Wednesday, December 3, 2014

Treatments & prevention 
One in four people entering treatment for cocaine addiction will still be using on a weekly basis 5 years after treatment (Simpson et al., 2002). The obvious question would be why the majority of abstainers show protracted resistance to relapse while a significant minority will continue to be at high risks of recidivism after long periods of time. Furthermore, how do we identify those individuals most likely to relapse, in order to give them additional or even a different course of treatment?



To address this issue, Bell et al., 2014 used functional magnetic resonance imaging to examine brain regions associated with inhibitory control –cortical response inhibition circuit (RIC)- and compulsivity associated with drug seeking (such as the ventral and dorsal striatum) in abstinent cocaine dependent (CD) individuals and non-using control. While no significant differences were found between groups regarding activation, at the individual participant level, abstinent CD individuals displayed an association between cocaine cue-related neural activations in the right ventral striatum and compulsive cocaine craving scores. Furthermore, CD individuals also showed a positive association between motor impulsiveness and neural activations in regions within the RIC. 
In conclusion, while former users as a group did not shown deficits in inhibitory function or cocaine-cue reactivity, participant-level results pointed to activation patterns in a minority of these individuals that likely contributes to enduring relapse vulnerability  (Bell et al., 2014). These findings might shed light on a potential relapse phenotype and contribute to the identification of “high-probability” relapse individuals.

References:

Bell RP, Garavan H & Foxe JJ (2014). Neural correlates of craving and impulsivity in abstinent former cocaine users: towards biomarkers of relapse risk. Neuropharmachology, 2014, 85:461-470.
Simpson DD, Joe GW, Broome KM. (2002). A national 5-year follow-up of treatment outcomes for cocaine dependence. Arch. Gen. Psychiatry 59, 538-544. 
 Hallmark behaviors of addiction


     Drug addiction is a chronically relapsing brain disease. In fact, environmental conditioned cue associations with drug experience are significant factors in the ongoing cycle of relapse in addiction (Hsiang et al, 2014). Relapse to drug addiction can occur even after prolonged abstinence and is often precipitated by exposure to drug-associated cues that provoke drug craving.  For example, it has been observed that in current abstinent, former-cocaine users, mere exposure to environmental cues present at the time of previous cocaine use may evoke powerful memories of the rewarding properties of cocaine, induce drug craving, and facilitate relapse to cocaine seeking and consumption. Similarly, recall of a cocaine related memory may be sufficient to induce relapse to cocaine-seeking and/or cocaine taking in drug-free rodents with a history of cocaine administration. 
The incubation of drug craving, a phenomenon characterized by the progressive potentiation of cue-induced drug cravings after withdrawal, is partially mediated by drug-induced accumulation of GluA2-lacking, calcium permeable AMPA receptors in the nucleus accumbens (NAc) (Bossert et al., 2013; Kalivas et al., 2009). However, the molecular events involved are unknown. In order to shed light on this question, Lee et al., 2013 studied silent or immature synapses in the  basolateral amygdala (BLA) to NAc projection on rodents. Silent or immature synapses express stable NMDA receptors and are abundant during early developmental; and subsequently mature into fully functional synapses by recruiting AMPA receptors. The researchers found that cocaine self-administration generates these silent synapses, and as the withdrawal period progressed, these silent synapses become unsilenced, a process involving synaptic insertion of calcium-permeable AMPA receptors. Moreover, by using in vivo optogenetic stimulation to conduct a long term depression (LTD) protocol on withdrawal day 45 that would internalize the newly inserted AMPA receptors, a re-silencing of some of the previously silent synapses was observed. This event correlated with a significant reduction in cocaine craving incubation. Taken altogether, these results suggest that this synapse-based reorganization is critical for persistent cocaine craving and relapse after withdrawal.

     References: 
     Bossert JM, Marchant NJ, Calu DJ, Shaham Y. (2013). The reinstatemt model of drug relapse: recent neurobiological findings, emerging research topics, and translational research. Psychopharmacology, 229(3): 453-76.
      Kalivas PW. (2009). The glutamate homeostasis hypothesis of addiction. Nature reviews Neuroscience, 10:561-572.
 


