Rat Dorsal Striatum Research Articles

Evaluation of the potential role of glutamatergic, cholinergic, and nitrergic systems in the dopamine release induced by the pesticide glyphosate in rat striatum.

Glyphosate (GLY) is a pesticide that severely alters nigrostriatal dopaminergic neurotransmission, inducing great increases in dopamine release from rat dorsal striatum. This GLY-induced striatal dopamine overflow occurs through mechanisms not yet fully understood, hence the interest in evaluating the role of other neurotransmitter systems in such effects. So, the main objective of this mechanistic study was to evaluate the possible mediation of the glutamatergic, cholinergic, and nitrergic systems in the GLY-induced in vivo dopamine release from rat dorsal striatum. The extracellular dopamine levels were measured by cerebral microdialysis and HPLC with electrochemical detection. Intrastriatal administration of GLY (5mmol/L) significantly increased the dopamine release (1102%). Pretreatment with MK-801 (50 or 400 μmol/L), a non-competitive antagonist of NMDA receptors, significantly decreased the effect of GLY (by 70% and 74%, respectively), whereas AP-5 (400 μmol/L), a competitive antagonist of NMDA receptors, or CNQX (500 μmol/L), an AMPA/kainate receptor antagonist, had no significant effect. Administration of the nitric oxide synthase inhibitors, L-nitroarginine (L-NAME, 100 μmol/L) or 7-nitroindazole (7-NI, 100 μmol/L), also did not alter the effect of GLY on dopamine release. Finally, pretreatment of the animals with mecamylamine, an antagonist of nicotinic receptors, decreased the effect of GLY on dopamine release by 49%, whereas atropine, a muscarinic antagonist, had no significant effect. These results indicate that GLY-induced dopamine release largely depends on the activation of NMDA and nicotinic receptors in rat dorsal striatum. Future research is needed to determine the effects of this pesticide at environmentally relevant concentrations.

Incubation of methamphetamine craving in punishment-resistant individuals is associated with activation of specific gene networks in the rat dorsal striatum

Methamphetamine use disorder (MUD) is characterized by loss of control over compulsive drug use. Here, we used a self-administration (SA) model to investigate transcriptional changes associated with the development of early and late compulsivity during contingent footshocks. Punishment initially separated methamphetamine taking rats into always shock-resistant (ASR) rats that continued active lever pressing and shock-sensitive (SS) rats that reduced their lever pressing. At the end of the punishment phase, rats underwent 15 days of forced abstinence at the end of which they were re-introduced to the SA paradigm followed by SA plus contingent shocks. Interestingly, 36 percent of the initial SS rats developed delayed shock-resistance (DSR). Of translational relevance, ASR rats showed more incubation of methamphetamine craving than DSR and always sensitive (AS) rats. RNA sequencing revealed increased striatal Rab37 and Dipk2b mRNA levels that correlated with incubation of methamphetamine craving. Interestingly, Bdnf mRNA levels showed HDAC2-dependent decreased expression in the AS rats. The present SA paradigm should help to elucidate the molecular substrates of early and late addiction-like behaviors.

Region-specific alterations in the expression and phosphorylation of NMDA receptor subunits in the rat prefrontal cortex and dorsal striatum accompanying behavioral sensitization induced by cocaine and ethanol

Behavioral sensitization is defined as the enhanced behavioral response to drugs of abuse after repeated exposure, which can serve as a behavioral model of addiction. Our previous study demonstrated that behavioral cross-sensitization occurs between cocaine and ethanol, suggesting commonalities between these drugs. N-methyl-d-aspartate (NMDA) receptors play important roles in synaptic plasticity, learning, memory, and addiction-associated behaviors. However, little is known about whether NMDA receptor–mediated signaling regulation is a common feature following behavioral sensitizations induced by cocaine and ethanol. Thus, the present study examined the expression of phospho-S896-NR1, NR2A, and NR2B subunits in the prefrontal cortex and dorsal striatum following reciprocal cross-sensitization between cocaine and ethanol. We also examined the mRNA expression of the NR2A and NR2B subunits. In the ethanol-sensitized state, phosphorylation of NR1 and expression of NR2A and NR2B subunits were increased in both the prefrontal cortex and dorsal striatum. In the cocaine-sensitized state, phosphorylation of NR1 and expression of the NR2A and NR2B subunits were increased in the prefrontal cortex but not in the dorsal striatum. Corresponding changes in mRNA expression were observed in the ethanol-sensitized state but not in the cocaine-sensitized state. Acute treatment with either cocaine or ethanol had no effect on the phosphorylation and expression of NMDA receptor subunits in either the prefrontal cortex or dorsal striatum, regardless of the sensitization state. These results indicate a partially overlapping neural mechanism for cocaine and ethanol that may induce the development of behavioral sensitization.

