Addiction

From: <a href="https://www.evergreendrugrehab.com/blog/traumatic-brain-injury-link-addiction/">Traumatic Brain Injury and It's Link to Addiction</a>

Alternatively, studies that occurred in substance abuse treatment centers found that up to 63% of addicts in recovery suffered from traumatic brain disorder. One study involved 8,000 addicts in state-funded<a href="https://www.evergreendrugrehab.com/"> substance abuse treatment programs</a>. One in three of those had one or more head injuries in the past. The head injuries were severe enough that the person had to be hospitalized for a night or lead them to become unconscious.

While there is no solid proof as of yet, it is believed that TBI can increase the risk of substance abuse directly. If traumatic brain injury is related to alcohol use, it increases the risk of further brain injury. The risk will exist for many years after the first injury occurred.

The changes in the brain after an injury are believed to create further risk of<a href="https://www.evergreendrugrehab.com/how-we-treat-addiction.php"> addiction</a>. Some evidence is suggesting that parts of the brain affected by a head injury can be the culprit. An injury can cause negative cognitive effects. This includes self-regulation and mental control. The thought is that TBI can cause people to make bad choices.

From: <a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195">Oncotarget | Effect of traumatic brain injury on nicotine-induced modulation of dopamine release in the striatum and nucleus accumbens shell</a>

Traumatic brain injury is associated with alterations in physiological reward processing that may explain behavioral changes and substance abuse often seen in this population [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R1">1</a>, <a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R2">2</a>]. 1. Head injury patients without mental illness or substance abuse-related service utilization prior to injury showed increased rates of substance use dependence (SUD) and depression compared with community controls [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R3">3</a>, <a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R4">4</a>]. These patients have a 4.5 odds ratio of substance abuse within the first year post-injury, dropping to 1.4 at 25–36 months post-injury [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R5">5</a>]. Moreover, soldiers with mild TBI were 2.6 times and those with a moderate TBI were 5.4 times more likely to be discharged for alcoholism or drug use [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R6">6</a>, <a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R7">7</a>].

The striatal dopamine (DA) system is crucial for habit formation [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R8">8</a>, <a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R9">9</a>], and the mesocorticolimbic system is strongly linked to reward behavior [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R10">10</a>]. Thus, analysis of DA release from different systems after exposure to addictive agents has clarified the mechanism of the reward behavior process [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R11">11</a>]. Investigation of DA release may provide an explanation for substance abuse formation among certain patient groups, such as patients with traumatic brain injury (TBI) [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R12">12</a>] or stroke [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R13">13</a>, <a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R14">14</a>].

Several mechanisms induced by TBI that affect neurotransmission especially dopamine (DA) transmission were elucidated, involving the systemic and microenvironmental effects of neuroinflammation induced after the initial insult in TBI [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R15">15</a>, <a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R16">16</a>] and playing a crucial role in secondary neurodegeneration [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R15">15</a>]. TBI induces time-dependent upregulation of apoptosis-related genes during the 3–48 h post-injury period that include inflammatory cytokines such as interleukin 1 (IL-1), and tumor necrosis factor (TNF) as well as prostaglandin (PG) synthases and cyclooxygenase (COX) 1 and 2. These may contribute to inflammation in the brain [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R17">17</a>]. Thus, the neurodegenerative changes in expression of apoptosis-related genes after TBI may be associated with inflammatory responses [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R18">18</a>]. Moreover, significant decreases of TH-positive expression in the surviving dopaminergic neurons of the SN pars compacta (SNpc) and increased a-synuclein accumulation in inflammation-infiltrated SN of rats exposed to chronic TBI were shown [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R16">16</a>]. These phenomena may be a pathological link between chronic effects of TBI and PD symptoms and may be one of critical mechanisms of dopamine transmission impairment after TBI [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R15">15</a>].

Previous studies have demonstrated that low-frequency stimulation evokes DA release suppression and that higher frequency enhancement is caused by nicotine desensitization and blockade through the α4β2 receptor in the striatum [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R19">19</a>–<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R21">21</a>]; furthermore, frequency-dependent augmentation was found in the nucleus accumbens (NAc) shell [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R22">22</a>, <a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R23">23</a>].

There are two different patterns of DA release in vivo that have distinct physiological effects: tonic low-frequency release (5–10 Hz), which represents baseline DA neuron firing, and phasic burst-like release (20–100 Hz), typically associated with reinforcers or reward predictors [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R24">24</a>]. Paired-pulse stimulation to determine the interaction between firing frequency and dynamic release probabilities at varying interpulse intervals can provide insight into efficacy of reinforcement [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R25">25</a>]. Paired-pulse facilitation in the presence of nicotine and a nicotine inhibitor (Mec) has been observed in both the striatum and NAc shell with intervals of less than 80 ms (>12.5 Hz), which suggests that nicotine acts as a switch of the frequency filter [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R24">24</a>]. By enhancing the contrast in DA release when DA neuron activity switches from tonic to phasic firing in response to salient primary rewards or conditioned reward predictions [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R26">26</a>], nicotine might enhance the reinforcement efficacy of any reward-related stimuli [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R24">24</a>].

