The Cerebellum on Cocaine

The traditional cerebellum’s role has been linked to the high computational demands for sensorimotor control. However, several findings have pointed to its involvement in executive and emotional functions in the last decades. First in 2009 and then, in 2016, we raised why we should consider the cerebellum when thinking about drug addiction. A decade later, mounting evidence strongly suggests the cerebellar involvement in this disorder. Nevertheless, direct evidence is still partial and related mainly to drug-induced reward memory, but recent results about cerebellar functions may provide new insights into its role in addiction. The present review does not intend to be a compelling revision on available findings, as we did in the two previous reviews. This minireview focuses on specific findings of the cerebellum’s role in drug-related reward memories and the way ahead for future research. The results discussed here provide grounds for involving the cerebellar cortex’s apical region in regulating behavior driven by drug-cue associations. They also suggest that the cerebellar cortex dysfunction may facilitate drug-induced learning by increasing glutamatergic output from the deep cerebellar nucleus (DCN) to the ventral tegmental area (VTA) and neural activity in its projecting areas

Papel del prelímbico en la adquisición de la memoria de preferencia hacia estímulos asociados a la cocaína

I Jornades d'Investigació per als estudiants de la Facultat de Ciències de la SalutIntroducción: Hallazgos previos sugieren que el desarrollo de la adicción a las drogas puede ser entendido en términos de interacción entre los mecanismos cerebrales de memoria pavloviana e instrumental que subyacen a la búsqueda e ingesta de drogas. Se argumenta que el consumo de drogas es un comportamiento inicialmente dirigido a un objeto, pero después de la experiencia repetida puede convertirse en un hábito desencadenado automáticamente por los estímulos asociados al consumo. En este caso, uno de los procesos que subyace a este cambio de comportamiento es la adqui-sición de la memoria de preferencia hacia las señales ambientales asociadas a la droga. La evidencia apoya que la red prefronto-estriado-límbica sustenta el almacena-miento de estas memorias inducidas por drogas. objetivo y métodos: El presente estudio tuvo como objetivo evaluar los efectos de la inactivación de la corteza prefron-tal medial (prelímbica-infralímbica) (cPfm) en la adquisición de la preferencia hacia una señal de olor emparejada con la cocaína (cS+). La inactivación del cPfm se llevó a cabo mediante la infusión de lidocaína en dicha región diez minutos antes del entre-namiento. resultados: Los resultados indicaron que la inactivación de la cPfm au-mentó hasta el 100 % el porcentaje de animales que adquieren preferencia condicio-nada por la cocaína. conclusiones: Nuestros resultados demuestran que el desarrollo de la preferencia condicionada inducida por la cocaína se promueve cuando la activi-dad del cPfm disminuye. Por lo tanto, estos resultados sugieren que la corteza pre-frontal medial trabaja en la adquisición de la inhibición de memorias emocionales rela-cionadas con las drogas.Introduction: Previous findings suggest that the development of drug addiction can be understood in terms of interactions between Pavlovian and instrumental memory mechanisms in the brain that underlie drug seeking and taking. It is argued that drug use is a behavior initially goal-directed, but after repeated experience it can become a habit automatically triggered by drug-associated stimuli. In this case, one of the processes underlying this behavioral shift is the acquisition of preference memories towards drug-related environmental cues. Evidence supports that prefronto-striatal-limbic networks underpin storage of these drug-induced memories. Aim and meth-ods: The present study aimed at evaluating the effects of medial prefrontal cortex (mPfc) deactivations on the acquisition of preference towards an odour cue paired to cocaine (cS+). Medial Pfc deactivation was accomplished by infusing lidocaine into the region ten minutes before training. results: The results indicated that deactiva-tion of mPfc increased up to 100 % the percentage of animals acquiring conditioned preference for cocaine. conclusions: Our findings demonstrated that the develop-ment of cocaine-induced conditioned preference is promoted when mPfc activity de-creases. Therefore, these results suggest that the medial prefrontal cortex works on inhibiting acquisition of drug-related emotional memories