Differential patterns of basal and naloxone-evoked dopamine efflux in the rat dorsal and ventral striatum following prolonged-intermittent exposure to morphine.

Hypodopaminergia in the ventral striatum is a putative neurobiological correlate of withdrawal in opioid-dependent individuals. This perspective stands in contrast to brain imaging studies with chronic opioid users showing that naloxone-enhanced dopamine (DA) release in the dorsal striatum is positively correlated with withdrawal aversion. Here, we examined regional differences in striatal DA function associated with opioid withdrawal in rats exposed to intermittent morphine injections for 31 days. Basal concentrations of DA were reduced (i.e., indicating a hypodopaminergic state) in the ventral striatum on Day 10 of morphine exposure, whereas a more prolonged period of morphine treatment was required to reveal hypodopaminergia in the dorsal striatum on Day 31. The ventral striatum consistently exhibited naloxone-induced transient reductions in DA below the hypodopaminergic basal levels, whereas morphine enhanced DA efflux. In the dorsal striatum, DA responsivity to naloxone shifted from a significant decrease on Day 10 to a notable increase above hypodopaminergic basal levels on Day 31, corroborating the findings in the human dorsal striatum. Unexpectedly, the magnitude of morphine-evoked increases in DA efflux on Day 31 was significantly blunted relative to values on Day 10. These findings indicate that prolonged-intermittent access to morphine results in a sustained hypodopaminergic state as reflected in basal levels in the striatum, which is accompanied by regional differences in DA responsivity to naloxone and morphine. Overall, our findings suggest that prolonging the duration of morphine exposure to 31 days is sufficient to reveal neuroadaptations that may underlie the transition from initial drug exposure to opioid dependence.

Dopamine D4 Receptor Is a Regulator of Morphine-Induced Plasticity in the Rat Dorsal Striatum.

Long-term exposition to morphine elicits structural and synaptic plasticity in reward-related regions of the brain, playing a critical role in addiction. However, morphine-induced neuroadaptations in the dorsal striatum have been poorly studied despite its key function in drug-related habit learning. Here, we show that prolonged treatment with morphine triggered the retraction of the dendritic arbor and the loss of dendritic spines in the dorsal striatal projection neurons (MSNs). In an attempt to extend previous findings, we also explored whether the dopamine D4 receptor (D4R) could modulate striatal morphine-induced plasticity. The combined treatment of morphine with the D4R agonist PD168,077 produced an expansion of the MSNs dendritic arbors and restored dendritic spine density. At the electrophysiological level, PD168,077 in combination with morphine altered the electrical properties of the MSNs and decreased their excitability. Finally, results from the sustantia nigra showed that PD168,077 counteracted morphine-induced upregulation of μ opioid receptors (MOR) in striatonigral projections and downregulation of G protein-gated inward rectifier K+ channels (GIRK1 and GIRK2) in dopaminergic cells. The present results highlight the key function of D4R modulating morphine-induced plasticity in the dorsal striatum. Thus, D4R could represent a valuable pharmacological target for the safety use of morphine in pain management.

Overexpressing Histone Deacetylase 5 in Rat Dorsal Striatum Alters Reward-Guided Decision-Making and Associated Neural Encoding.

