction. Rat pup maternal separation (MS) is a widely used rodent early-life stress model. MS induces changes in the dopamine and endocannabinoid systems in the nucleus accumbens (NAcc) that facilitate alcohol consumption. In this study, our endeavor was to determine if social isolation during adolescence (aSI) was as efficient as MS to facilitate alcohol intake; and moreover, if their combination (MS + aSI) induces even higher alcohol intake and exacerbates anxiety-like behaviors. Also, we evaluated dopamine and endocannabinoid receptors in the NAcc to describe potential changes caused by MS, aSI or both. Wistar rats were reared under 4 different conditions: non-MS + social housing (SH), MS + SH, non-MS + aSI and MS + aSI. Once these rats became adults they were submitted to a voluntary alcohol intake protocol for 10 days. Similar groups of rats with no exposure to alcohol whatsoever, were sacrificed to dissect out the NAcc to analyze the expression of cannabinoid (CB1R and CB2R) and dopamine (D2R and D3R) receptors. Results showed that MS, aSI and MS + aSI increase both CB1R, D2R and D3R expression in the NAcc and also increase alcohol intake and anxiety. These results suggest that early life adverse experiences induce a reprogramming of the brain's dopamine and endocannabinoid systems which increases subject's vulnerability to develop anxiety, alcohol abuse and dependence.

Marihuana: legalización y atención médica / Marihuana: Legalization and Medical Care

Resumen A pesar de que el uso de marihuana se considera ilegal en la mayoría de los países del mundo, es una de las drogas más utilizadas. El 8,6% de la población mexicana, entre 12 y 65 años, ha probado la marihuana alguna vez (2017). Este porcentaje ha aumentado significativamente en los últimos años. Casos fatales asociados con el consumo de cannabis no se documentaron durante mucho tiempo; sin embargo, recientemente se ha informado de muertes causada por un síndrome de hiperémesis de cannabis (CHS) y muerte por automutilación. Si bien se ha documentado que la marihuana sintetiza sustancias activas con potenciales propiedades terapéuticas, en la actualidad, el mayor uso de la marihuana en nuestro país y en el mundo es recreativo. Esta revisión analiza las consecuencias del uso recreativo de marihuana, el contexto social y de salud con respecto a la legalización y los posibles usos terapéuticos de compuestos extraídos de la planta, de acuerdo a estudios reportados en la literatura científica. La contribución que hacemos es alertar sobre el impacto negativo en la salud del uso recreativo de marihuana y la urgencia de favorecer la investigación sobre sus efectos en el cerebro. Asimismo, identificar los principios activos que tengan potencial para el uso terapéutico.

Abstract Despite the fact that the use of marihuana is illegal in most countries of the world, it still is one of the most commonly used drugs worldwide. 8.6% of the Mexican population, between 12-65 years old, has smoked marihuana at least once in their lifetime (2017). There has been a significant increase in the number of consumers in the last few years. Fatal cases associated with cannabis use had not been recognized for a long time, however, lately, deaths due to a cannabis hyperemesis syndrome (CHS) and deaths from self-mutilation have been reported. Although marihuana synthesizes several active substances with potential therapeutic properties, nowadays, the greatest use of marihuana in our country and in the world is recreational. This review discusses the consequences of using marihuana for recreational use, the social and health contexts regarding legalization and potential therapeutic uses of compounds isolated from the plant based on the scientific literature. Our contribution is to warn people about the potential negative impact on the health of recreational use marihuana and the urgency of supporting the research of its effects on the brain. Similarly, we aim to identify the active principles with potential therapeutic use.

Opposed cannabinoid 1 receptor (CB1R) expression in the prefrontal cortex vs. nucleus accumbens is associated with alcohol consumption in male rats.

Abusive alcohol consumption is a health problem, worldwide. There is extensive literature indicating that cannabinoid 1 receptor (CB1R) plays a crucial role in mediating alcohol's reward effects. Maternal care deprivation (MCD) is a reliable rodent model of early life stress that leads to high levels of anxiety and alterations in motivation, which may increase vulnerability to alcohol consumption. The present study researched whether anxiety-like behaviors and the level of motivation for a natural reward, and CB1R expression in the prefrontal cortex (PFC) and nucleus accumbens (NAcc) can predict alcohol consumption in non-MCD and MCD male rats. Results indicate that MCD increases anxiety-like behaviors, i.e., reduces time in open arms in the elevated plus maze and increases alcohol intake. In turn, the motivation for a palatable reward, i.e., a chocolate flavored pellet, was not affected by MCD. MCD reduces CB1R expression in the PFC and increases it in the NAcc. Hence, both higher anxiety-like behaviors and higher CB1R expression in the NAcc and lower CB1R expression in the PFC are associated with higher alcohol intake. These results suggest that early life adverse experiences induce a reprogramming of the brain's endocannabinoid system that very likely contributes to making the brain vulnerable to develop alcohol abuse and dependence.

