The high rate of recidivism in cocaine addiction after prolonged periods of abstinence poses a significant problem for the effective treatment of this condition. Moreover, the neurobiological basis of this relapse phenomenon remains poorly understood. In this review, we will discuss the evidence currently available regarding the neurobiological changes during the extinction of cocaine self-administration. Specifically, we will focus on alterations in the dopaminergic, opioidergic, glutamatergic, cholinergic, serotoninergic and CRF systems described in self-administration experiments and extinction studies after chronic cocaine administration. We will also discuss the differences related to contingent versus non-contingent cocaine administration, which highlights the importance of environmental cues on drug effects and extinction. The findings discussed in this review may aid the development of more effective therapeutic approaches to treat cocaine relapse. Full article

The endocannabinoid system (ECS) has been implicated in many physiological functions, including the regulation of appetite, food intake and energy balance, a crucial involvement in brain reward systems and a role in psychophysiological homeostasis (anxiety and stress responses). We first introduce this important regulatory system and chronicle what is known concerning the signal transduction pathways activated upon the binding of endogenous cannabinoid ligands to the G_i/0-coupled CB1 cannabinoid receptor, as well as its interactions with other hormones and neuromodulators which can modify endocannabinoid signaling in the brain. Anorexia nervosa (AN) and bulimia nervosa (BN) are severe and disabling psychiatric disorders, characterized by profound eating and weight alterations and body image disturbances. Since endocannabinoids modulate eating behavior, it is plausible that endocannabinoid genes may contribute to the biological vulnerability to these diseases. We present and discuss data suggesting an impaired endocannabinoid signaling in these eating disorders, including association of endocannabinoid components gene polymorphisms and altered CB1-receptor expression in AN and BN. Then we discuss recent findings that may provide new avenues for the identification of therapeutic strategies based on the endocannabinod system. In relation with its implications as a reward-related system, the endocannabinoid system is not only a target for cannabis but it also shows interactions with other drugs of abuse. On the other hand, there may be also a possibility to point to the ECS as a potential target for treatment of drug-abuse and addiction. Within this framework we will focus on enzymatic machinery involved in endocannabinoid inactivation (notably fatty acid amide hydrolase or FAAH) as a particularly interesting potential target. Since a deregulated endocannabinoid system may be also related to depression, anxiety and pain symptomatology accompanying drug-withdrawal states, this is an area of relevance to also explore adjuvant treatments for improving these adverse emotional reactions. Full article

The amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is widely abused as a recreational drug due to its unique psychological effects. Of interest, MDMA causes long-lasting deficits in neurochemical and histological markers of the serotonergic neurons in the brain of different animal species. Such deficits include the decline in the activity of tryptophan hydroxylase in parallel with the loss of 5-HT and its main metabolite 5-hydoxyindoleacetic acid (5-HIAA) along with a lower binding of specific ligands to the 5-HT transporters (SERT). Of concern, reduced 5-HIAA levels in the CSF and SERT density have also been reported in human ecstasy users, what has been interpreted to reflect the loss of serotonergic fibers and terminals. The neurotoxic potential of MDMA has been questioned in recent years based on studies that failed to show the loss of the SERT protein by western blot or the lack of reactive astrogliosis after MDMA exposure. In addition, MDMA produces a long-lasting down-regulation of SERT gene expression; which, on the whole, has been used to invoke neuromodulatory mechanisms as an explanation to MDMA-induced 5-HT deficits. While decreased protein levels do not necessarily reflect neurodegeneration, the opposite is also true, that is, neuroregulatory mechanisms do not preclude the existence of 5-HT terminal degeneration. Full article

Drugs of abuse induce plastic changes in the brain that seem to underlie addictive phenomena. These plastic changes can be structural (morphological) or synaptic (biochemical), and most of them take place in the mesolimbic and mesostriatal circuits. Several addiction-related changes in brain circuits (hypofrontality, sensitization, tolerance) as well as the outcome of treatment have been visualized in addicts to psychostimulants using neuroimaging techniques. Repeated exposure to psychostimulants induces morphological changes such as increase in the number of dendritic spines, changes in the morphology of dendritic spines, and altered cellular coupling through new gap junctions. Repeated exposure to psychostimulants also induces various synaptic adaptations, many of them related to sensitization and neuroplastic processes, that include up- or down-regulation of D1, D2 and D3 dopamine receptors, changes in subunits of G proteins, increased adenylyl cyclase activity, cyclic AMP and protein kinase A in the nucleus accumbens, increased tyrosine hydroxylase enzyme activity, increased calmodulin and activated CaMKII in the ventral tegmental area, and increased deltaFosB, c-Fos and AP-1 binding proteins. Most of these changes are transient, suggesting that more lasting plastic brain adaptations should take place. In this context, protein synthesis inhibitors block the development of sensitization to cocaine, indicating that rearrangement of neural networks must develop for the long-lasting plasticity required for addiction to occur. Self-administration studies indicate the importance of glutamate neurotransmission in neuroplastic changes underlying transition from use to abuse. Finally, plastic changes in the addicted brain are enhanced and aggravated by neuroinflammation and neurotrophic disbalance after repeated psychostimulants. Full article

