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Opioid signaling mediates steroid abuse: The dopamine system in the brain mediates feelings of "reward" and is implicated in addiction to various drugs, including anabolic androgenic steroids. Bontempi and Bonci found that the neurological and behavioral effects of androgenic steroids were mediated not by androgen receptors but indirectly by opioid receptors on dopaminergic neurons. A single subcutaneous injection of the steroids nandrolone or testosterone in mice stimulated the release of β-endorphins in a dopaminergic neuron-rich brain region. β-Endorphins activated mu (μ)–opioid receptor (MOR) signaling, which induced excitatory synaptic plasticity in neurons. Blocking MOR activation prevented drug-seeking behavior in steroid-injected mice. The findings may explain the addictive nature of anabolic steroid use. Anabolic androgenic steroids (AAS) have medical utility but are often abused, and the effects of AAS on reward circuits in the brain have been suggested to lead to addiction. We investigated the previously reported correlations between AAS and the endogenous μ-opioid system in the rewarding properties of AAS in mice. We found that a single injection of a supraphysiological dose of natural or synthetic AAS strengthened excitatory synaptic transmission in putative ventral tegmental area (VTA) dopaminergic neurons. This effect was associated with the activation of μ-opioid receptors (MORs) and an increase in β-endorphins released into the VTA and the plasma. Irreversible blockade of MORs in the VTA counteracted two drug-seeking behaviors, locomotor activity and place preference. These data suggest that AAS indirectly stimulate a dopaminergic reward center of the brain through activation of endogenous opioid signaling and that this mechanism mediates the addictive effects of AAS. [ABSTRACT FROM AUTHOR]

The advent of the noninvasive brain stimulation (NIBS) technique has paved the way for neural circuit-based treatments for addiction. Recently, evidence from both preclinical and clinical studies has evaluated the use of transcranial magnetic stimulation (TMS) as a safe and cost-effective therapeutic tool for substance use disorders (SUDs). Indeed, repetitive TMS impacts on neural activity inducing short- and long-term effects involving neuroplasticity mechanisms locally within the target area of stimulation and the network level throughout the brain. Here, we provide an integrated view of evidence highlighting the mechanisms of TMS-induced effects on modulating the maladaptive brain circuitry of addiction. We then review the preclinical and clinical findings suggesting rTMS as an effective interventional tool for the treatment of SUDs. [ABSTRACT FROM AUTHOR]

Dopamine neurons in the ventral tegmental area (VTA) are involved in a variety of physiological and pathological conditions, ranging from motivated behaviours to substance use disorders. While many studies have shown that these neurons can express plasticity at excitatory and inhibitory synapses, little is known about how inhibitory inputs and glial activity shape the output of DA neurons and therefore, merit greater discussion. In this review, we will attempt to fill in a bit more of the puzzle, with a focus on inhibitory transmission and astrocyte function. We summarize the findings within the VTA as well as observations made in other brain regions that have important implications for plasticity in general and should be considered in the context of DA neuron plasticity. [ABSTRACT FROM AUTHOR]

The brain is wired to predict future outcomes. Experience-dependent plasticity at excitatory synapses within dopamine neurons of the ventral tegmental area, a key region for a broad range of motivated behaviors, is thought to be a fundamental cellular mechanism that enables adaptation to a dynamic environment. Thus, depending on the circumstances, dopamine neurons are capable of processing both positive and negative reinforcement learning strategies. In this review, we will discuss how changes in synaptic plasticity of dopamine neurons may affect dopamine release, as well as behavioral adaptations to different environmental conditions falling at opposite ends of a saliency spectrum ranging from reward to aversion. [ABSTRACT FROM AUTHOR]

Exposure to drugs of abuse, such as cocaine, leads to plastic changes in the activity of brain circuits, and a prevailing view is that these changes play a part in drug addiction. Notably, there has been intense focus on drug-induced changes in synaptic excitability and much less attention on intrinsic excitability factors (that is, excitability factors that are remote from the synapse). Accumulating evidence now suggests that intrinsic factors such as K+ channels are not only altered by cocaine but may also contribute to the shaping of the addiction phenotype. [ABSTRACT FROM AUTHOR]

