While many techniques are available to manipulate deep brain structures (optogenetics, deep brain... more While many techniques are available to manipulate deep brain structures (optogenetics, deep brain stimulation, ultrasound, transcranial magnetic stimulation) to treat psychiatric and neurologic disorders, there are issues that remain which decrease clinical utility. For example, DBS is invasive and only able to directly impact a small portion of the brain at a time. Recent data has shown that mechanical stimulation of neurons depolarizes the cells increasing their firing rate. Here we implanted magnetic nanorods into neural tissue of live rats. We then designed a magnetic coil to provide external magnetic stimulation to the implanted nanorods while rats were awake and ambulatory.Male rats were stereotactically implanted with magnetic nanorods. Control animals experienced sham surgeries. One week following surgery, animals were placed in a small open space within a coil. Low-magnitude (5 mT, 20 Hz) external magnetic stimulation was applied. Total locomotion, rotations, and chewing behaviors of the rats for the duration of the experiment (7 minutes) were measured. Animals with implanted nanorods showed significantly increased levels of chewing behavior compared to sham controls. These data demonstrate the ability of mechanical stimulation of striatal neurons to modify rat behavior. Potential future applications of the technology include the use of wearable generators of low magnetic fields applied to intra-nasally administered magnetic nanoparticles.
Cocaine use and abuse remains a major public health issue characterized by relapse to drug seekin... more Cocaine use and abuse remains a major public health issue characterized by relapse to drug seeking and taking following periods of abstinence. This dissertation sought to examine a potential novel therapeutic modality for the treatment of drug addiction as well as explore the consequences of drug abuse on offspring. Drug addiction and relapse in humans is modeled in rodents using the self-administration/reinstatement paradigm. The shell and core of the nucleus accumbens play a central role in addiction and reinstatement. Accumbal deep brain stimulation (DBS) is a promising therapeutic modality for the treatment of addiction. In Chapter 2 we examined the influence of DBS of the nucleus accumbens shell and core on cocaine priming-induced reinstatement. Using DBS and pharmacological manipulations, the roles of the nucleus accumbens core and shell were systematically examined and different hypotheses for the mechanism of action of DBS tested. We found DBS of the nucleus accumbens shell effectively attenuates cocaine priming-induced reinstatement in a reinforcer and anatomically specific manner. Moreover, in Chapter 3 we provide evidence that the mechanism of action of DBS is antidromic stimulation of glutamatergic afferent fibers from the prefrontal cortex (PFC), which stimulates putative GABAergic interneurons. In Chapter 4 we developed a model to explore paternal transmission of drug addiction phenotype. We found male cocaine sired animals demonstrate delayed acquisition of cocaine self-administration and decreased intake of cocaine. This was accompanied by increases in BDNF protein and mRNA expression in the PFC. We also found evidence that the mechanism of transmission of the phenotype is via epigenetic modifications of the sperm. Thus, we found increases of acetylated histone H3 associated with BDNF promoters in the sperm of cocaine-experienced sires. This dissertation provides evidence that DBS of the nucleus accumbens shell may be an effective therapeutic modality for the treatment of severe cocaine addiction and that paternal cocaine use causes aberrant changes in the behavior and molecular composition of F1 males inherited via the sperm
This study aims to understand the impact of prolonged vs. short oxycodone on the sensory and rewa... more This study aims to understand the impact of prolonged vs. short oxycodone on the sensory and reward processing in opioid-exposed offspring. As stated, opioid-exposed neonates exhibit NOWS (neonatal opioid withdrawal syndrome), a constellation of withdrawal signs after birth following an in utero exposure of prenatal opioids. Non-pharmacological measures remain the primary method to manage NOWS, however, some neonates continue to manifest severe withdrawal that interferes with basic physiological functions, e.g., feeding, sleeping, growth, such that pharmacological interventions are needed. Using a rodent model, the authors conducted an experiment categorizing mice into 4 groups: Short Oxy, Short Veh, Long Oxy, Long Veh to mimic situations where neonates require postnatal pharmacotherapy compared to those who do not require postnatal pharmacotherapy. The current design extends previous findings, primarily on weight and USVs, to explore long term outcomes including social behavior, anxiety related behaviors, sensorimotor, cognitive, and reward behaviors. Strengths: 1. Investigators built this study on their published work on the same topic (Minakova, Front Behav Neurosci, 2021). 2. Well-described methodology focusing on several behavioral tasks to understand the impact of oxycodone on
Small soft robotic systems are being explored for myriad applications in medicine. Specifically, ... more Small soft robotic systems are being explored for myriad applications in medicine. Specifically, magnetically actuated microrobots capable of remote manipulation hold significant potential for the targeted delivery of therapeutics and biologicals. Much of previous efforts on microrobotics have been dedicated to locomotion in aqueous environments and hard surfaces. However, our human bodies are made of dense biological tissues, requiring researchers to develop new microrobotics that can locomote atop tissue surfaces. Tumbling microrobots are a sub-category of these devices capable of walking on surfaces guided by rotating magnetic fields. Using microrobots to deliver payloads to specific regions of sensitive tissues is a primary goal of medical microrobots. Central nervous system (CNS) tissues are a prime candidate given their delicate structure and highly region-specific function. Here we demonstrate surface walking of soft alginate capsules capable of moving on top of a rat cortex and mouse spinal cord ex vivo, demonstrating multi-location small molecule delivery to up to six different locations on each type of tissue with high spatial specificity. The softness of alginate gel prevents injuries that may arise from friction with CNS tissues during millirobot locomotion. Development of this technology may be useful in clinical and preclinical applications such as drug delivery, neural stimulation, and diagnostic imaging.
Prolonged treatment of Parkinson's disease with levodopa leads to disabling side effects collecti... more Prolonged treatment of Parkinson's disease with levodopa leads to disabling side effects collectively referred to as 'dyskinesias'. We hypothesized that bioenergetic function in the putamen might play a crucial role in the development of dyskinesias. To test this hypothesis we used post-mortem samples of the human putamen and applied real time-PCR approaches and gene expression microarrays. We found that mitochondrial DNA levels are decreased in patients who have developed dyskinesias, and mitochondrial DNA damage is concomitantly increased. These pathologies were not observed in Parkinson's disease subjects without signs of dyskinesias. The group of nuclear mRNA transcripts coding for the proteins of the mitochondrial electron transfer chain was decreased in patients with dyskinesias to a larger extent than in patients who had not developed dyskinesias. To examine if dopamine fluctuations affect mitochondrial DNA levels in dopaminoceptive neurons, rat striatal neurons in culture were repeatedly exposed to levodopa, dopamine or their metabolites. Mitochondrial DNA levels were reduced after treatment with dopamine, but not after treatment with dopamine metabolites. Levodopa led to an increase in mitochondrial DNA levels. We conclude that mitochondrial susceptibility in the putamen plays a role in the development of dyskinesias.