The capacity of the brain to generate new adult neurons is a recent discovery that challenges the old theory of an immutable adult brain. A new and fascinating field of research now focuses on this regenerative process. The two brain systems that constantly produce new adult neurons, known as the adult neurogenic systems, are the dentate gyrus (DG) of the hippocampus and the lateral ventricules/olfactory bulb system. Both systems are involved in memory and learning processes. Different drugs of abuse, such as cocaine and MDMA, have been shown to produce cellular and molecular changes that affect adult neurogenesis. This review summarizes the effects that these drugs have on the adult neurogenic systems. The functional relevance of adult neurogenesis is obscured by the functions of the systems that integrate adult neurons. Therefore, we explore the effects that cocaine and MDMA produce not only on adult neurogenesis, but also on the DG and olfactory bulbs. Finally, we discuss the possible role of new adult neurons in cocaine- and MDMA-induced impairments. We conclude that, although harmful drug effects are produced at multiple physiological and anatomical levels, the specific consequences of reduced hippocampus neurogenesis are unclear and require further exploration. Full article

Sigma₁ receptors (σ₁Rs) represent a structurally unique class of intracellular proteins that function as chaperones. σ₁Rs translocate from the mitochondria-associated membrane to the cell nucleus or cell membrane, and through protein-protein interactions influence several targets, including ion channels, G-protein-coupled receptors, lipids, and other signaling proteins. Several studies have demonstrated that σR antagonists block stimulant-induced behavioral effects, including ambulatory activity, sensitization, and acute toxicities. Curiously, the effects of stimulants have been blocked by σR antagonists tested under place-conditioning but not self-administration procedures, indicating fundamental differences in the mechanisms underlying these two effects. The self administration of σR agonists has been found in subjects previously trained to self administer cocaine. The reinforcing effects of the σR agonists were blocked by σR antagonists. Additionally, σR agonists were found to increase dopamine concentrations in the nucleus accumbens shell, a brain region considered important for the reinforcing effects of abused drugs. Although the effects of the σR agonist, DTG, on dopamine were obtained at doses that approximated those that maintained self administration behavior those of another agonist, PRE-084 required higher doses. The effects of DTG were antagonized by non-selective or a preferential σ₂R antagonist but not by a preferential σ₁R antagonist. The effects of PRE-084 on dopamine were insensitive to σR antagonists. The data suggest that the self administration of σR agonists is independent of dopamine and the findings are discussed in light of a hypothesis that cocaine has both intracellular actions mediated by σRs, as well as extracellular actions mediated through conventionally studied mechanisms. The co-activation and potential interactions among these mechanisms, in particular those involving the intracellular chaperone σRs, may lead to the pernicious addictive effects of stimulant drugs. Full article

Amphetamine derivatives such as methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) are widely abused drugs in a recreational context. This has led to concern because of the evidence that they are neurotoxic in animal models and cognitive impairments have been described in heavy abusers. The main targets of these drugs are plasmalemmal and vesicular monoamine transporters, leading to reverse transport and increased monoamine efflux to the synapse. As far as neurotoxicity is concerned, increased reactive oxygen species (ROS) production seems to be one of the main causes. Recent research has demonstrated that blockade of a7 nicotinic acetylcholine receptors (nAChR) inhibits METH- and MDMA-induced ROS production in striatal synaptosomes which is dependent on calcium and on NO-synthase activation. Moreover, a7 nAChR antagonists (methyllycaconitine and memantine) attenuated in vivo the neurotoxicity induced by METH and MDMA, and memantine prevented the cognitive impairment induced by these drugs. Radioligand binding experiments demonstrated that both drugs have affinity to a7 and heteromeric nAChR, with MDMA showing lower K_i values, while fluorescence calcium experiments indicated that MDMA behaves as a partial agonist on a7 and as an antagonist on heteromeric nAChR. Sustained Ca increase led to calpain and caspase-3 activation. In addition, modulatory effects of MDMA on a7 and heteromeric nAChR populations have been found. Full article

Drug addiction is a chronic illness characterized by high rates of relapse. Relapse to drug use can be triggered by re-exposure to drug-associated cues, stressful events, or the drug itself after a period of abstinence. Pharmacological intervention to reduce the impact of relapse-instigating factors offers a promising target for addiction treatment. Growing evidence has implicated an important role of the orexin/hypocretin system in drug reward and drug-seeking, including animal models of relapse. Here, we review the evidence for the role of orexins in modulating reward and drug-seeking in animal models of addiction and the potential for orexin receptors as specific targets for anti-relapse medication approaches. Full article

Eukaryotic cells comprise a set of organelles, surrounded by membranes with a unique composition, which is maintained by a complex synthesis and transport system. Cells also synthesize the proteins destined for secretion. Together, these processes are known as the secretory pathway or exocytosis. In addition, many molecules can be internalized by cells through a process called endocytosis. Chronic and acute alcohol (ethanol) exposure alters the secretion of different essential products, such as hormones, neurotransmitters and others in a variety of cells, including central nervous system cells. This effect could be due to a range of mechanisms, including alcohol-induced alterations in the different steps involved in intracellular transport, such as glycosylation and vesicular transport along cytoskeleton elements. Moreover, alcohol consumption during pregnancy disrupts developmental processes in the central nervous system. No single mechanism has proved sufficient to account for these effects, and multiple factors are likely involved. One such mechanism indicates that ethanol also perturbs protein trafficking. The purpose of this review is to summarize our understanding of how ethanol exposure alters the trafficking of proteins in different cell systems, especially in central nervous system cells (neurons and astrocytes) in adult and developing brains. Full article