Accumulating evidence in the past decade implicates histone-modifying enzymes, such as class I histone deacetylases (HDACs), in learning and memory and, recently, habit formation. However, it is unclear whether HDACs play roles in complex cognitive function. To address this issue, we examined the role of dorsal striatal HDAC5, a class II HDAC, in reward-guided decision-making and associated neural encoding in rats. We first injected adeno-associated virus to overexpress a nuclear-localized HDAC5 in dorsal striatum (DS). We then recorded neural correlates from dorsolateral striatum (DLS) as rats performed two reward-guided choice tasks, in which we manipulated either the size of or delay to reward. During these tasks, rats first learned which of two options led to the better reward and then reversed those contingencies in a second block of trials. We found that rats with HDAC5 overexpression in DS responded faster and chose higher value reward more often during the first block of trials but were less able to reverse those contingencies in the second block of trials. At the neural level, HDAC5 overexpression in DS elevated and reduced the number of cells in DLS that increased firing to stimuli and reward, respectively, and shifted encoding toward cues that predicted more immediate reward. These results suggest that the HDAC5 overexpression in DS contributes to inflexible decision-making, demonstrating a role of histone-modifying enzymes in complex cognitive function.SIGNIFICANCE STATEMENT HDACs are important for learning and habit formation. Here, we expanded on these functions and found that overexpression of HDAC5 produced faster and more automatic behavior, and related changes in dorsolateral striatal neural firing in rats performing a value-based decision-making task. These results implicate HDAC5 as a potential therapeutic target for psychiatric conditions that impair decision-making and executive function.

Differential Influence of Amyloid-β on the Kinetics of Dopamine Release in the Dorsal and Ventral Striatum of Rats.

Dopaminergic dysfunction is a part of Alzheimer's disease pathology. The brain accumulation of amyloid-β of toxic form is a key link of the pathology, which, according to the literature, is also true for dopaminergic dysfunction. An increase in the amyloid-β level in the brain changes the maximum of the evoked dopamine release in the dorsal and ventralparts of the striatum of the experimental animals. Theoretically, this may be due to the change in the intensity of dopamine release from the nerve terminals or its reuptake. However, it has not been studied. To fill this gap, we examined the amyloid-β induced changes in the kinetics of the evoked dopamine release in the dorsal striatum and the nucleus accumbens core and shell. Amyloid-β solution (fragments 25-35) was injected into the ventricular system of the anesthetized male Wistar rats. Before and after injection, electrically evoked dopamine kinetics was registered with fast-scan cyclic voltammetry. The results had shown that the amount of dopamine release decreases in the dorsal striatum and increases in the nucleus accumbens shell. No changes were found in the intensity of dopamine reuptake.

Oxycodone self-administration activates the mitogen-activated protein kinase/ mitogen- and stress-activated protein kinase (MAPK-MSK) signaling pathway in the rat dorsal striatum

To identify signaling pathways activated by oxycodone self-administration (SA), Sprague–Dawley rats self-administered oxycodone for 20 days using short—(ShA, 3 h) and long-access (LgA, 9 h) paradigms. Animals were euthanized 2 h after SA cessation and dorsal striata were used in post-mortem molecular analyses. LgA rats escalated their oxycodone intake and separated into lower (LgA-L) or higher (LgA-H) oxycodone takers. LgA-H rats showed increased striatal protein phosphorylation of ERK1/2 and MSK1/2. Histone H3, phosphorylated at serine 10 and acetylated at lysine 14 (H3S10pK14Ac), a MSK1/2 target, showed increased abundance only in LgA-H rats. RT-qPCR analyses revealed increased AMPA receptor subunits, GluA2 and GluA3 mRNAs, in the LgA-H rats. GluA3, but not GluA2, mRNA expression correlated positively with changes in pMSK1/2 and H3S10pK14Ac. These findings suggest that escalated oxycodone SA results in MSK1/2-dependent histone phosphorylation and increases in striatal gene expression. These observations offer potential avenues for interventions against oxycodone addiction.

Anterior cingulate cortex and adaptive control of brain and behavior.

Research examining the functional underpinnings of anterior cingulate cortex (ACC) and its relationship to cognitive control have been described as "perennially controversial" and a "Rorschach Test" for modern neuroscience. Although there is near universal agreement that ACC is important for the adaptation of behavior, debate, despite decades of work, stems from the exact manner in which ACC goes about doing this. This chapter provides a brief overview of the various past and present theoretical arguments and research surrounding ACC function, and highlights an emerging literature of single unit ACC recordings from several species that support these theories. We will finish the chapter by focusing on our work examining the firing of single neurons in rat dorsal medial striatum (DMS) and ACC, and examining DMS's dependency on ACC to accurately signal adaptive behavioral output. Ultimately, we will conclude that ACC carries a myriad of signals (error detection, reinforcement/feedback, value, response conflict, etc.) necessary for the modulation of attention and task-relevant/irrelevant signals so that difficult decisions can be made and action plans adapted when necessary.