Cold Spring Harbor Perspectives in Medicine, Jun 29, 2020
Substance abuse and the ongoing opioid epidemic represents a large societal burden. This review w... more Substance abuse and the ongoing opioid epidemic represents a large societal burden. This review will consider the long-term impact of opioid exposure on future generations. Prenatal, perinatal, and preconception exposure are reviewed with discussion of both maternal and paternal influences. Opioid exposure can have long-lasting effects on reproductive function, gametogenesis, and germline epigenetic programming, which can influence embryogenesis and alter the developmental trajectory of progeny. The potential mechanisms by which preconception maternal and paternal opioid exposure produce deleterious consequences on the health, behavior, and physiology of offspring that have been identified by clinical and animal studies will be discussed. The timing, nature, dosing, and duration of prenatal opioid exposure combined with other important environmental considerations influence the extent to which these manipulations affect parents and their progeny. Epigenetic inheritance refers to the transmission of environmental insults across generations via mechanisms independent of the DNA sequence. This topic will be further explored in the context of prenatal, perinatal, and preconception opioid exposure for both the maternal and paternal lineage.
The present study measured postnatal ultrasonic vocalization (USV) and gene expression to examine... more The present study measured postnatal ultrasonic vocalization (USV) and gene expression to examine potential changes in communication and/or attachment in the offspring of mothers exposed to morphine during adolescence. Offspring of morphine-exposed (Mor-F1), salineexposed (Sal-F1), or non-handled control (Con-F1) female Sprague-Dawley rats were tested for separation-induced distress calls and maternal potentiation of distress calls during early postnatal development. We also examined relative expression of dopamine D2 receptor and mu opioid receptor (oprm1) mRNA in the nucleus accumbens and hypothalamus in these offspring, as their activity has been implicated in the regulation of postnatal USV in response to maternal separation. The findings indicate that adolescent experiences of future mothers, including their 10 daily saline or morphine injections, can result in significant region-specific differences in gene expression. In addition, these experiences resulted in fewer numbers of separation-induced distress calls produced by offspring. In contrast, augmented maternal potentiation was only observed in Mor-F1 offspring.
Global opioid use and misuse remains high, despite efforts to decrease rates of prescribing and d... more Global opioid use and misuse remains high, despite efforts to decrease rates of prescribing and diversion. Chronic exposure to opioids, particularly during critical periods of development, can lead to long-lasting effects, including effects that may extend to future generations. Using a rodent model, we have demonstrated significant transgenerational effects of female adolescent morphine exposure, despite the absence of in utero drug exposure. While these effects have been observed in both sexes, effects on anxiety-like behavior were only observed in F1 females. The current study was designed to examine both inter- and transgenerational effects of adolescent morphine exposure on anxiety-like behavior. Female Sprague Dawley rats were administered increasing doses of morphine (5-25 mg/kg s.c.) or saline for 10 days during adolescence (PND30-39). Adult diestrous female offspring (MORF1 or SALF1) and grand offspring (F2) were tested for anxiety-like behavior using the elevated plus maze (EPM). F1 females cross-fostered to donor mothers were also examined. The results show that MORF1 and MORF2 females spend significantly more time on the open arms of the EPM compared to SALF1 controls, an effect that persisted in cross-fostered females. Additional studies demonstrate that this effect is estrous cycle dependent, as decreased anxiety-like behavior was observed in diestrus, while increased anxiety-like behavior was observed in estrus. These behavioral effects were not associated with any differences in circulating corticosterone either at baseline or following EPM testing. Thus, female adolescent morphine exposure alters the regulation of anxiety-like behavior in an estrous-dependent manner and this effect persists in the F2 generation.
Opioid use disorder is a leading cause of morbidity and mortality in the United States. Increasin... more Opioid use disorder is a leading cause of morbidity and mortality in the United States. Increasing pre-clinical and clinical evidence demonstrates sex differences in opioid use and dependence. However, the underlying molecular mechanisms contributing to these effects, including neuroinflammation, are still obscure. Therefore, in this study, we investigated the effect of oxycodone exposure and withdrawal on sex- and region-specific neuroimmune response. Real-time PCR and multiplex cytokine array analysis demonstrated elevated neuroinflammation with increased pro-inflammatory cytokine levels, and aberrant oligodendroglial response in reward neurocircuitry, following withdrawal from chronic oxycodone treatment. Chronic oxycodone and withdrawal treated male mice had lower mRNA expression of TMEM119 along with elevated protein levels of pro-inflammatory cytokines/chemokines and growth factors (IL-1β, IL-2, IL-7, IL-9, IL-12, IL-15, IL17, M-CSF, VEGF) in the prefrontal cortex (PFC) as compared to their female counterparts. In contrast, reduced levels of pro-inflammatory cytokines/chemokines (IL-1β, IL-6, IL-9, IL-12, CCL11) was observed in the nucleus accumbens (NAc) of oxycodone and withdrawal-treated males as compared to female mice. No treatment specific effects were observed on the mRNA expression of putative microglial activation markers (Iba1, CD68), but an overall sex specific decrease in the mRNA expression of Iba1 and CD68 was found in the PFC and NAc of male mice as compared to females. Moreover, a sex and region-specific increase in the mRNA levels of oligodendrocyte lineage markers (NG2, Sox10) was also observed in oxycodone and withdrawal treated animals. These findings may open a new avenue for development of sex-specific therapeutics for opioid dependence by targeting region-specific neuroimmune signaling.