Brain electrical activity from encoding to retrieval while maintaining and manipulating information in working memory.

Differences between working memory maintenance (Mt) and manipulation (Mp) have been studied, mostly in the absence of stimuli (delay period); encoding and retrieval phases have been less explored. The present study assessed differences between Mt and Mp, by means of event-related potentials (ERPs) and event-related synchronisation (ERS) and desynchronisation (ERD) for theta, alpha and beta bands at: encoding, delay period and retrieval; using a delayed-match to sample task (DMST). Twenty-six young volunteers solved two DMST conditions (one for Mt and one for Mp). Higher behavioural accuracy for Mt than for Mp was observed. At encoding, higher amplitude for Mt at posterior regions to N1, P2 and P3 components were observed. In the delay period, differences in ERP components and frontal theta ERD were observed. Meanwhile, at retrieval, P3 amplitude and latency, as well as the theta band were modulated by both process (Mt or Mp) and type of trial (target or non-target stimuli). These findings mainly suggest different attentional implications at encoding, differences at the delay period related with task difficulty, and differential retrieval for Mt or Mp dependent on the process which the information comes from, suggesting that Mt and Mp differ at the very beginning of the processing.

CB1R mediates oleamide's reward while 5HT2cR mediates aversion in the nucleus accumbens shell of rats.

In this study, we have pursued to assess oleamide's potential role in reward and aversion mechanisms. To reach this goal we infused oleamide, either 1 µg into the nucleus accumbens shell (NAccS) and evaluated its effects on conditioned place preference (CCP) or 10 µg, to evaluate conditioned place aversion (CPA). Extinction and reinstatement were also evaluated in both cases. We sought to determine if CPP occurs via cannabinoid receptor 1 (CB1R) and CPA via serontoninergic 2c receptor (5HT2cR). Results revealed that 1 µg of oleamide administered bilaterally into the NAccS induced CPP, while 10 µg induced CPA. In both conditions CPP or CPA, reinstatement after extinction was induced. AM251 (CB1R inverse-agonist) prevented CPP induced with 1 µg; while SB242084 (5HT2cR antagonist) not only prevented CPA induced with 10 µg but caused a switch to CPP. These results suggest that oleamide at low doses promotes reward through CB1R, and aversion at high doses via 5HT2cR.

Endocannabinoids as Therapeutic Targets.

Most of the drugs of abuse affect the brain by interacting with naturally expressed molecular receptors. Marihuana affects a series of receptors including cannabinoid receptor 1 (CB1R) and CB2R, among others. Endogenous molecules with cannabinoid activity interact with these receptors naturally. Receptors, ligands, synthesizing and degrading enzymes, as well as transporters, have been described. This endocannabinoid system modulates behaviors and physiological processes, i.e. food intake, the sleep-waking cycle, learning and memory, motivation, and pain perception, among others. The rather broad distribution of endocannabinoids in the brain explains the different effects marihuana induces in its users. However, this very same anatomical and physiological distribution makes this system a useful target for therapeutic endeavors. In this review, we briefly discuss the potential of small molecules that target the endocannabinoids as therapeutic tools to improve behaviors and treat illnesses. We believe that under medical supervision, endocannabinoid targets offer new advantages for patients for controlling multiple medical disorders.

Possible role of hippocampal GPR55 in spatial learning and memory in rats.

Endocannabinoids (eCBs) are involved in the hippocampal mechanisms of spatial learning and memory in rats. Although eCBs exert many of their actions on spatial learning and memory via CB1 receptors, the putative cannabinoid receptor GPR55 (expressed in the hippocampus, cortex, forebrain, cerebellum and striatum) seems to be also involved. To investigate the potential role of GPR55 in spatial learning and memory, Wistar rats received bilateral infusions of lysophosphatidylinositol (LPI, GPR55­agonist) into the hippocampus 5­minutes before training­phase in the Barnes­maze (BM). This manipulation increased the use of serial navigation while preventing the learning of spatial navigation strategy and decreasing the use of random activity to find the escape­tunnel in the BM. In contrast, CID16020046 (GPR55­antagonist) increased the use of random activity at the expense of spatial and serial navigation strategies. Finally, CID16020046 significantly reduced the time spent in the target zone during a retention test. Our results suggest: (i) a potential role of GPR55 in developing navigation strategies; (ii) a prospective function for LPI acting in hippocampal CA1 (probably via GPR55) to perform a serial navigation strategy; and (iii) a potential role of GPR55 in the mechanisms involved in spatial memory (object placement memory).