Relationship of DRD5 and MAO-B VNTR polymorphisms with paranoid and antisocial personality disorders in polydrug users

Although multiple studies have shown the role genetics plays in personality disorders and in addictions, few have studied the genetic aspects of their comorbidity. Here, we carried out a cross-sectional study in a sample comprising 303 Caucasian polydrug-consuming patients. The presence of personality disorders was evaluated using the International Personality Disorder Examination, and genes related to dopamine, serotonin and monoamine oxidase (MAO) were genotyped. A significant relationship was observed between the bp 279 DRD5 variable number of tandem repeat (VNTR) polymorphism and paranoid personality disorder OR 95 ð Þ ð Þ¼ %CI 2:186 1ð Þ :074;4:449 ;p ¼ 0:006 . The bp 182 OR 95 ð Þ ð Þ¼ %CI 0:407 0ð Þ :178;0:931 ;p ¼ 0:033 and bp 184 OR 95 ð Þ ð Þ¼ %CI 0:391 0ð Þ :188;0:813 ;p ¼ 0:012 alleles of the MAOB VNTR were also associated with antisocial personality disorder. Among patients with addictions, paranoid personality disorder should also be considered in addition to the importance of antisocial and borderline personality disorders. The higher frequency of the bp 279 DRD5 VNTR allele found in patients with paranoid personality disorder, as well as the associations between alleles of the MAOB VNTR and antisocial personality disorder, support the monoaminergic bases of these personality disorders, especially when dealing with patients with addictions

Prepulse Inhibition in Cocaine Addiction and Dual Pathologies

Cocaine addiction is frequently associated with different psychiatric disorders, especially schizophrenia and antisocial personality disorder. A small number of studies have used prepulse inhibition (PPI) as a discriminating factor between these disorders. This work evaluated PPI and the phenotype of patients with cocaine-related disorder (CRD) who presented a dual diagnosis of schizophrenia or antisocial personality disorder. A total of 74 men aged 18–60 years were recruited for this research. The sample was divided into four groups: CRD (n = 14), CRD and schizophrenia (n = 21), CRD and antisocial personality disorder (n = 16), and a control group (n = 23). We evaluated the PPI and other possible vulnerability factors in these patients by using different assessment scales. PPI was higher in the CRD group at 30 ms (F(3, 64) = 2.972, p = 0.038). Three discriminant functions were obtained which allowed us to use the overall Hare Psychopathy Checklist Revised score, reward sensitivity, and PPI at 30 ms to predict inclusion of these patients in the different groups with a success rate of 79.7% (42.9% for CRD, 76.2% for CRD and schizophrenia, 100% for CRD and antisocial personality disorder, and 91.3% in the control group). Despite the differences we observed in PPI, this factor is of little use for discriminating between the different diagnostic groups and it acts more as a non-specific endophenotype in certain mental disorders, such as in patients with a dual diagnosis

The role of the cerebellum in drug-cue associative memory: functional interactions with the medial prefrontal cortex

Drug-induced Pavlovian memories are thought to be crucial for drug addiction because they guide behaviour towards environments with drug availability. Drug-related memory depends on persistent changes in dopamine-glutamate interactions in the medial pre- frontal cortex (mPFC), basolateral amygdala, nucleus accumbens core and hippocampus. Recent evidence from our laboratory indi- cated that the cerebellum is also a relevant node for drug-cue associations. In the present study, we tested the role that specific regions of the cerebellum and mPFC play in the acquisition of cocaine-induced preference conditioning. Quinolinic acid was used to manage a permanent deactivation of lobule VIII in the vermis prior to conditioning. Additionally, lidocaine was infused into the prelim- bic and infralimbic (IL) cortices for reversible deactivation before every training session. The present findings show, for the first time, that the cerebellum and mPFC might act together in order to acquire drug-cue Pavlovian associations. Either a dorsal lesion in lobule VIII or an IL deactivation encouraged cocaine-induced preference conditioning. Moreover, simultaneous IL-cerebellar deactivation prevented the effect of either of the separate deactivations. Therefore, similar to the IL cortex, neural activity in the cerebellum may be crucial for ensuring inhibitory control of the expression of cocaine-related memories