Rationale A growing body of evidence demonstrates that environmental exposures can impact the phy... more Rationale A growing body of evidence demonstrates that environmental exposures can impact the physiology and behavior of subsequent generations. We have previously demonstrated reduced morphine self-administration in the F1 and F2 offspring of female rats exposed to morphine during adolescence. Objectives The current study was designed to determine whether attenuated self-administration for a substance not in the opioid class is also observed in the F1 progeny of adolescent morphine exposed females. Methods Female adolescent rats were administered morphine at increasing doses for 10 days (P30-39). Females then remained drug free for at least 3 weeks prior to mating with drug-naïve males. As adults, male and female offspring (F1 animals) were tested for cocaine self-administration acquisition, progressive ratio, extinction, and reinstatement. In addition, β-endorphin peptide levels were measured in the nucleus accumbens (NAc) of behaviorally experienced animals following reinstatement and in behaviorally naïve littermates after acute cocaine (0 or 10 mg/kg, i.p.). Proopiomelanocortin, the polypeptide that is cleaved to produce β-endorphin, as well as β-endorphin, was examined in the arcuate nucleus of the hypothalamus and the nucleus accumbens, respectively. Finally, corticosterone was measured following acute cocaine. Results While no differences were observed during the cocaine acquisition phase (FR-1 and FR-5 schedules), under a PR schedule, Mor-F1 animals (both males and females) had increased motivated responding for cocaine. In addition, Mor-F1 males demonstrated enhanced reinstatement compared to Sal-F1 males. In Mor-F1 males, an acute injection of cocaine (10 mg/kg, i.p.) decreased β-endorphin levels in the NAc compared to a saline injection while acute cocaine increased β-endorphin in the NAc in Sal-F1 males compared to saline injection. Following acute cocaine, Mor-F1 males had significantly lower levels of β-endorphin in the Nac compared to Sal-F1 males. Additionally, β-endorphin levels in the nucleus accumbens were negatively correlated with reinstatement behavior only in Mor-F1 males. Levels of POMC in the arcuate nucleus were elevated in Mor-F1 males compared to Sal-F1 males, a main effect driven primarily by POMC levels in the acute cocaine condition. These changes were not observed in Mor-F1 females. Finally, plasma corticosterone was increased in Mor-F1 males regardless of acute injection while Mor-F1 females displayed increased corticosterone in response to acute cocaine. Conclusions These data indicate that morphine prior to conception increases the rewarding effects of cocaine in male and female offspring. In addition, sex-specific alterations in endogenous opioids and hypothalamic physiology were observed.
Our previous work indicated that male, but not female, offspring of cocaine experienced sires dis... more Our previous work indicated that male, but not female, offspring of cocaine experienced sires display blunted cocaine self-administration. We extended this line of investigation to examine behavioral sensitization, a commonly used model of cocaine-induced behavioral and neuronal plasticity. Results indicated that male, but not female, offspring of cocaine-taking sires showed deficits in the ability of repeated systemic cocaine injections to induce augmented locomotor activity. The reduced cocaine sensitization phenotype in male progeny was associated with changes in histone post-translational modifications, epigenetic processes that regulate gene expression by controlling the accessibility of genes to transcriptional machinery, in the nucleus accumbens of first-generation male progeny. Thus, five histone PTMs were significantly altered in the male progeny of cocaine-exposed sires. Moreover, self-administration of nicotine was unaltered in male and female offspring suggesting that the intergenerational effects of paternal cocaine taking may be drug-specific. Interestingly, the reduced sensitivity to cocaine previously observed in the male offspring of cocaine-taking sires dissipated in the grand-offspring. Both male and female grand-progeny of cocaine-exposed sires showed unaltered cocaine-induced behavioral sensitization and cocaine self-administration. Taken together, these findings indicate that paternal cocaine taking produces changes in multiple cocaine addiction-related behaviors in male progeny,
A number of parental experiences, even when occurring prior to conception, have been shown to ind... more A number of parental experiences, even when occurring prior to conception, have been shown to induce transgenerational effects beyond the first generation. In the case of exposure to drugs of abuse, studies in rodents suggest that offspring demonstrate significant differences in how they respond to the drug to which their parent was exposed. We have previously observed significant alterations in morphine analgesia, conditioned place preference and self-administration in the offspring of females exposed to morphine during adolescent development. In addition to effects on pain perception and reward, morphine also modulates the hypothalamic pituitary adrenal (HPA) axis. The purpose of the current study was to determine whether female adolescent morphine exposure results in transgenerational effects on regulation of the HPA axis by morphine in future generations. Adolescent morphine was administered to female Sprague Dawley rats using a 10 day, escalating dose regimen of morphine (5-25 mg/kg; from 30-39 days of age). Control animals received saline. Both saline and morphine exposed females (SAL-F0 and MOR-F0, respectively) were mated with drug naïve males beginning at least 3 weeks after the final injection. Plasma corticosterone levels were measured in male and female offspring (F1) during adulthood following 0, 0.1, or 10 mg/kg morphine. In addition, expression of corticotropin releasing hormone (Crh) and mu opioid receptor (Oprm1) in the paraventricular nucleus (PVN) were measured using quantitative PCR. MOR-F1 males, but not females, had blunted morphine-induced corticosterone secretion. This effect was specific to offspring from females exposed to morphine during adolescence as those exposed during adulthood produced offspring in which the effect was absent. In addition, MOR-F1 males had significantly lower levels of PVN Crh following saline. These effects were not driven by PVN oprm1 in the F1 males as there were no differences based on maternal adolescent exposure. To determine the persistence of the blunted morphine-induced corticosterone effect, SAL-F2 and MOR-F2 males were examined. Blunted morphine-induced corticosterone secretion extended into the MOR-F2 generation, as well as effects on Crh. In
Background-Administration of cocaine during adolescence alters neurotransmission and behavioral s... more Background-Administration of cocaine during adolescence alters neurotransmission and behavioral sensitization in adulthood, but its effect on the acquisition of fear memories and the development of emotion-based neuronal circuits is unknown. Methods-We examined fear learning and anxiety-related behaviors in adult male rats that were subjected to binge cocaine treatment during adolescence. We furthermore conducted gene expression analyses of the amygdala 22 hours after the last cocaine injection to identify molecular patterns that might lead to altered emotional processing. Results-Rats injected with cocaine during adolescence displayed less anxiety in adulthood than their vehicle-injected counterparts. In addition, cocaine-exposed animals were deficient in their ability to develop contextual fear responses. Cocaine administration caused transient gene expression changes in the Wnt signaling pathway, of axon guidance molecules, and of synaptic proteins, suggesting that cocaine perturbs dendritic structures and synapses in the amygdala. Phosphorylation of glycogen synthase kinase 3 beta, a kinase in the Wnt signaling pathway, was altered immediately following the binge cocaine paradigm and returned to normal levels 22 hours after the last cocaine injection.