Exposure to addictive drugs can result in maladaptive alterations in neural circuit function. This review highlights recent progress made in identifying the organization, function, and cellular plasticity of the ventral tegmental area (VTA) and nucleus accumbens (NAc), two brain regions strongly implicated in substance use disorders. Emphasis is given to advances made with new research methodologies, particularly optogenetics, which have provided scientists with an unprecedented ability to map neural circuitry and pinpoint drug-induced synaptic modifications. A better understanding of these adaptive events will aid the development of pharmacological treatments for drug addiction and, more generally, further our understanding of motivated behaviors. [ABSTRACT FROM AUTHOR]

The striatum is considered to be critical for the control of goal-directed action, with the lateral dorsal striatum (latDS) being implicated in modulation of habits and the nucleus accumbens thought to represent a limbic–motor interface. Although medium spiny neurons from different striatal subregions exhibit many similar properties, differential firing and synaptic plasticity could contribute to the varied behavioral roles across subregions. Here, we examined the contribution of small-conductance calcium-activated potassium channels (SKs) to action potential generation and synaptic plasticity in adult rat latDS and nucleus accumbens shell (NAS) projection neurons in vitro. The SK-selective antagonist apamin exerted a prominent effect on latDS firing, significantly decreasing the interspike interval. Furthermore, prolonged latDS depolarization increased the interspike interval and reduced firing, and this enhancement was reversed by apamin. In contrast, NAS neurons exhibited greater basal firing rates and less regulation of firing by SK inhibition and prolonged depolarization. LatDS neurons also had greater SK currents than NAS neurons under voltage-clamp. Importantly, SK inhibition with apamin facilitated long-term depression (LTD) induction in the latDS but not the NAS, without alterations in glutamate release. In addition, SK activation in the latDS prevented LTD induction. Greater SK function in the latDS than in the NAS was not secondary to differences in sodium or inwardly rectifying potassium channel function, and apamin enhancement of firing did not reflect indirect action through cholinergic interneurons. Thus, these data demonstrate that SKs are potent modulators of action potential generation and LTD in the dorsal striatum, and could represent a fundamental cellular mechanism through which habits are regulated. [ABSTRACT FROM AUTHOR]

Chronic morphine drives adaptations in synaptic transmission thought to underlie opiate dependence. Here we examine the role of μ-opioid receptor (MOR) trafficking in one of these adaptations, specifically, changes in GABA transmission in the ventral tegmental area (VTA). To address this question, we used a knock-in mouse, RMOR (for recycling MOR), in which genetic change in the MOR promotes morphine-induced receptor desensitization and endocytosis in GABA interneurons of the VTA. In wild-type mice (postnatal days 23-28) chronic morphine (10 mg/kg, s.c., twice daily for 5 d), induced a cAMP-dependent increase in the probability of GABA release onto VTA dopamine neurons. The increased GABA release frequency correlated with physical dependence on morphine measured by counting somatic signs of morphine withdrawal, such as, tremors, jumps, rears, wet-dog shakes, and grooming behavior precipitated by subcutaneous administration of naloxone (NLX) (2 mg/kg). This adaptation in GABA release was prevented in RMOR mice given the same morphine treatment, implicating MOR trafficking in this morphine-induced change in plasticity. Importantly, treatment with the cAMP activity inhibitor rp-cAMPS [(R)-adenosine, cyclic 3′,5′-(hydrogen phosphorothioate) triethylammonium] (50 ng/0.5μl), directly to the VTA, attenuated somatic withdrawal signs to systemic morphine produced by intra-VTA NLX (500 ng/0.5 μl), directly tying enhanced cAMP-driven GABA release to naloxone-precipitated morphine withdrawal in the VTA. [ABSTRACT FROM AUTHOR]