Key brain circuits


Simplified schematic of the circuitry of the mesolimbic dopamine system in the rat brain highlighting the major inputs to the nucleus accumbens (NAc) and ventral tegmental area (VTA) (glutamatergic projections, blue; dopaminergic projections, red; GABAergic projections, orange; orexinergic projections, green). Glutamatergic synapses excite postsynaptic neurons and GABAergic synapses inhibit postsynaptic neurons. Dopamine release exerts more complex modulatory effects. The release of dopamine from VTA neurons increases in response to administration of all drugs of abuse

The mesolimbic dopaminergic system, consisting of midbrain dopaminergic (DA) neurons in the ventral tegmental area (VTA) that project to the nucleus accumbens (NAc) and prefrontal cortex, plays a key role in reward and motivation and is a major target of abused drugs.
First of all, the VTA, which is the origin of the mesolimbic DA system, has been implicated in both the signaling of natural rewards and in the formation of drug addiction. Neurons of the VTA release DA in target regions including the nucleus accumbens (NAc) and the prefrontal cortex as well as locally. On the other hand, the NAc has two major populations of neurons which together comprise >95% NAc neurons (Lobo et al., 2010): medium spiny neurons (MSN) divided into two subtypes based on their distinct projections through cortical-basal ganglia circuits and their differential gene expression, including enrichment of dopamine D1 vs. D2 receptors. They project to the dorsal striatum. In a sophisticated set of experiments, Lobo et al., 2010 demonstrated that activation of D2+ neurons suppresses cocaine reward, while D1+ neurons induces cocaine reward. The relevance of this finding to the addicted brain lies in the possibility of a potential imbalance of these two MSN: overactive D1 MSN while a hypoactive D2 MSNs; which may contribute to the persistence of addiction.
Another key area of the reward circuit is the the lateral nucleus of the amygdala (LA). Specifically, the LA has been implicated in the process by which an initially neutral cue acquired conditioned rewarding properties by virtue of being paired with rewarding stimuli, such as food or cocaine. For example, Heldt et al., 2014 demonstrated that disrupting synaptic plasticity in the LA/BLA amygdala in rodents impairs the acquisition of cocaine conditioning, in which an initially neutral environmental cue is paired with cocaine administration. Furthermore, presentation of cues previously associated with a history of cocaine use induces craving and increase activation in brain regions such as the amygdala, as measured by functional magnetic resonance imaging studies.
References: 

Heldt SA, Zimmermann K, Parker K, Gaval M, Weinshenker D, Ressler KJ. (2014). BDNF deletion or TrkB impairment in amygdala inhibits both appetitive and aversive learning. J Neurosci 34(7): 2444-50.   

Lobo MK, Covington HE, Chaudhury D., Friedman AK, et al. Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward. Science; 2010;330:385-390. 

Epigenetic remodelling



Chronic exposure to drugs of abuse or stress regulates transcription factors, chromatin-modifying enzymes and histone post-translational modifications in discrete brain regions. Given the promiscuity of the enzymes involved, it has not yet been possible to obtain direct causal evidence to implicate the regulation of transcription and consequent behavioral plasticity by chromatin remodeling that occurs at a single gene. Grueter et al investigated the mechanism linking chrimatin dynamics to neurobiological phenomena by applying engineered transcription factors to selectively modify chromatin at a specific mouse gene in vivo. They found that histone  methylation or acetylation at the Fosb locus in nucleus accumbens, a brain reward region, was sufficient to control drug- and stress-evoked transcriptional and behavioral responses via interactions with the endogenous transcriptional machinery. This approach allowed us to relate the epigenetic landscape at a given gene directly to regulation of its expression and to its subsequent effects on reward behavior. 

In another study, Heller E.A. et al  showed that synaptic modifications in nucleus accumbens medium spiny neurons  (MSNs) play a key role in adaptive and pathological reward-dependent learning, including maladaptive responses involved in drug addiction. NAc MSNs participate in two parallel circuits, direct and indirect pathways that subserve distinct behavioral functions. Modifications of NAc MSN synapses  may occur in part via changes in the trancscriptional potential of certain genes in a cell type-specific manner. The transcription factor ΔFosB is of the key proteins implicated in the gene expression changes in NAc caused by drugs of abuse, yet its effects on synaptic function in NAc MSNs are unknown. The same study demonstrated that overexpression of ΔFosB decreased excitatory synaptic strength and likely increased silent synapses onto D1 dopamine receptor-expressing direct pathway MSNs in both the NAc shell and core. In contrast, ΔFosB likely decreased silent synapses onto NAc shell, but not core, D2 dopamine receptor-expressing indirect pathway MSNs. Analysis of NAc MSN dendritic spine morphology revealed that ΔFosB increased the density of immature spines in D1 direct but not D2 indirect pathway MSNs. Also, direct but indirect pathway MSN expression enhances behavioral responses to cocaine. These results reveal that ΔFosB in NAc differentially modulated synaptic properties and reward-related behaviors in a cell type- and subregion-specific fashion.


