For example, ɑ2/3 subunit-enriched GABAA receptors are predominant during early developmental stages and are gradually replaced by ɑ1 subunit-enriched GABA receptors in the adult112,113 A. This developmental switch of GABAA receptor subunit composition substantially accelerates the activation and inactivation rate of inhibitory postsynaptic currents (IPSCs), presumably improving the precision of temporal inhibition over the neural circuit. Optogenetics takes advantage of light‐sensitive ion channels to perturb neural circuits by either depolarizing or hyperpolarizing neurons. The most common ion channel used is the H134 channelrhodopsin, which opens when illuminated with blue light and depolarizes neurons when optically stimulated. While the animal is traditionally tethered to a fiber optic cable inserted into the expressing brain region, this restraint can limit the types of behavior and analyses that can be conducted.181 Similar limitations can come from traditional drug self‐administration apparatus.
Substance use disorder
Mutant mice that have depleted levels of the HAT CBP show less behavioural sensitization to cocaine following 10 days of exposure, which correlates with decreased histone acetylation and FosB expression (though FosB expression was normal prior to cocaine) 198. Prior drug exposure may also prime the response to another drug of abuse by enhancing the transcription of FosB, through inhibition of HDAC, and enhancing the depression of LTP in the NAcc 199. There is also a close association between the regulation of gene expression by transcription factors or via epigenetic modification with interplay between the activating or repressing effects of a transcription factor and chromatin-mediating enzymes at certain genes. As CBP is a HAT it is able to acetylate histones thus increasing gene expression, while also being a transcriptional coactivator regulating the expression of ΔFosB (see 200). ΔFosB can also regulate lysine dimethyltransferases, which mediate histone methylation and contribute to dendritic spine plasticity and cocaine preference 194. There is also growing evidence that long-term impairments in LTD may play a role in the maintenance of an addicted state.
Transgenic mouse studies
Several studies to date show that different addiction groups have reduced grey matter volume compared to healthy controls in regions of the brain targeted by the specific drug of abuse, including alcohol 13, cocaine 14, 15, amphetamine 16 and nicotine 17, 18, 19. However, the approaches taken in these studies appear to neglect the contribution to structural deficits that arise from relapse, treatment outcome and abstinence; it is unclear how former addicts remain abstinent even with severe structural deficits in brain regions implicated in addiction 20. Abnormalities in frontostriatal brain systems in both stimulant‐dependent individuals and their biological siblings who have no history of chronic drug abuse 21 potentially devalue the clinical significance of these outcome measures for addiction. We have used siRNAs to demonstrate the critical role of the MOP-r in the substantia nigra andventral tegmental area (where cell bodies for the nigrostriatal and mesolimbic dopaminergicsystems are located) on heroin-induced rewarding effects (53). SiRNA directed toward the mouse Oprm1 or GFP (as a control) wereinfused bilaterally into mouse midbrain dopaminergic areas.
Effects of marijuana on the adolescent brain
The elevation of frontal activity appears to undergo a shift from the left to right hemisphere over the course of abstinence. Activation of the LIFG has been observed in children performing a task requiring both response inhibition and interference suppression (Bunge et al., 2002). Furthermore, the left IFG has recently been shown to be important for response inhibition (Swick et al., 2008) and in a task similar to that described here, older adults have been shown to rely more on left PFC (Garavan et al., 2006). The reliance of the SA group on this region suggests that early in abstinence users may adopt an alternative cognitive strategy in that they may recruit the LIFG in a manner akin to children and older adults to achieve behavioral results similar to the other groups. Recruitment of the LIFG may be indicative of short-term abstinence whereas with prolonged abstinence a pattern topographically typical of normal, healthy controls may emerge, though with the LA group displaying elevated activity levels. Should the transition from relying on left to right IFG be a result of abstinence, it is likely this may only develop with protracted abstinence as short periods of abstinence followed by relapse may not allow this to occur (Volkow et al., 2001; Wang et al., 2004).
Social learning models
- Dopamine-responsive cells are highly concentrated in this system, which controls emotional responses and links them with memories.
- It has been shown that infusion of cAMP analogs that activate PKA into the nucleus accumbens of rats caused a time-delayed increase in intravenous cocaine self-administration behavior and shifted the cocaine dose–response curve to the right (Self et al, 1998).
- They further regulate the amount of dopamine available to stimulate the receptors by pulling some previously released dopamine molecules back into themselves.
- In animal studies, increased levels of Bdnf transcripts are observed in the NAc and related brain regions immediately after acute or repeated i.p.
- Chronic drug exposure-induced neurochemical changes in systems that are implicated in acute drug reward are called within-system neuroadaptations.