Small (SK) and large conductance (BK) Ca2+-activated K+ channels contribute to action potential repolarization, shape dendritic Ca2+spikes and postsynaptic responses, modulate the release of hormones and neurotransmitters, and contribute to hippocampal-dependent synaptic plasticity. Over the last decade, SK and BK channels have emerged as important targets for the development of acute ethanol tolerance and for altering neuronal excitability following chronic ethanol consumption. In this mini-review, we discuss new evidence implicating SK and BK channels in ethanol tolerance and ethanol-associated homeostatic plasticity. Findings from recent reports demonstrate that chronic ethanol produces a reduction in the function of SK channels in VTA dopaminergic and CA1 pyramidal neurons. It is hypothesized that the reduction in SK channel function increases the propensity for burst firing in VTA neurons and increases the likelihood for aberrant hyperexcitability during ethanol withdrawal in hippocampus. There is also increasing evidence supporting the idea that ethanol sensitivity of native BK channel results from differences in BK subunit composition, the proteolipid microenvironment, and molecular determinants of the channel-forming subunit itself. Moreover, these molecular entities play a substantial role in controlling the temporal component of ethanol-associated neuroadaptations in BK channels. Taken together, these studies suggest that SK and BK channels contribute to ethanol tolerance and adaptive plasticity. [ABSTRACT FROM AUTHOR]

Abstract: Dopamine neurons in the ventral tegmental area (VTA) play a very important role in a variety of physiological as well as addictive behaviors. However, a clear understanding of the cellular mechanisms underlying these behaviors is still missing. Within the VTA, recent studies have shown that forms of synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD) are produced by drugs of abuse. The main goal of this review is to discuss the relationship between plasticity at excitatory synapses in the VTA and addiction-associated behaviors such as behavioral sensitization and cocaine self-administration. Furthermore, recent studies have highlighted the role of orexin/hypocretin and corticotropin-releasing factor (CRF) as powerful modulators of excitatory synaptic transmission in the VTA. Here, we will discuss the potential correlation between the ability of these peptides in mediating excitatory synaptic transmission and the development of stress- and drug-dependent behaviors. Taken together, the results from the studies reviewed here shed new light on the mechanistic role of plasticity at glutamatergic synapses in the VTA in mediating addictive, as well as stress-dependent behaviors. [Copyright &y& Elsevier]

Growing evidence indicates that the expression of synaptic plasticity in the central nervous system results in dendritic reorganization and spine remodeling. Although long-term potentiation of glutamatergic synapses after cocaine exposure in the ventral tegmental area (VTA) has been proposed as a cellular mechanism underlying addictive behaviors, the relationship between long-term potentiation and dendritic remodeling induced by cocaine on the dopaminergic neurons of the VTA has not been demonstrated. Here we report that rat VTA cells classified as type I and II showed distinct morphological responses to cocaine, as a single cocaine exposure significantly increased dendritic spine density in type I but not in type II cells. Further, only type I cells had a significant increase in the AMPA receptor : NMDA receptor ratio after a single cocaine exposure. Taken together, our data provide evidence that increased spine density and synaptic plasticity are coexpressed within the same VTA neuronal population and that only type I neurons are structurally and synaptically modified by cocaine. [ABSTRACT FROM AUTHOR]

Recent studies have suggested that the development of addictive behaviours shares common features with traditional learning models. Synaptic plasticity, a possible substrate for learning, has been demonstrated in neural reward circuits and might contribute to the learning of addictive behaviours. Changes in the strength of synaptic connections have been investigated in dopaminergic cells of the ventral tegmental area in response to several addictive drugs. Rapid and persistent forms of synaptic plasticity (specifically, long-lasting synaptic potentiation) have been demonstrated to accompany some of the behavioural effects of addictive drugs. We hypothesize that drug-induced synaptic plasticity might play a role in reward-related learning and addiction by modifying the fine tuning of dopaminergic cell firing. [Copyright &y& Elsevier]

The article focuses on a study by Z.-X. Xi and colleagues, which examined the role of the activation of brain cannabinoid type 2 (CB2) receptors in cocaine addiction. It says that endocannabinoids are mediating several forms of plasticity in brain regions. It says that the effects of selective CB2 receptor agonist JWH133 such as reduction of dopamine release in the nucleus accumbens (NAcc) were not observed in mice lacking CB2 receptors.