Application of different stimulation frequencies can be used to mimic tonic and phasic DA release from slices in vitro [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R27">27</a>], and this can provide insight into the effect of fluid-percussion injury on these processes, especially the effect of nicotine on dynamic DA release probability and comparison of tonic and phasic reinforcing efficacy of the reward-stimuli response [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R28">28</a>]. In this study, we used fast-scan cyclic voltammetry (FSCV) study to determine DA release patterns in brain slices with fluid percussion injury (FPI) to detect DA tonic release, frequency-dependent responses, the reaction to increments in high-frequency stimulation (HFS) trains, and paired-pulse ratios in different paired-pulse intervals in response to nicotine desensitization to determine the effect on impairment of reward behavior after head injury. By using paired pulses at different stimulation intervals (from 10 to 80 μsec), the paired-pulse release ratios (p2/p1) could be measured to determine the interaction between firing frequency and dynamic release probability.

Habit formation is thought to be related to striatal activity [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R8">8</a>, <a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R31">31</a>], whereas activation of the mesolimbic DA system is central to associative learning, reinforcement, and drug addiction [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R30">30</a>, <a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R32">32</a>, <a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R33">33</a>]. There is evidence that drug addiction involves multiple functional areas, including the mesolimbic dopaminergic pathway [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R33">33</a>], which processes reward-related stimuli; the amygdala [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R34">34</a>], which generates emotions; the hippocampus, which facilitates learning and memory creation [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R35">35</a>]; and the prefrontal cortex, which underlies executive action [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R36">36</a>]. Furthermore, all these process are governed by the corticolimbic network [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R37">37</a>].

In chronic smokers, the upregulation of nAChR subtypes may be induced after long-term exposure to nicotine [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R38">38</a>, <a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R39">39</a>], which indicates that the number of high-affinity nicotine binding sites in multiple regions of the brain has increased [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R40">40</a>–<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R42">42</a>]. Furthermore, higher nicotine exposure may cause rapid nAChR desensitization, which induces receptor function loss. Subsequently, after long-term desensitization, upregulation may be promoted to compensate for the weakening signal from the inactivated receptors [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R43">43</a>, <a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R44">44</a>]. These changes may induce higher sensitivity to nicotine and are related to nicotine addiction [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R45">45</a>]. A previous study indicated that DA transmission was affected after a head injury, and our previous data indicate that FPI suppressed DA release in both the striatum and NAc region [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R46">46</a>–<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R49">49</a>].

A nationwide population-based cohort study revealed that TBI increases the risk of developing a substance-related disorder (SRD) [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R50">50</a>, <a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R51">51</a>]. Addiction has been linked to dysfunctions in the DA system [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R52">52</a>, <a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R53">53</a>], and chronic drug exposure was reported to suppress tonic DA levels, increase phasic DA release, and promote peculiar stimulus–reinforcer associations, all leading to the development of addiction [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R54">54</a>]. The nature of the relationship between TBI and a substance-related disorder or addiction, particularly smoking, is controversial, and the role of nicotine desensitization in this behavioral process has yet to be determined.

In summary, because of the suppression of DA release by FPI and nicotine desensitization, DA release was observed to be lowered by FPI in this study, and stronger stimulation was required to induce phasic DA release. The enhanced deviation between tonic and phasic DA release augments the signal-to-noise phenomenon that might enhance reinforcing information under the exposure of stimuli, which in turn may explain why patients with head injury may require more powerful stimuli. The induction of higher phasic DA release and the difference between tonic and phasic DA release may be the reason why an epidemiologic report indicated that TBI increases the risk of SRDs [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R50">50</a>].In summary, because of the suppression of DA release by FPI and nicotine desensitization, DA release was observed to be lowered by FPI in this study, and stronger stimulation was required to induce phasic DA release. The enhanced deviation between tonic and phasic DA release augments the signal-to-noise phenomenon that might enhance reinforcing information under the exposure of stimuli, which in turn may explain why patients with head injury may require more powerful stimuli. The induction of higher phasic DA release and the difference between tonic and phasic DA release may be the reason why an epidemiologic report indicated that TBI increases the risk of SRDs [<a href="http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=24245&path[]=76195#R50">50</a>].