References 
Grueter BA, Robison AJ, Neve RL, et al. (2012) ΔFosB differentially modulates nucleus accumbens direct and indirect pathway function. PNAS, 2012, 110(5):1923-1928
Heller EA, Cates HM, Peña CJ, et al. (2014) Locus-specific epigenetic remodeling controls addiction and depression-relared behaviors. Nature Neuroscience, 2014. doi:10.1038/nn.3871.


 Anaplasticity and changes in synaptic transmission



Activity-dependent long-term depression (LTD) and long-term potentiation (LTP) of synaptic-transmission are the two principal forms of synaptic plasticity that permit strengthening (LTP) or weakening (LTD) of synapses in a dynamic that allows the adaptation of neuronal circuits necessary to respond to an ever-changing environment. Drugs of abuse modify LTP and LTD in different areas of the mesocorticolimbic system.
In a study published by Kazanetsz et al it is shown that during the acquisition phase synaptic plasticity in the nucleus accumbens is not impaired by cocaine, supporting a role for NMDAR-LTP in de the NAC in learning new reward-response associations. Once the learning has been consolidated, LTD is suppressed in all subjects. However, subsequently, a normal NMDAR-LTD is progressively recovered in animals that maintain a controlled drug intake, whereas it is persistently lost in animals undergoing the transition to addiction. This persistent impairment in LTD could explain the loss of control on drug intake observed in Addict rats. LTD in the NAC is considered important in rescaling synapses that were enhanced during acquisition of motor responses and cue-reward associations, allowing those synapses to encode furute associations and restore flexibility to neural circuits. The persistent inability to rescale synapsis in Addict animals may render drug-seekling behavior consistently resistant to modulation by environmental contingencies, finally resulting in loss of control over drug intake. 

Our results also provide unanticipated insight into the type of homeostatic alterations that characterize Addicts. We expected, as largely assumed in the field, to discover specific pathological adaptation –a particular phenotype- characterizing synaptic plasticity in Addicts. In contrast, the transition to addiction as associated, at least in the NAC, with a form of anaplasticity, i.e., the incapacity of Addicts to counteract initial drug-induced impairments. 

The anaplasticity of Addict rats is relevant to  revising conceptualizations of the transition to addiction, currently seen as the progressive development of specific brain adaptations that lead to loss of control over drug intake. Our data suggest that instead, the transition to addiction could be mediated by the incapacity to engage the active processes that allow control of drug intake. After a prolonged exposure to drugs, all the subjects are probably at the point of losing control over drug-intake behavior, as shown by the loss of LTD in all rats. This probably corresponds to the situation when an individual engaged in sustained drug use experiences the sensation that “it is becoming too much”and that “a line is being crossed”. Fortunately, for most individuals, the brain adapts to recover a normal plasticity and allows learning to control drug intake. In contrast, the anaplasticity that characterizes addicts makes them enter a downward spiral in which drug-associated stimuli, which can no longer be over-ridden by other associations, gain more and more power in controlling behavior, finally leading to the compulsive drug intake that characterizes addiction.


 All drugs of abuse have in common that they cause surges in dopamine concentration in the mesolimbic reward system and elicit synaptic plasticity in dopaminergic (DA) neurons of the ventral tegmental area (VTA). Plasticity is defined as the activity-dependent modifications of synapses and/or neural circuits at the central nervous system level. Previous work has shown that plasticity at excitatory glutamatergic synapses plays a critical role in memory acquisition and consolidation. Several signal transduction cascades, initiated by Ca2+ influx through NMDA receptors, mediate a rapid and sustained enhancement of glutamatergic synapses by regulating local synaptic strength through the modulation of AMPA receptors number and function, in a process known as long-term potentiation (LTP).
It is of our interest to note that drug-evoked synaptic plasticity in the VTA appears at excitatory afferents onto DA neurons of the VTA already 24 h after a single injection of addictive drugs (Ungless et al., 2001; Saal et al., 2003). In particular, acute exposure to cocaine in vivo induces NMDAR-dependent delayed AMPA receptor potentiation of dopaminergic neurons in the VTA (Argilli et al., 2008). Moreover, Brown et al., 2010 showed that in mice where the effect of cocaine on DAT was genetically blocked, there was no AMPAR redistribution following administration of cocaine. Furthermore, the researchers observed that other addictive drugs, such as morphine and nicotine, also cause a similar AMPAR redistribution. Taken together, these results suggest that 1) DA signaling within the VTA drives AMPA receptor distribution; and 2) posits glutamate signaling and synaptic plasticity in the mesolimbic DA circuit as an underlying mechanism for drug addiction.
References: 

Ungless MA, Whistler JL, Malenka RC, Bonci A. (2001). Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411:583-587.