Angiogenesis and increased permeability of the blood-brain barrier have been reported to occur in... more Angiogenesis and increased permeability of the blood-brain barrier have been reported to occur in animal models of Parkinson's disease and L-dopa-induced dyskinesia, but the significance of these phenomena has remained unclear. Using a validated rat model of L-dopa-induced dyskinesia, this study demonstrates that chronic treatment with L-dopa dose dependently induces the expression of vascular endothelial growth factor in the basal ganglia nuclei. Vascular endothelial growth factor was abundantly expressed in astrocytes and astrocytic processes in the proximity of blood vessels. When co-administered with L-dopa, a small molecule inhibitor of vascular endothelial growth factor signalling significantly attenuated the development of dyskinesia and completely blocked the angiogenic response and associated increase in blood-brain barrier permeability induced by the treatment. The occurrence of angiogenesis and vascular endothelial growth factor upregulation was verified in post-mortem basal ganglia tissue from patients with Parkinson's disease with a history of dyskinesia, who exhibited increased microvascular density, microvascular nestin expression and an upregulation of vascular endothelial growth factor messenger ribonucleic acid. These congruent findings in the rat model and human patients indicate that vascular endothelial growth factor is implicated in the pathophysiology of L-dopa-induced dyskinesia and emphasize an involvement of the microvascular compartment in the adverse effects of L-dopa pharmacotherapy in Parkinson's disease.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Pharmacology, Biochemistry and Behavior, Oct 1, 2018
Opioid use and abuse has reached epidemic levels in the United States. As these drugs are frequen... more Opioid use and abuse has reached epidemic levels in the United States. As these drugs are frequently used by women of reproductive age, there has been a significant increase in the number of infants born to opioid dependent women. Few preclinical studies have examined voluntary opioid intake during pregnancy, and none have used intravenous self-administration. Thus, the purpose of the current set of studies was to utilize a translational model of oxycodone selfadministration in rats to determine the effects of oxycodone intake during pregnancy on early postnatal outcomes. Females were trained to intravenously self-administer oxycodone several weeks prior to mating and then continuously throughout pregnancy followed by withdrawal around the time of parturition. Offspring were monitored for weight gain and separation-induced ultrasonic vocalizations (i.e. number of calls) while dams were examined for motivated maternal responding. Neural expression of the mu opioid receptor gene OPRM1 was examined in offspring *
Prescription opiate use and abuse has increased dramatically over the past two decades, including... more Prescription opiate use and abuse has increased dramatically over the past two decades, including increased use in adolescent populations. Recently, it has been proposed that use during this critical period may affect future offspring even when use is discontinued prior to conception. Here, we utilize a rodent model to examine the effects of adolescent morphine exposure on the reward functioning of the offspring. Female Sprague Dawley rats were administered morphine for 10 days during early adolescence (post-natal day 30-39) using an escalating dosing regimen. Animals then remained drug free until adulthood at which point they were mated with naïve males. Adult offspring (F1 animals) were tested for their response to morphine-induced (0, 1, 2.5, 5, and 10 mg/kg, s.c.) conditioned place preference (CPP) and context-independent morphine-induced sensitization. Naïve littermates were used to examine mu opiate receptor expression in the nucleus accumbens and ventral tegmental area. Results indicate that F1 females whose mothers were exposed to morphine during adolescence (Mor-F1) demonstrate significantly enhanced CPP to the lowest doses of morphine compared with Sal-F1 females. There were no differences in contextindependent sensitization between maternal treatment groups. Protein expression analysis showed significantly increased levels of accumbal mu opiate receptor in Mor-F1 offspring and decreased levels in the VTA. Taken together, these findings demonstrate a shift in the dose response curve with regard to the rewarding effects of morphine in Mor-F1 females which may in part be due to altered mu opiate receptor expression in the nucleus accumbens and VTA.
The transcription factor cAMP response element-binding protein (CREB) is required for stress-but ... more The transcription factor cAMP response element-binding protein (CREB) is required for stress-but not drug-induced reinstatement of cocaine conditioned place preference. To reveal the neural circuitry associated with this CREB dependence, we injected a retrograde tracer into the ventral tegmental area (VTA) and identified afferents that were activated after stress or cocaine exposure in both naive and cocaine-conditioned mice. Neuronal activation, as assessed by Fos expression, was greatly reduced in the dorsal and ventral bed nucleus of the stria terminalis (BNST), lateral septum, and nucleus accumbens shell in mice lacking CREB (CREB␣⌬ mice) after a 6 min swim stress but not after cocaine exposure (20 mg/kg). Additionally, activation of VTA afferent neurons in the ventral BNST and the infralimbic cortex in CREB␣⌬ mice was blunted in response to stress. This pattern of neuronal activation persisted in mice that were conditioned to a cocaine place preference procedure before stress exposure. Furthermore, lidocaine inactivation (0.4 l, 4%) studies demonstrated the necessity of BNST activation for swim-stress-induced reinstatement of cocaine-conditioned reward. Together, the present studies demonstrate that CREB is required for the activation of a unique circuit that converges on the dopamine reward pathway to elicit reinstatement of drug reward and points to the BNST as a key intersection between stress and reward circuits.
Rationale-Deep brain stimulation (DBS) has achieved substantial success as a treatment for moveme... more Rationale-Deep brain stimulation (DBS) has achieved substantial success as a treatment for movement disorders such as Parkinson's disease. The therapeutic efficacy and relative lack of serious side effects resulted in the expansion of DBS into the treatment of many other diseases, including obsessive-compulsive disorder, Tourette's and depression, among others. More recently, a limited number of basic and clinical studies indicated that DBS may also be useful in the treatment of various addictions. Objectives-Here, we briefly summarize the history of DBS and review the basic and clinical studies focused on DBS and addiction. We also examine the potential mechanisms that may underlie the effects of DBS. Results and Conclusions-The available data indicate that DBS is a promising therapeutic modality for the treatment of addiction. Thus far, the nucleus accumbens and subthalamic nucleus are the most promising sites for DBS reversing aspects of addiction. The mechanisms underlying DBS are complex and likely vary from region to region. Emerging evidence indicates that DBS of the nucleus accumbens produces its effects, at least in part, by antidromic activation of corticoaccumbal afferents that stimulate inhibitory mPFC interneurons via recurrent collaterals.