Comparative analyses of transgene expression patterns after intra-striatal injections of rAAV2-retro in rats and rhesus monkeys: A light and electron microscopic study.

Retrogradely-transducing viral vectors are versatile tools for anatomical and functional interrogations of neural circuits. These vectors can be applied in nonhuman primates (NHPs), powerful model species for neuroscientific studies with limited genetic tractability, but limited data are available regarding the tropism and transgene expression patterns of such viruses after injections in NHP brains. Consequently, NHP researchers must often rely on related data available from other species for experimental planning. To evaluate the suitability of rAAV2-retro in the NHP basal ganglia, we studied the transgene expression patterns at the light and electron microscope level after injections of rAAV2-retro vector encoding the opsin Jaws conjugated to a green fluorescent protein (GFP) in the putamen of rhesus macaques. For inter-species comparison, we injected the same vector in the rat dorsal striatum. In both species, GFP expression was observed in numerous cortical and subcortical regions with known striatal projections. However, important inter-species differences in pathway transduction were seen, including labeling of the intralaminar thalamostriatal projection in rats, but not monkeys. Electron microscopic ultrastructural observations within the basal ganglia revealed GFP labeling in both postsynaptic dendrites and presynaptic axonal terminals; the latter likely derived from anterograde transgene transport in neurons that project to the striatum, and from collaterals of these neurons. Our results suggest that certain neural pathways may be refractory to transduction by retrograde vectors in a species-specific manner, highlighting the need for caution when determining the suitability of a retrograde vector for NHP studies based solely on rodent data.

Histamine H3 Receptor Activation Modulates Glutamate Release in the Corticostriatal Synapse by Acting at CaV2.1 (P/Q-Type) Calcium Channels and GIRK (KIR3) Potassium Channels

The striatum is innervated by histaminergic fibers and expresses a high density of histamine H3 receptors (H3Rs), present on medium spiny neurons (MSNs) and corticostriatal afferents. In this study, in sagittal slices from the rat dorsal striatum, excitatory postsynaptic potentials (EPSPs) were recorded in MSNs after electrical stimulation of corticostriatal axons. The effect of H3R activation and blockers of calcium and potassium channels was evaluated with the paired-pulse facilitation protocol. In the presence of the H3R antagonist/inverse agonist clobenpropit (1μM), the H3R agonist immepip (1μM) had no effect on the paired-pulse ratio (PPR), but in the absence of clobenpropit, immepip induced a significant increase in PPR, accompanied by a reduction in EPSP amplitude, suggesting presynaptic inhibition. The blockade of CaV2.1 (P/Q-type) channels with ω-agatoxin TK (400nM) increased PPR and prevented the effect of immepip. The CaV2.2 (N-type) channel blocker ω-conotoxin GVIA (1μM) also increased PPR, but did not occlude the immepip action. Functional KIR3 channels are present in corticostriatal terminals, and in experiments in which immepip increased PPR, the KIR3 blocker tertiapin-Q (30nM) prevented the effect of the H3R agonist. These results indicate that the presynaptic modulation by H3Rs of corticostriatal synapses involves the inhibition of Cav2.1 calcium channels and the activation of KIR3 potassium channels.

Continuous infusion of substance P inhibits acute, but not subacute, inflammatory pain induced by complete Freund’s adjuvant

Previous studies have reported that continuous infusion with substance P (SP) into rat dorsal striatum ameliorated both mechanical allodynia in both formalin-evoked transient inflammatory pain and neuropathic pain models. However, a role of striatal SP in persistent inflammatory pain has not been demonstrated. The current study examined the effect of continuous infusion of SP into the rat dorsal striatum by reverse microdialysis on persistent inflammatory pain induced by complete Freund’s adjuvant (CFA). Intraplantar injection of CFA evoked both mechanical allodynia and paw edema 3 and 7 days post-injection. The continuous infusion of SP ameliorated the CFA-evoked mechanical allodynia, but not paw edema, 3 days after the CFA injection. This antinociceptive effect of SP was partially inhibited by co-infusion with the neurokinin-1 (NK1) receptor antagonist CP96345. Conversely, at 7 days both CFA-evoked mechanical allodynia and paw edema were not affected by SP treatment. To clarify why the effect of SP treatment on CFA-induced pain changed, we evaluated NK1 receptor protein levels at both time points. The NK1 receptor protein level was decreased at 7, but not 3, days post CFA injection. These data suggest that persistent inflammatory pain can downregulate the striatal NK1 receptor. The current study demonstrates that striatal SP-NK1 receptor pathway can exert antinociceptive effect only on the third days of inflammatory pain phase defined as an acute but not the 7 days defined as a subacute.