The Association between a MAOB Variable Number Tandem Repeat Polymorphism and Cocaine and Opiate Addictions in Polyconsumers

Genetic analysis of the association between alcohol, cocaine, and opiate addiction and variable number tandem repeat (VNTR) polymorphisms in monoamine oxidase B (MAOB) and serotonergic 5-hydroxytryptamine (serotonin) receptor 1B and 2C (HTR1B 21 and HTR2C) pathway genes was performed in a sample of 302 polyconsumers. Our genetic association analysis revealed a significant association between a 184 base pair (bp) VNTR polymorphism in the MAOB gene and addiction to cocaine and opiates. This work highlights new genetic marker associations in cocaine and opiate polyconsumer addictions. These data help to clarify and quantify the complex role of genetics in addictive disorders, as well as their future contribution to the prevention (genetic counselling), diagnosis (genetic diagnosis of vulnerability), and treatment (pharmacogenomics) of these disorders.This research was funded by Centro Superior de Investigación en Salud Pública (CSISP), Spain (grant number CS2003-05-05); Valencian Reginal Government Department of Health, Spain (grant number T4591000); and Research Foundation of the Hospital Provincial de Castellón (Ref. CAF 15-049 and 21-026)

Mapping cFos expression after cerebellar and medial prefrontal deactivations in rats trained to acquire cocaine-induced preference conditioning

6th Mediterranean Conference of Neuroscience (MNS Malta 2017

Cocaine-Induced Preference Conditioning: a Machine Vision Perspective

Existing work on drug-induced synaptic changes has shown that the expression of perineuronal nets (PNNs) at the cerebellar cortex can be regulated by cocaine-related memory. However, these studies on animals have mostly relied on limited manually-driven procedures, and lack some more rigorous statistical approaches and more automated techniques. In this work, established methods from computer vision and machine learning are considered to build stronger evidence of those previous findings. To that end, an image descriptor is designed to characterize PNNs images; unsupervised learning (clustering) is used to automatically find distinctive patterns of PNNs; and supervised learning (classification) is adopted for predicting the experiment group of the mice from their PNN images. Experts in neurobiology, who were not aware of the underlying computational procedures, were asked to describe the patterns emerging from the automatically found clusters, and their descriptions were found to align surprisingly well with the two types of PNN images revealed from previous studies, namely strong and weak PNNs. Furthermore, when the set of PNN images corresponding to every mice in the saline (control) group and the conditioned (experimental) group were characterized using a bag-of-words representation, and subject to supervised learning (saline vs conditioned mice), the high classification results suggest the ability of the proposed representation and procedures in recognizing these groups. Therefore, despite the limited size of the dataset (1,032 PNN images of 6 saline and 6 conditioned mice), the results support existing evidence on the drug-related brain plasticity, while providing higher objectivit

From back to front: A functional model for the cerebellar modulation in the establishment of conditioned preferences for cocaine‐related cues