While many techniques are available to manipulate deep brain structures (optogenetics, deep brain... more While many techniques are available to manipulate deep brain structures (optogenetics, deep brain stimulation, ultrasound, transcranial magnetic stimulation) to treat psychiatric and neurologic disorders, there are issues that remain which decrease clinical utility. For example, DBS is invasive and only able to directly impact a small portion of the brain at a time. Recent data has shown that mechanical stimulation of neurons depolarizes the cells increasing their firing rate. Here we implanted magnetic nanorods into neural tissue of live rats. We then designed a magnetic coil to provide external magnetic stimulation to the implanted nanorods while rats were awake and ambulatory.Male rats were stereotactically implanted with magnetic nanorods. Control animals experienced sham surgeries. One week following surgery, animals were placed in a small open space within a coil. Low-magnitude (5 mT, 20 Hz) external magnetic stimulation was applied. Total locomotion, rotations, and chewing behaviors of the rats for the duration of the experiment (7 minutes) were measured. Animals with implanted nanorods showed significantly increased levels of chewing behavior compared to sham controls. These data demonstrate the ability of mechanical stimulation of striatal neurons to modify rat behavior. Potential future applications of the technology include the use of wearable generators of low magnetic fields applied to intra-nasally administered magnetic nanoparticles.
Cocaine use and abuse remains a major public health issue characterized by relapse to drug seekin... more Cocaine use and abuse remains a major public health issue characterized by relapse to drug seeking and taking following periods of abstinence. This dissertation sought to examine a potential novel therapeutic modality for the treatment of drug addiction as well as explore the consequences of drug abuse on offspring. Drug addiction and relapse in humans is modeled in rodents using the self-administration/reinstatement paradigm. The shell and core of the nucleus accumbens play a central role in addiction and reinstatement. Accumbal deep brain stimulation (DBS) is a promising therapeutic modality for the treatment of addiction. In Chapter 2 we examined the influence of DBS of the nucleus accumbens shell and core on cocaine priming-induced reinstatement. Using DBS and pharmacological manipulations, the roles of the nucleus accumbens core and shell were systematically examined and different hypotheses for the mechanism of action of DBS tested. We found DBS of the nucleus accumbens shell effectively attenuates cocaine priming-induced reinstatement in a reinforcer and anatomically specific manner. Moreover, in Chapter 3 we provide evidence that the mechanism of action of DBS is antidromic stimulation of glutamatergic afferent fibers from the prefrontal cortex (PFC), which stimulates putative GABAergic interneurons. In Chapter 4 we developed a model to explore paternal transmission of drug addiction phenotype. We found male cocaine sired animals demonstrate delayed acquisition of cocaine self-administration and decreased intake of cocaine. This was accompanied by increases in BDNF protein and mRNA expression in the PFC. We also found evidence that the mechanism of transmission of the phenotype is via epigenetic modifications of the sperm. Thus, we found increases of acetylated histone H3 associated with BDNF promoters in the sperm of cocaine-experienced sires. This dissertation provides evidence that DBS of the nucleus accumbens shell may be an effective therapeutic modality for the treatment of severe cocaine addiction and that paternal cocaine use causes aberrant changes in the behavior and molecular composition of F1 males inherited via the sperm
This study aims to understand the impact of prolonged vs. short oxycodone on the sensory and rewa... more This study aims to understand the impact of prolonged vs. short oxycodone on the sensory and reward processing in opioid-exposed offspring. As stated, opioid-exposed neonates exhibit NOWS (neonatal opioid withdrawal syndrome), a constellation of withdrawal signs after birth following an in utero exposure of prenatal opioids. Non-pharmacological measures remain the primary method to manage NOWS, however, some neonates continue to manifest severe withdrawal that interferes with basic physiological functions, e.g., feeding, sleeping, growth, such that pharmacological interventions are needed. Using a rodent model, the authors conducted an experiment categorizing mice into 4 groups: Short Oxy, Short Veh, Long Oxy, Long Veh to mimic situations where neonates require postnatal pharmacotherapy compared to those who do not require postnatal pharmacotherapy. The current design extends previous findings, primarily on weight and USVs, to explore long term outcomes including social behavior, anxiety related behaviors, sensorimotor, cognitive, and reward behaviors. Strengths: 1. Investigators built this study on their published work on the same topic (Minakova, Front Behav Neurosci, 2021). 2. Well-described methodology focusing on several behavioral tasks to understand the impact of oxycodone on
Small soft robotic systems are being explored for myriad applications in medicine. Specifically, ... more Small soft robotic systems are being explored for myriad applications in medicine. Specifically, magnetically actuated microrobots capable of remote manipulation hold significant potential for the targeted delivery of therapeutics and biologicals. Much of previous efforts on microrobotics have been dedicated to locomotion in aqueous environments and hard surfaces. However, our human bodies are made of dense biological tissues, requiring researchers to develop new microrobotics that can locomote atop tissue surfaces. Tumbling microrobots are a sub-category of these devices capable of walking on surfaces guided by rotating magnetic fields. Using microrobots to deliver payloads to specific regions of sensitive tissues is a primary goal of medical microrobots. Central nervous system (CNS) tissues are a prime candidate given their delicate structure and highly region-specific function. Here we demonstrate surface walking of soft alginate capsules capable of moving on top of a rat cortex and mouse spinal cord ex vivo, demonstrating multi-location small molecule delivery to up to six different locations on each type of tissue with high spatial specificity. The softness of alginate gel prevents injuries that may arise from friction with CNS tissues during millirobot locomotion. Development of this technology may be useful in clinical and preclinical applications such as drug delivery, neural stimulation, and diagnostic imaging.
Prolonged treatment of Parkinson's disease with levodopa leads to disabling side effects collecti... more Prolonged treatment of Parkinson's disease with levodopa leads to disabling side effects collectively referred to as 'dyskinesias'. We hypothesized that bioenergetic function in the putamen might play a crucial role in the development of dyskinesias. To test this hypothesis we used post-mortem samples of the human putamen and applied real time-PCR approaches and gene expression microarrays. We found that mitochondrial DNA levels are decreased in patients who have developed dyskinesias, and mitochondrial DNA damage is concomitantly increased. These pathologies were not observed in Parkinson's disease subjects without signs of dyskinesias. The group of nuclear mRNA transcripts coding for the proteins of the mitochondrial electron transfer chain was decreased in patients with dyskinesias to a larger extent than in patients who had not developed dyskinesias. To examine if dopamine fluctuations affect mitochondrial DNA levels in dopaminoceptive neurons, rat striatal neurons in culture were repeatedly exposed to levodopa, dopamine or their metabolites. Mitochondrial DNA levels were reduced after treatment with dopamine, but not after treatment with dopamine metabolites. Levodopa led to an increase in mitochondrial DNA levels. We conclude that mitochondrial susceptibility in the putamen plays a role in the development of dyskinesias.