The impact of 3,4-methylendioxymetamphetamine (MDMA) abstinence on seeking behavior and the expression of the D2-like and mGlu5 receptors in the rat brain using saturation binding analyses.

The abundance of research indicates that enriched environment acts as a beneficial factor reducing the risks of relapse in substance use disorder. There is also strong evidence showing the engagement of brain dopaminergic and glutamatergic signaling through the dopamine D2-like and metabotropic glutamate type 5 (mGlu5) receptors, respectively, that has a direct impact on drug reward and drug abstinence. The present study involved 3,4-methylendioxymethamphetamine (MDMA) self-administration with the yoked-triad procedure in rats kept under different housing conditions during abstinence - enriched environment (EE) or isolation cage (IC) conditions - aimed at evaluating changes in brain receptors affecting drug-seeking behavior as well as density and affinity of the D2-like and mGlu5 receptors in several regions of the animal brain. Our results show that exposure to EE conditions strongly reduced active lever presses during cue-induced drug-seeking. At the neurochemical level, we demonstrated marked decreases of D2-like receptor affinity in the dorsal striatum in rats previously self-administering MDMA under EE and increases in density under IC conditions. Moreover, we found the increases in the density and decreases in the affinity of the D2-like receptor in the prefrontal cortex and nucleus accumbens provoked by IC conditions. The mGlu5 receptor density decreased only in the prefrontal cortex after IC and EE abstinence. Moreover, our study has revealed a clear decrease in mGlu5 receptor density in the nucleus accumbens in the group actively administering MDMA only under EE conditions. This study demonstrates that housing conditions have impact on drug-seeking behavior in rats during abstinence from MDMA self-administration. The observed changes in the dopamine D2-like and mGlu5 receptor Bmax and/or Kd values were brain-region specific and related to either pharmacological and/or motivational features of MDMA.

Compulsive methamphetamine taking induces autophagic and apoptotic markers in the rat dorsal striatum

Methamphetamine (METH) use disorder (MUD) is often accompanied by psychotic symptoms, cognitive deficits, and pathological changes in the brains of users. Animals that experimenters injected with drugs also show neurodegenerative changes in their brains. Recently, we have been investigating METH-induced molecular and biochemical consequences in animals that had infused themselves with METH using the drug self-administration (SA) paradigm. In that model, footshocks administered contingently help to separate rats that had already escalated their METH intake into resilient-to-drug (shock-sensitive, SS) or compulsive (shock-resistant, SR) METH takers. Herein, we used that model to test the idea that compulsive METH takers might show evidence of drug-induced autophagic changes in their brains. There were significant increases in mRNA levels of autophagy-related genes including Atg2a, Atg5, Atg14, and Atg16L1 in the rat dorsal striatum. Levels of two autophagy biomarkers, autophagy activating kinase (ULK1) and phospho-Beclin1, were also increased. In addition, we found increased p53 but decreased Bcl-2 protein levels. Moreover, the expression of cleaved initiator caspase-9 and effector caspase-6 was higher in compulsive METH takers in comparison to shock-sensitive rats. When taken together, these results suggest that the striata of rats that had escalated and continue to take METH compulsively the presence of adverse consequences exhibit some pathological changes similar to those reported in post-mortem human striatal tissues. These results provide supporting evidence that compulsive METH taking is neurotoxic. Our observations also support the notion of developing neuro-regenerative agents to add to the therapeutic armamentarium against METH addiction.