Cocaine-induced plasticity of glutamatergic synaptic transmission in the ventral tegmental area (VTA) plays an important role in brain adaptations that promote addictive behaviors. However, the mechanisms responsible for triggering these synaptic changes are unknown. Here, we examined the effects of acute cocaine application on glutamatergic synaptic transmission in rat midbrain slices. Cocaine caused a delayed increase in NMDA receptor (NMDAR)-mediated synaptic currents in putative VTA dopamine (DA) cells. This effect was mimicked by a specific DA reuptake inhibitor and by a DA D1 /D5 receptor agonist. The effect of cocaine was blocked by a DA D1 /D5 receptor antagonist as well as by inhibitors of the cAMP/cAMP-dependent protein kinase A (PKA) pathway. Furthermore, biochemical analysis showed an increase in the immunoreactivity of the NMDAR subunits NR1 and NR2 Band their redistribution to the synaptic membranes in VTA neurons. Accordingly, NMDAR-mediated EPSC decay time kinetics were significantly slower after cocaine, suggesting an increased number of NR2B-containing NMDARs. Finally, pharmacological analysis indicates that NR2B subunits might be incorporated in triheteromeric NR1/NR2A/NR2B complexes rather than in "pure" NR1/NR2B NMDA receptors. Together, our data suggest that acute cocaine increases NMDAR function in the VTA via activation of the cAMP/PKA pathway mediated by a DA D5-like receptor, leading to the insertion of NR2B-containing NMDARs in the membrane. These results provide a potential mechanism by which acute cocaine promotes synaptic plasticity of VTA neurons, which could ultimately lead to the development of addictive behaviors. [ABSTRACT FROM AUTHOR]

Abstract: Stress plays a key role in modulating the development and expression of addictive behavior, and is a major cause of relapse following periods of abstinence. In this review we focus our attention on recent advances made in understanding how stress, aversive events, and drugs of abuse, cocaine in particular, interact directly with dopamine neurons in the ventral tegmental area, and how these interactions may be involved in stress-induced relapse. We start by outlining how dopamine neurons respond to aversive stimuli and stress, particularly in terms of firing activity and modulation of excitatory synaptic inputs. We then discuss some of the cellular mechanisms underlying the effects of cocaine on dopamine neurons, again with a selective focus on synaptic plasticity. Finally, we examine how the effects of stress and cocaine interact and how these cellular mechanisms in ventral tegmental area dopamine neurons may be engaged in stress-induced relapse. [ABSTRACT FROM AUTHOR]

Experience-dependent plasticity at excitatory synapses of the mesocorticolimbic system is a fundamental brain mechanism that enables adaptation to an ever-changing environment. These synaptic responses are critical for the planning and execution of adaptive behaviors that maximize survival. The mesocorticolimbic system mediates procurement of positive reinforcers such as food and sex; however, drugs of abuse resculpt this crucial circuitry to promote compulsive drug-seeking behavior. This review will discuss the long-term changes in glutamatergic neurotransmission that occur within the mesolimbic system following cocaine exposure. In addition, we will examine how these long-lasting neuroadaptations may drive the pathology of psychostimulant addiction. Finally, we review clinical trials that highlight antagonists at excitatory AMPA receptors as promising targets against cocaine abuse. [Copyright &y& Elsevier]

Highlights • Cocaine drives plasticity to enhance excitation of VTA dopamine neurons. • Dopamine release is decreased after chronic cocaine. • Neuromodulation therapies show promise in treating cocaine addiction. Cocaine exposure induces persistent changes in synaptic transmission and intrinsic properties of ventral tegmental area (VTA) dopamine neurons. Despite significant progress in understanding cocaine-induced plasticity, an effective treatment of cocaine addiction is lacking. Chronic cocaine potentiates excitatory and alters inhibitory transmission to dopamine neurons, induces dopamine neuron hyperexcitability, and reduces dopamine release in projection areas. Understanding how intrinsic and synaptic plasticity interact to control dopamine neuron firing and dopamine release could prove useful in the development of new therapeutics. In this review, we examine recent literature discussing cocaine-induced plasticity in the VTA and highlight potential therapeutic interventions. [ABSTRACT FROM AUTHOR]