Cold Spring Harbor Perspectives in Medicine, Jun 29, 2020
Substance abuse and the ongoing opioid epidemic represents a large societal burden. This review w... more Substance abuse and the ongoing opioid epidemic represents a large societal burden. This review will consider the long-term impact of opioid exposure on future generations. Prenatal, perinatal, and preconception exposure are reviewed with discussion of both maternal and paternal influences. Opioid exposure can have long-lasting effects on reproductive function, gametogenesis, and germline epigenetic programming, which can influence embryogenesis and alter the developmental trajectory of progeny. The potential mechanisms by which preconception maternal and paternal opioid exposure produce deleterious consequences on the health, behavior, and physiology of offspring that have been identified by clinical and animal studies will be discussed. The timing, nature, dosing, and duration of prenatal opioid exposure combined with other important environmental considerations influence the extent to which these manipulations affect parents and their progeny. Epigenetic inheritance refers to the transmission of environmental insults across generations via mechanisms independent of the DNA sequence. This topic will be further explored in the context of prenatal, perinatal, and preconception opioid exposure for both the maternal and paternal lineage.
The present study measured postnatal ultrasonic vocalization (USV) and gene expression to examine... more The present study measured postnatal ultrasonic vocalization (USV) and gene expression to examine potential changes in communication and/or attachment in the offspring of mothers exposed to morphine during adolescence. Offspring of morphine-exposed (Mor-F1), salineexposed (Sal-F1), or non-handled control (Con-F1) female Sprague-Dawley rats were tested for separation-induced distress calls and maternal potentiation of distress calls during early postnatal development. We also examined relative expression of dopamine D2 receptor and mu opioid receptor (oprm1) mRNA in the nucleus accumbens and hypothalamus in these offspring, as their activity has been implicated in the regulation of postnatal USV in response to maternal separation. The findings indicate that adolescent experiences of future mothers, including their 10 daily saline or morphine injections, can result in significant region-specific differences in gene expression. In addition, these experiences resulted in fewer numbers of separation-induced distress calls produced by offspring. In contrast, augmented maternal potentiation was only observed in Mor-F1 offspring.
Global opioid use and misuse remains high, despite efforts to decrease rates of prescribing and d... more Global opioid use and misuse remains high, despite efforts to decrease rates of prescribing and diversion. Chronic exposure to opioids, particularly during critical periods of development, can lead to long-lasting effects, including effects that may extend to future generations. Using a rodent model, we have demonstrated significant transgenerational effects of female adolescent morphine exposure, despite the absence of in utero drug exposure. While these effects have been observed in both sexes, effects on anxiety-like behavior were only observed in F1 females. The current study was designed to examine both inter- and transgenerational effects of adolescent morphine exposure on anxiety-like behavior. Female Sprague Dawley rats were administered increasing doses of morphine (5-25 mg/kg s.c.) or saline for 10 days during adolescence (PND30-39). Adult diestrous female offspring (MORF1 or SALF1) and grand offspring (F2) were tested for anxiety-like behavior using the elevated plus maze (EPM). F1 females cross-fostered to donor mothers were also examined. The results show that MORF1 and MORF2 females spend significantly more time on the open arms of the EPM compared to SALF1 controls, an effect that persisted in cross-fostered females. Additional studies demonstrate that this effect is estrous cycle dependent, as decreased anxiety-like behavior was observed in diestrus, while increased anxiety-like behavior was observed in estrus. These behavioral effects were not associated with any differences in circulating corticosterone either at baseline or following EPM testing. Thus, female adolescent morphine exposure alters the regulation of anxiety-like behavior in an estrous-dependent manner and this effect persists in the F2 generation.
Opioid use disorder is a leading cause of morbidity and mortality in the United States. Increasin... more Opioid use disorder is a leading cause of morbidity and mortality in the United States. Increasing pre-clinical and clinical evidence demonstrates sex differences in opioid use and dependence. However, the underlying molecular mechanisms contributing to these effects, including neuroinflammation, are still obscure. Therefore, in this study, we investigated the effect of oxycodone exposure and withdrawal on sex- and region-specific neuroimmune response. Real-time PCR and multiplex cytokine array analysis demonstrated elevated neuroinflammation with increased pro-inflammatory cytokine levels, and aberrant oligodendroglial response in reward neurocircuitry, following withdrawal from chronic oxycodone treatment. Chronic oxycodone and withdrawal treated male mice had lower mRNA expression of TMEM119 along with elevated protein levels of pro-inflammatory cytokines/chemokines and growth factors (IL-1β, IL-2, IL-7, IL-9, IL-12, IL-15, IL17, M-CSF, VEGF) in the prefrontal cortex (PFC) as compared to their female counterparts. In contrast, reduced levels of pro-inflammatory cytokines/chemokines (IL-1β, IL-6, IL-9, IL-12, CCL11) was observed in the nucleus accumbens (NAc) of oxycodone and withdrawal-treated males as compared to female mice. No treatment specific effects were observed on the mRNA expression of putative microglial activation markers (Iba1, CD68), but an overall sex specific decrease in the mRNA expression of Iba1 and CD68 was found in the PFC and NAc of male mice as compared to females. Moreover, a sex and region-specific increase in the mRNA levels of oligodendrocyte lineage markers (NG2, Sox10) was also observed in oxycodone and withdrawal treated animals. These findings may open a new avenue for development of sex-specific therapeutics for opioid dependence by targeting region-specific neuroimmune signaling.