Two prominent and extensively studied transcriptional responses in the NAc after exposure to cocaine or other drugs of abuse are activation of CREB and accumulation of ΔFosB, two transcriptional factors that regulate synaptogenesis and circuitry development12,13. MiRNAs are recently discovered small (∼22 nucleotides) RNA transcripts that do not code for protein, but function by repressing target mRNA translation (Im and Kenny, 2012; see also article by Schaefer et al (2010)). Many miRNAs have been identified (Landgraf et al, 2007) and each miRNA can potentially target hundreds to thousands of mRNA transcripts (John et al, 2004), suggesting that miRNAs play an influential regulatory role in gene expression. After transcription of miRNA genes, primary miRNA is generated that forms a characteristic hairpin secondary structure (for a recent review, see Im and Kenny (2012)). Cleavage of this hairpin by Dicer then produces mature miRNA, which is loaded into the RNA-induced silencing complex (RISC).
- Here, our current knowledge of the neurobiology of addiction is summarized with data from human studies using established methodologies for measuring the structure and function of the brain with MRI.
- In 1931, Edwin Holt suggested in his well-known essay, entitled “Animal drive and the learning process,” that some embryonic or developmental mechanisms might be used during learning4.
- It is likely that many more miRNAs in addition to miR-212 play a role in the development of compulsive cocaine intake.
- This enables the control of heritable changes to phenotypes that are not dependent on changes in the genetic code itself (see 178, 179).
The number of long-term cocaine-dependent patients entering drug treatment has been increasing in Europe for several years. However, there is no specific pharmacotherapy with established efficacy for the treatment of cocaine addiction and basic research on this field represents one of the most important tool to face and counteract this important public health problem. Hyperactivity in ACC relative to posterior cingulate cortex has been linked with greater likelihood of avoiding relapse with those participants showing this hyperactivity prior to scanning having longer periods of abstinence (Kosten et al., 2006).
Golgi-Cox staining has illustrated a significant increase in the density and a 2.6-fold increase in branching of dendritic spines of MSNs in the shell of the NAcc following abstinence from cocaine for one month after one month of self-administration in rats 56. Kim et al. have shown that cocaine repetitively injected into transgenic mice expressing green fluorescent protein under the control of promoters for either D1 or D2 receptors results in a selective increase in spine density for MSNs expressing D1 but not D2 57. This correlates with decreased membrane excitability in these neurons, with no corresponding change observed in D2 expressing MSNs. This highlights that neurons within the same cell population may differentially contribute to a drug-induced neuroadaptation. Drug-induced changes to dendritic spines may also occur via separate but interactive signaling pathways resulting in more than one structural alteration 58 having the potential to cause regional, compartmental, or type-specific changes to dendritic spines themselves 59. This paper will provide an overview of the current knowledge base of the the neurobiology of cocaine addiction pmc complex mechanisms mediating addictive behaviours, incorporating the literature from both human studies and preclinical animal models.
Functional response to cognitive tasks
In animals that are sensitized to cocaine there is long-lasting depression at excitatory synapses made by PFC afferents onto MSNs in the NAcc shell 80. However LTD does not appear to be impaired during the initial phase of learning in a cocaine self-administration paradigm, but once learning has been consolidated, LTD is suppressed 81 and remains suppressed in the NAcc even during the initial stages of abstinence 82. In animals that do not display the hallmarks of addiction deficits in LTD progressively recover even though these animals maintain a controlled drug intake. The same group has gone on to show that this effect can be related to LTD mediated by stimulation of specific receptor subtypes (endocannabinoid mediated versus glutamatergic) in the PFC 83. In rats, blocking LTD at glutamatergic synapses in the NAcc is sufficient to prevent the expression of amphetamine-induced behavioural sensitization 84.
Although the contribution of radioisotope imaging has been highly significant in the discovery and mapping of the role of dopamine in addiction 8, magnetic resonance imaging (MRI) is the mainstay of addiction imaging research due its safety, absence of radioactivity and flexibility in the information obtained. Advances in MRI technology continue, along with postprocessing algorithms that are creating new representations of MRI data, refreshing the vocabulary describing the brain in health and disorder. In humans, stress plays a major role in drug addiction and elevates drug craving.Stress-induced HPA activity predicted relapse to drug use and amounts of subsequent use,indicating that stress not only elicits craving, but also independently predicts relapse (54). Cocaine addiction is a worldwide public health problem with consequences beyond its somatic and psychiatric effects including socio-economic and judicial complications.
Another research approach is to recruit and characterize individuals known to have been abstinent for varying durations. While this approach cannot reveal whether neurobiological differences in abstinent users preceded or arose from that abstinence, it can nonetheless characterize the functioning of those who have demonstrated the ability to abstain for either short or long periods. We hypothesized that any changes that may occur with prolonged abstinence or any pre-existing differences that might facilitate successful abstinence would be reflected in functional brain measurements of cognitive control.