Summary Fear learning is a fundamental behavioral process that requires dopamine (DA) release. Experience-dependent synaptic plasticity occurs on DA neurons while an organism is engaged in aversive experiences. However, whether synaptic plasticity onto DA neurons is causally involved in aversion learning is unknown. Here, we show that a stress priming procedure enhances fear learning by engaging VTA synaptic plasticity. Moreover, we took advantage of the ability of the ATPase Thorase to regulate the internalization of AMPA receptors (AMPARs) in order to selectively manipulate glutamatergic synaptic plasticity on DA neurons. Genetic ablation of Thorase in DAT + neurons produced increased AMPAR surface expression and function that lead to impaired induction of both long-term depression (LTD) and long-term potentiation (LTP). Strikingly, animals lacking Thorase in DAT + neurons expressed greater associative learning in a fear conditioning paradigm. In conclusion, our data provide a novel, causal link between synaptic plasticity onto DA neurons and fear learning. [ABSTRACT FROM AUTHOR]

Background: Chronic methamphetamine (METH) exposure causes neuroadaptations at glutamatergic synapses. Methods: To identify the METH-induced epigenetic underpinnings of these neuroadaptations, we injected increasing METH doses to rats for 2 weeks and measured striatal glutamate receptor expression. We then quantified the effects of METH exposure on histone acetylation. We also measured METH-induced changes in DNA methylation and DNA hydroxymethylation. Results: Chronic METH decreased transcript and protein expression of GluA1 and GluA2 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) and GluN1 N-methyl-D-aspartate receptor subunits. These changes were associated with altered electrophysiological glutamatergic responses in striatal neurons. Chromatin immunoprecipitation-polymerase chain reaction revealed that METH decreased enrichment of acetylated histone H4 on GluA1, GluA2, and GluN1 promoters. Methamphetamine exposure also increased repressor element-1 silencing transcription factor (REST) corepressor 1, methylated CpG binding protein 2, and histone deacetylase 2 enrichment, but not of sirtuin 1 or sirtuin 2, onto GluA1 and GluA2 gene sequences. Moreover, METH caused interactions of REST corepressor 1 and methylated CpG binding protein 2 with histone deacetylase 2 and of REST with histone deacetylase 1. Surprisingly, methylated DNA immunoprecipitation and hydroxymethylated DNA immunoprecipitation-polymerase chain reaction revealed METH-induced decreased enrichment of 5-methylcytosine and 5-hydroxymethylcytosine at GluA1 and GluA2 promoter sequences. Importantly, the histone deacetylase inhibitor, valproic acid, blocked METH-induced decreased expression of AMPAR and N-methyl-D-aspartate receptor subunits. Finally, valproic acid also attenuated METH-induced decrease H4K16Ac recruitment on AMPAR gene sequences. Conclusions: These observations suggest that histone H4 hypoacetylation may be the main determinant of METH-induced decreased striatal glutamate receptor expression. [Copyright &y& Elsevier]

Sigma-1 receptors (Sig-1Rs) have been implicated in many neurological and psychiatric conditions. Sig-1Rs are intracellular chaperones that reside specifically at the endoplasmic reticulum (ER)–mitochondrion interface, referred to as the mitochondrion-associated ER membrane (MAM). Here, Sig-1Rs regulate ER–mitochondrion Ca2+ signaling. In this review, we discuss the current understanding of Sig-1R functions. Based on this, we suggest that the key cellular mechanisms linking Sig-1Rs to neurological disorders involve the translocation of Sig-1Rs from the MAM to other parts of the cell, whereby Sig-1Rs bind and modulate the activities of various ion channels, receptors, or kinases. Thus, Sig-1Rs and their associated ligands may represent new avenues for treating aspects of neurological and psychiatric diseases. [ABSTRACT FROM AUTHOR]

The N-methyl-D-aspartate receptor (NMDAR) plays a critical role in synaptic plasticity and is one of the main targets for alcohol (ethanol) in the brain. Trafficking of the NMDAR is emerging as a key regulatory mechanism that underlies channel activity and synaptic plasticity. Here we show that exposure of hippocampal neurons to ethanol increases the internalization of the NR2A but not NR2B subunit of the NMDAR via the endocytic pathway. We further observed that ethanol exposure results in NR2A endocytosis through the activation of H-Ras and the inhibition of the tyrosine kinase Src. Importantly, ethanol treatment alters functional subunit composition from NR2A/NR2B- to mainly NR2B-containing NMDARs. Our results suggest that addictive drugs such as ethanol alter NMDAR trafficking and subunit composition. This may be an important mechanism by which ethanol exerts its effects on NMDARs to produce alcohol-induced aberrant plasticity. [ABSTRACT FROM AUTHOR]