Saal D., Dong Y., Bonci A., Malenka RC. (2003). Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37: 577-582.

Malinow R and Malenka RC. (2002). AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci 25: 103-26.
Kasanetz F, Deroche-Gamonet V, Berson N, et al. (2012). Transition to addiction is associated with a persistent impairment in synaptic plasticity. Science, 2012:328:1709-1712. 
    



Memory of Addiction


The specific neural mechanisms that mediate how drug memories are encoded, consolidated and stored are unknown. In order to address this issue, Hsiang et al. investigated this year which particular LA neurons are critical for encoding and storing a memory of the cocaine cue association in mice. They found that about 10% of LA neurons were recruited during cocaine conditioning using a conditioning place preference (CPP) paradigm. Moreover, neurons with increased levels of cyclic-AMP response binding element (CREB) during training –by means of infection with a viral vector- were preferentially allocated to the cocaine engram; while silencing neurons overexpressing CREB before testing disrupted the expression of the previously acquired cocaine memory. It is worth mentioning that overexpression of CREB results in increased neuronal excitability. From this and other studies, we conclude that LA plays a significant role in assigning biological salience to previously neutral cues, which in turn might posit it as a suitable target for pharmacological intervention. 
Reference:
1.     Hsiang HL, Epp JR et al. (2014) Manipulating a cocaine engram in mice. J. Neuroscience, 2014, 34(42):15115-14127.




The gateway hypothesis  and the Common liability model 
Two distinct frameworks have been proposed to explain the development of drug involvement and co-occurrence of addiction to different drugs. The “gateway hypothesis” (GH) and the general common liability model (CLA).
According to the gateway hypothesis it is drug use itself that is viewed as the cause of drug use development. Likewise, the “stages” are defined in a circular manner: a stage is said to be reached when a certain drug(s) is used, but this drug is supposed to be used only upon reaching this stage. In other words, the stage both is identified by the drug and identifies that drug. In effect, the drug is identical to the stage (“marihuana is a crucial stage . . .”)  
 
(Illustration by Michael Helfenbein) 
In contrast to the GH, the concept of common (general) liability to addiction (CLA) involves mechanisms and biobehavioral characteristics that seek to           explain the entire course of development of the disorder and changes in the risk It also overlaps with the psychological and psychopathological constructs that have been previously used to explicate addiction and its mechanisms. For a particular individual that develops addiction the CLA describes the developmental trajectory phenotype, with genetic and environmental factors acting as vectors, whose salience changes over time.


Whereas the “gateway” hypothesis does not specify mechanistic connections between “stages”, and does not extend to the risks for addictions, the concept of common liability to addictions incorporates sequencing of drug use initiation as well as extends to related addictions and their severity, provides a parsimonious explanation of substance use and addiction co-occurrence, as well as targeted non-drug-specific prevention and early intervention. 


In a recent study a group of scientist combined the two frameworks and studied the epigenetic changes initiated by nicotine prime gene expression by cocaine. The showed that nicotine alters the brain to make it more susceptible to cocaine’s addicting effects, and suggest that interfering with this reprogramming may rein in cocaine abuse.The authors pretreated mice with nicotine to mimic the effects of smoking and detected an increase in the behavioral and neuronal activity responses that mice typically exhibit when given cocaine, relative to animals that had not been pretreated. In contrasty, cocaine did not have the reciprocal effect on nicotine responses. By taking a close look at histome proteins – which package DNA as chromatin- in the reward centers of the brain (the striatum), the authors found that certain histone were hyperacetylated, a state that results in augmented gene expression, consistent with the exaggerated response to cocaine.  
An epidemiological analysis described in the paper by Levine et al. reinforces the urgency of translating these results: most cocaine addicts began using the drug after they started smoking cigarettes, as would be expected if the mechanism operative in mice is mimicked in humans. Cocaine abusers are often administered nicotine replacement therapy to help curb their smoking habits; if the authors’ findings hold up in humans, nicotine replacement therapy might actually exacerbate the patient’s cocaine addiction, a highly undesirable effect. Finally, using cocaine while smoking increases the risk of becoming dependent on the drug: another healthy reason not to smoke.