Rationale A growing body of evidence demonstrates that environmental exposures can impact the phy... more Rationale A growing body of evidence demonstrates that environmental exposures can impact the physiology and behavior of subsequent generations. We have previously demonstrated reduced morphine self-administration in the F1 and F2 offspring of female rats exposed to morphine during adolescence. Objectives The current study was designed to determine whether attenuated self-administration for a substance not in the opioid class is also observed in the F1 progeny of adolescent morphine exposed females. Methods Female adolescent rats were administered morphine at increasing doses for 10 days (P30-39). Females then remained drug free for at least 3 weeks prior to mating with drug-naïve males. As adults, male and female offspring (F1 animals) were tested for cocaine self-administration acquisition, progressive ratio, extinction, and reinstatement. In addition, β-endorphin peptide levels were measured in the nucleus accumbens (NAc) of behaviorally experienced animals following reinstatement and in behaviorally naïve littermates after acute cocaine (0 or 10 mg/kg, i.p.). Proopiomelanocortin, the polypeptide that is cleaved to produce β-endorphin, as well as β-endorphin, was examined in the arcuate nucleus of the hypothalamus and the nucleus accumbens, respectively. Finally, corticosterone was measured following acute cocaine. Results While no differences were observed during the cocaine acquisition phase (FR-1 and FR-5 schedules), under a PR schedule, Mor-F1 animals (both males and females) had increased motivated responding for cocaine. In addition, Mor-F1 males demonstrated enhanced reinstatement compared to Sal-F1 males. In Mor-F1 males, an acute injection of cocaine (10 mg/kg, i.p.) decreased β-endorphin levels in the NAc compared to a saline injection while acute cocaine increased β-endorphin in the NAc in Sal-F1 males compared to saline injection. Following acute cocaine, Mor-F1 males had significantly lower levels of β-endorphin in the Nac compared to Sal-F1 males. Additionally, β-endorphin levels in the nucleus accumbens were negatively correlated with reinstatement behavior only in Mor-F1 males. Levels of POMC in the arcuate nucleus were elevated in Mor-F1 males compared to Sal-F1 males, a main effect driven primarily by POMC levels in the acute cocaine condition. These changes were not observed in Mor-F1 females. Finally, plasma corticosterone was increased in Mor-F1 males regardless of acute injection while Mor-F1 females displayed increased corticosterone in response to acute cocaine. Conclusions These data indicate that morphine prior to conception increases the rewarding effects of cocaine in male and female offspring. In addition, sex-specific alterations in endogenous opioids and hypothalamic physiology were observed.
Our previous work indicated that male, but not female, offspring of cocaine experienced sires dis... more Our previous work indicated that male, but not female, offspring of cocaine experienced sires display blunted cocaine self-administration. We extended this line of investigation to examine behavioral sensitization, a commonly used model of cocaine-induced behavioral and neuronal plasticity. Results indicated that male, but not female, offspring of cocaine-taking sires showed deficits in the ability of repeated systemic cocaine injections to induce augmented locomotor activity. The reduced cocaine sensitization phenotype in male progeny was associated with changes in histone post-translational modifications, epigenetic processes that regulate gene expression by controlling the accessibility of genes to transcriptional machinery, in the nucleus accumbens of first-generation male progeny. Thus, five histone PTMs were significantly altered in the male progeny of cocaine-exposed sires. Moreover, self-administration of nicotine was unaltered in male and female offspring suggesting that the intergenerational effects of paternal cocaine taking may be drug-specific. Interestingly, the reduced sensitivity to cocaine previously observed in the male offspring of cocaine-taking sires dissipated in the grand-offspring. Both male and female grand-progeny of cocaine-exposed sires showed unaltered cocaine-induced behavioral sensitization and cocaine self-administration. Taken together, these findings indicate that paternal cocaine taking produces changes in multiple cocaine addiction-related behaviors in male progeny,
A number of parental experiences, even when occurring prior to conception, have been shown to ind... more A number of parental experiences, even when occurring prior to conception, have been shown to induce transgenerational effects beyond the first generation. In the case of exposure to drugs of abuse, studies in rodents suggest that offspring demonstrate significant differences in how they respond to the drug to which their parent was exposed. We have previously observed significant alterations in morphine analgesia, conditioned place preference and self-administration in the offspring of females exposed to morphine during adolescent development. In addition to effects on pain perception and reward, morphine also modulates the hypothalamic pituitary adrenal (HPA) axis. The purpose of the current study was to determine whether female adolescent morphine exposure results in transgenerational effects on regulation of the HPA axis by morphine in future generations. Adolescent morphine was administered to female Sprague Dawley rats using a 10 day, escalating dose regimen of morphine (5-25 mg/kg; from 30-39 days of age). Control animals received saline. Both saline and morphine exposed females (SAL-F0 and MOR-F0, respectively) were mated with drug naïve males beginning at least 3 weeks after the final injection. Plasma corticosterone levels were measured in male and female offspring (F1) during adulthood following 0, 0.1, or 10 mg/kg morphine. In addition, expression of corticotropin releasing hormone (Crh) and mu opioid receptor (Oprm1) in the paraventricular nucleus (PVN) were measured using quantitative PCR. MOR-F1 males, but not females, had blunted morphine-induced corticosterone secretion. This effect was specific to offspring from females exposed to morphine during adolescence as those exposed during adulthood produced offspring in which the effect was absent. In addition, MOR-F1 males had significantly lower levels of PVN Crh following saline. These effects were not driven by PVN oprm1 in the F1 males as there were no differences based on maternal adolescent exposure. To determine the persistence of the blunted morphine-induced corticosterone effect, SAL-F2 and MOR-F2 males were examined. Blunted morphine-induced corticosterone secretion extended into the MOR-F2 generation, as well as effects on Crh. In
Background-Administration of cocaine during adolescence alters neurotransmission and behavioral s... more Background-Administration of cocaine during adolescence alters neurotransmission and behavioral sensitization in adulthood, but its effect on the acquisition of fear memories and the development of emotion-based neuronal circuits is unknown. Methods-We examined fear learning and anxiety-related behaviors in adult male rats that were subjected to binge cocaine treatment during adolescence. We furthermore conducted gene expression analyses of the amygdala 22 hours after the last cocaine injection to identify molecular patterns that might lead to altered emotional processing. Results-Rats injected with cocaine during adolescence displayed less anxiety in adulthood than their vehicle-injected counterparts. In addition, cocaine-exposed animals were deficient in their ability to develop contextual fear responses. Cocaine administration caused transient gene expression changes in the Wnt signaling pathway, of axon guidance molecules, and of synaptic proteins, suggesting that cocaine perturbs dendritic structures and synapses in the amygdala. Phosphorylation of glycogen synthase kinase 3 beta, a kinase in the Wnt signaling pathway, was altered immediately following the binge cocaine paradigm and returned to normal levels 22 hours after the last cocaine injection.