This is the pre-peer reviewed version of the following article: From back to front: A functional model for the cerebellar modulation in the establishment of conditioned preferences for cocaine‐related cues, which has been published in final form at https://doi.org/10.1111/adb.12834. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.It is now increasingly clear that the cerebellum may modulate brain functions altered in drug addiction. We previously demonstrated that cocaine‐induced conditioned preference increased activity at the dorsal posterior cerebellar vermis. Unexpectedly, a neurotoxic lesion at this region increased the probability of cocaine‐induced conditioned preference acquisition. The present research aimed at providing an explanatory model for such as facilitative effect of the cerebellar lesion. First, we addressed a tracing study in which we found a direct projection from the lateral (dentate) nucleus to the ventral tegmental area (VTA) that also receives Purkinje axons from lobule VIII in the vermis. This pathway might control the activity and plasticity of the cortico‐striatal circuitry. Then we evaluated cFos expression in different regions of the medial prefrontal cortex and striatum after a lesion in lobule VIII before conditioning. Additionally, perineuronal net (PNN) expression was assessed to explore whether the cerebellar lesion might affect synaptic stabilization mechanisms in the medial prefrontal cortex (mPFC). Damage in this region of the vermis induced general disinhibition of the mPFC and striatal subdivisions that receive dopaminergic projections, mainly from the VTA. Moreover, cerebellar impairment induced an upregulation of PNN expression in the mPFC. The major finding of this research was to provide an explanatory model for the function of the posterior cerebellar vermis on drug‐related memory. In this model, damage of the posterior vermis would release striatum‐cortical networks from the inhibitory tonic control exerted by the cerebellar cortex over VTA, thereby promoting drug effects

Nucleus incertus projections to rat medial septum and entorhinal cortex: rare collateralization and septal-gating of temporal lobe theta rhythm activity

Nucleus incertus (NI) neurons in the pontine tegmentum give rise to ascending forebrain projections and express the neuropeptide relaxin-3 (RLN3) which acts via the relaxin-family peptide 3 receptor (RXFP3). Activity in the hippocampus and entorhinal cortex can be driven from the medial septum (MS), and the NI projects to all these centers, where a prominent pattern of activity is theta rhythm, which is related to spatial memory processing. Therefore, we examined the degree of collateralization of NI projections to the MS and the medial temporal lobe (MTL), comprising medial and lateral entorhinal cortex (MEnt, LEnt) and dentate gyrus (DG), and the ability of the MS to drive entorhinal theta in the adult rat. We injected fluorogold and cholera toxin-B into the MS septum and either MEnt, LEnt or DG, to determine the percentage of retrogradely labeled neurons in the NI projecting to both or single targets, and the relative proportion of these neurons that were RLN3-positive ( +). The projection to the MS was threefold stronger than that to the MTL. Moreover, a majority of NI neurons projected independently to either MS or the MTL. However, RLN3 + neurons collateralize significantly more than RLN3-negative (–) neurons. In in vivo studies, electrical stimulation of the NI induced theta activity in the MS and the entorhinal cortex, which was impaired by intraseptal infusion of an RXFP3 antagonist, R3(BΔ23-27)R/I5, particularly at ~ 20 min post-injection. These findings suggest that the MS plays an important relay function in the NI-induced generation of theta within the entorhinal cortex.Funding for open access charge: CRUE-Universitat Jaume IThis research was funded by the Postdoctoral Program of the UJI POSDOC/2021/19 (IG-M); UJI Predoctoral Program PREDOC/2021/19 (MN-S); Fundación Alicia Koplowitz, Spain, grant number 19I436 (FEO-B, FR-B, EC-G); the Spanish Ministerio de Ciencia, Innovación y Universidades, grant number RTI2018-095698-B-I00 (FEO-B, IG-M, FR-B, EC-G); AICO Generalitat Valenciana, grant number AICO/2021/246 (EC-G, FO-B, FR-B), National Health and Medical Research Council of Australia, grant number (ALG), the Spanish Ministerio de Ciencia, Innovación y Universidades, grant number PID2019-107809RB-I00 (AN-M) and Universitat Jaume I, grant numbers UJI-A2017-17 (FR-B) and UJI-B2019-54 (FEO-B).Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. Funding was provided by the Universitat Jaume I, POSDOC/2021/19, PREDOC/2021/19, UJI-A2017-17, Ministerio de Ciencia, Innovación y Universidades, PID2019-107809RB-I00, RTI2018-095698-B-I00, Fundación Alicia Koplowitz, 19I436, Conselleria de Innovación, Universidades, Ciencia y Sociedad Digital, Generalitat Valenciana, AICO/2021/246, National Health and Medical Research Council of Australia, 1067522