 References  
Vanyukov MM, Tarter RE, Kirillova GP, Kirisci L, Reynolds MD, Kreek MJ, Conway KP, Maher BS, Iacona WG, Bierut L, Neale MC, Clark DB, Ridenour TA (2012). Common liability to addiction and “gateway hypothesis”: Theoretical, empirical and evolutionary perspective. Drug Alcohol Depend.2012;123:S3–S17. 
 Levine A, Huang Y, Drisaldi B, et al. (2011). Molecular mechanism for a gateway drug: epigenetic changes initiated by nicotine prime gene expression by cocaine. Sci Transl Med.2011;3(107):107ra109. doi: 10.1126/scitranslmed.3003062. 

 


Tuesday, December 2, 2014

Reinforcement properties of addictive drugs 



To understand addiction we must elucidate the specific traces the drug experience leaves in the brain and how they lead to the development of addiction. Several key synaptic adaptations that occur after single or repetitive exposures to an addictive drug has been studied. 
Repetitive drug use induces changes in the normal circuitry of rewarding and adaptive behaviors, causing in neuroplastic changes that result in recurrent, drug-seeing behaviors; an inability to regulate such behaviors; continued use of drugs despite negative consequences, vulnerability to relapse and reduced drive to acquire biologically relevant natural reward important for survival and optimal functionality. Addictive drugs target the mesocoticolimbic dopamine (DA) system. This system originates in the ventral tegmental area (VTA) and projects mainly to the nucleus accumbens (NAc) and prefrontal cortex (PFC). It has been shown that addictive drugs leave an imprint in glutamatergic and GABAergic synaptic transmission in these three brain areas. Drug-evoked synaptic plasticity outlasts the presence of the drug in the brain and contributes to the reorganization of neural circuits. It is relevant to note that in most cases these early changes are not sufficient to induce the disease, with repetitive drug exposure, they may add up and cause addictive behavior. 
Converging evidence from many studies suggests that addictive drugs modify synaptic transmission in the mesocorticolimbic DA system by hijacking mechanisms normally used for adaptive forms of experience-dependent synaptic plasticity. Addictive drugs have in common that they increase mesolimbic DA levels. First, by reducing transmitter release from inhibitory afferents onto DA neurons, indirectly increasing the firing rate of DA neurons, a mechanism defined as disinhibition (opiods, cannabinoids and benzodiazepines). Second, drugs such as nicotine that directly depolarized DA neurons by activating acetylcholine receptors. Third, by targeting the dopamine transporters –such as psychostimulants.
However, it is important to note that drug exposure alone is necessarily sufficient to elicit synaptic plasticity. On the contrary, many forms of drug-evoked synaptic plasticity appear to depend on the context in which the drug has been experienced, presumably because the final synaptic adaptation will depend both on the molecular action of the drug and the pattern of neural activity in the brain at the time the drug is experienced. Although a single drug experience is certainly not sufficient to induce addiction, the synaptic and neural circuit adaptations caused by a drug experience often persist and lay the foundation upon which further drug-induced adaptations occur.



References 
Brown MTC, Bellone C, Mameli M, Labouèbe G, Bocklisch C, et al. (2010) Drug-Driven AMPA Receptor Redistribution Mimicked by Selective Dopamine Neuron Stimulation. PLoS ONE 5(12): e15870. doi:10.1371/journal.pone.0015870
 Luscher C, Malenka RC (2011) Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit  remodelingNeuron 69: 650–663



Bryan Lewis Saunders is an artist. He likes to take drugs, both legal and illegal, and then draw pictures of himself. 


"Near Death Experience" by Bryan Lewis Saunders & Spastic Dementia from Bryan Lewis Saunders on Vimeo.

"Luego de experimentar cambios drásticos en mi entorno, busqué experiencias que pudiesen afectar profundamente mi percepción de mi mismo. Luego de semanas me puse letárgico, y sufrí daños cerebrales que afortunadamente no fueron irreparables. Todos los días imágenes y sentimientos sobre el mundo vienen a mi y es inexcapable. Así que decidí hacer un autorretrato cada día, por el resto de mi vida, sin reglas, el mundo y yo podíamos estar más enlazados a mi sistema nervioso."