Angiogenesis and increased permeability of the blood-brain barrier have been reported to occur in... more Angiogenesis and increased permeability of the blood-brain barrier have been reported to occur in animal models of Parkinson's disease and L-dopa-induced dyskinesia, but the significance of these phenomena has remained unclear. Using a validated rat model of L-dopa-induced dyskinesia, this study demonstrates that chronic treatment with L-dopa dose dependently induces the expression of vascular endothelial growth factor in the basal ganglia nuclei. Vascular endothelial growth factor was abundantly expressed in astrocytes and astrocytic processes in the proximity of blood vessels. When co-administered with L-dopa, a small molecule inhibitor of vascular endothelial growth factor signalling significantly attenuated the development of dyskinesia and completely blocked the angiogenic response and associated increase in blood-brain barrier permeability induced by the treatment. The occurrence of angiogenesis and vascular endothelial growth factor upregulation was verified in post-mortem basal ganglia tissue from patients with Parkinson's disease with a history of dyskinesia, who exhibited increased microvascular density, microvascular nestin expression and an upregulation of vascular endothelial growth factor messenger ribonucleic acid. These congruent findings in the rat model and human patients indicate that vascular endothelial growth factor is implicated in the pathophysiology of L-dopa-induced dyskinesia and emphasize an involvement of the microvascular compartment in the adverse effects of L-dopa pharmacotherapy in Parkinson's disease.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Pharmacology, Biochemistry and Behavior, Oct 1, 2018
Opioid use and abuse has reached epidemic levels in the United States. As these drugs are frequen... more Opioid use and abuse has reached epidemic levels in the United States. As these drugs are frequently used by women of reproductive age, there has been a significant increase in the number of infants born to opioid dependent women. Few preclinical studies have examined voluntary opioid intake during pregnancy, and none have used intravenous self-administration. Thus, the purpose of the current set of studies was to utilize a translational model of oxycodone selfadministration in rats to determine the effects of oxycodone intake during pregnancy on early postnatal outcomes. Females were trained to intravenously self-administer oxycodone several weeks prior to mating and then continuously throughout pregnancy followed by withdrawal around the time of parturition. Offspring were monitored for weight gain and separation-induced ultrasonic vocalizations (i.e. number of calls) while dams were examined for motivated maternal responding. Neural expression of the mu opioid receptor gene OPRM1 was examined in offspring *
Prescription opiate use and abuse has increased dramatically over the past two decades, including... more Prescription opiate use and abuse has increased dramatically over the past two decades, including increased use in adolescent populations. Recently, it has been proposed that use during this critical period may affect future offspring even when use is discontinued prior to conception. Here, we utilize a rodent model to examine the effects of adolescent morphine exposure on the reward functioning of the offspring. Female Sprague Dawley rats were administered morphine for 10 days during early adolescence (post-natal day 30-39) using an escalating dosing regimen. Animals then remained drug free until adulthood at which point they were mated with naïve males. Adult offspring (F1 animals) were tested for their response to morphine-induced (0, 1, 2.5, 5, and 10 mg/kg, s.c.) conditioned place preference (CPP) and context-independent morphine-induced sensitization. Naïve littermates were used to examine mu opiate receptor expression in the nucleus accumbens and ventral tegmental area. Results indicate that F1 females whose mothers were exposed to morphine during adolescence (Mor-F1) demonstrate significantly enhanced CPP to the lowest doses of morphine compared with Sal-F1 females. There were no differences in contextindependent sensitization between maternal treatment groups. Protein expression analysis showed significantly increased levels of accumbal mu opiate receptor in Mor-F1 offspring and decreased levels in the VTA. Taken together, these findings demonstrate a shift in the dose response curve with regard to the rewarding effects of morphine in Mor-F1 females which may in part be due to altered mu opiate receptor expression in the nucleus accumbens and VTA.
The transcription factor cAMP response element-binding protein (CREB) is required for stress-but ... more The transcription factor cAMP response element-binding protein (CREB) is required for stress-but not drug-induced reinstatement of cocaine conditioned place preference. To reveal the neural circuitry associated with this CREB dependence, we injected a retrograde tracer into the ventral tegmental area (VTA) and identified afferents that were activated after stress or cocaine exposure in both naive and cocaine-conditioned mice. Neuronal activation, as assessed by Fos expression, was greatly reduced in the dorsal and ventral bed nucleus of the stria terminalis (BNST), lateral septum, and nucleus accumbens shell in mice lacking CREB (CREB␣⌬ mice) after a 6 min swim stress but not after cocaine exposure (20 mg/kg). Additionally, activation of VTA afferent neurons in the ventral BNST and the infralimbic cortex in CREB␣⌬ mice was blunted in response to stress. This pattern of neuronal activation persisted in mice that were conditioned to a cocaine place preference procedure before stress exposure. Furthermore, lidocaine inactivation (0.4 l, 4%) studies demonstrated the necessity of BNST activation for swim-stress-induced reinstatement of cocaine-conditioned reward. Together, the present studies demonstrate that CREB is required for the activation of a unique circuit that converges on the dopamine reward pathway to elicit reinstatement of drug reward and points to the BNST as a key intersection between stress and reward circuits.
Rationale-Deep brain stimulation (DBS) has achieved substantial success as a treatment for moveme... more Rationale-Deep brain stimulation (DBS) has achieved substantial success as a treatment for movement disorders such as Parkinson's disease. The therapeutic efficacy and relative lack of serious side effects resulted in the expansion of DBS into the treatment of many other diseases, including obsessive-compulsive disorder, Tourette's and depression, among others. More recently, a limited number of basic and clinical studies indicated that DBS may also be useful in the treatment of various addictions. Objectives-Here, we briefly summarize the history of DBS and review the basic and clinical studies focused on DBS and addiction. We also examine the potential mechanisms that may underlie the effects of DBS. Results and Conclusions-The available data indicate that DBS is a promising therapeutic modality for the treatment of addiction. Thus far, the nucleus accumbens and subthalamic nucleus are the most promising sites for DBS reversing aspects of addiction. The mechanisms underlying DBS are complex and likely vary from region to region. Emerging evidence indicates that DBS of the nucleus accumbens produces its effects, at least in part, by antidromic activation of corticoaccumbal afferents that stimulate inhibitory mPFC interneurons via recurrent collaterals.
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