Acute cocaine treatment enhances the antagonistic allosteric adenosine A2A-dopamine D2 receptor\u2013receptor interactions in rat dorsal striatum without increasing significantly extracellular dopamine levels

BackgroundAntagonistic adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) receptor–receptor interactions have previously been demonstrated in A2AR–D2R heteroreceptor complexes in the rat dorsal striatum. They mainly involve a reduction of affinity in the high-affinity component of the D2R agonist binding site upon activation in vivo of the A2AR by an A2AR agonist. Upon cocaine self-administration, this antagonistic A2AR–D2R interaction disappeared in the dorsal striatum.MethodsIn the current experiments, it was tested whether such modifications in the antagonistic A2AR–D2R receptor–receptor interactions can develop also after an acute systemic injection of a low cocaine dose (1 mg/kg; sc).ResultsMicrodialysis experiments indicated that acute cocaine did not significantly alter the extracellular dopamine levels in the dorsal striatum of the awake Wistar rats. Competition dopamine receptor binding experiments demonstrated that in the acute cocaine group, the A2AR agonist CGS-21680 produced significantly larger increases in the D2R Ki, High values (reduction of high-affinity) versus the saline-injected (i.e. control) group. Furthermore, in the dorsal striatum membrane preparation from acute cocaine-injected rats, CGS-21680 also produced significant increases in the D2R Ki, Low values (reduction of low-affinity) and in the proportion of D2Rs in the high-affinity state (RH). Such significant effects were not observed with CGS-21680 in the control group.ConclusionsThe molecular mechanism involved in the acute cocaine-induced increase in the antagonistic allosteric A2AR–D2R receptor–receptor interactions may be an increased formation of higher-order complexes A2AR–D2R-sigma1R in which cocaine by binding to the sigma1R protomer also allosterically enhances the inhibitory A2AR–D2R interaction in this receptor complex.

Escalated Oxycodone Self-Administration and Punishment: Differential Expression of Opioid Receptors and Immediate Early Genes in the Rat Dorsal Striatum and Prefrontal Cortex.

Opioid use disorder (OUD) is characterized by compulsive drug taking despite adverse life consequences. Here, we sought to identify neurobiological consequences associated with the behavioral effects of contingent footshocks administered after escalation of oxycodone self-administration. To reach these goals, Sprague-Dawley rats were trained to self-administer oxycodone for 4 weeks and were then exposed to contingent electric footshocks. This paradigm helped to dichotomize rats into two distinct behavioral phenotypes: (1) those that reduce lever pressing (shock-sensitive) and (2) others that continue lever pressing (shock-resistant) for oxycodone during contingent punishment. The rats were euthanized at 2-h after the last oxycodone plus footshock session. The dorsal striata and prefrontal cortices were dissected for use in western blot and RT-qPCR analyses. All oxycodone self-administration rats showed significant decreased expression of Mu and Kappa opioid receptor proteins only in the dorsal striatum. However, expression of Delta opioid receptor protein was decreased in both brain regions. RT-qPCR analyses documented significant decreases in the expression of c-fos, fosB, fra2, junB, egr1, and egr2 mRNAs in the dorsal striatum (but not in PFC) of the shock-sensitive rats. In the PFC, junD expression was reduced in both phenotypes. However, egr3 mRNA expression was increased in the PFC of only shock-resistant rats. These results reveal that, similar to psychostimulants and alcohol, footshocks can dichotomize rats that escalated their intake of oxycodone into two distinct behavioral phenotypes. These animals also show significant differences in the mRNA expression of immediate early genes, mainly, in the dorsal striatum. The increases in PFC egr3 expression in the shock-resistant rats suggest that Egr3 might be involved in the persistence of oxycodone-associated memory under aversive conditions. This punishment-driven model may help to identify neurobiological substrates of persistent oxycodone taking and abstinence in the presence of adverse consequences.

Voluntary wheel running during adolescence distinctly alters running output in adulthood in male and female rats

Adult female rats show greater running output compared with age-matched male rats, and the midbrain dopaminergic system may account for behavioral differences in running output. However, it is unknown if the lower running output in adult males can be regulated by wheel running experience during adolescence, and whether wheel running experience during adolescence will diminish the sex differences in running output during adulthood. We therefore determined and compared the exercise output in adult male and female rats that either had initiated voluntary wheel running only during adulthood or during adolescence. Our results demonstrate that running output in adult males were significantly higher when running was initiated during adolescence, and this higher running output was not significantly different from females. Running output did not differ during adulthood in females when wheel running was initiated during adolescence or during adulthood. Higher running output in females was associated with reduced expression of tyrosine hydroxylase and hyperactivation of calcium/calmodulin-dependent protein kinase II (CaMKII) in the dorsal striatum. Notably, running during adolescence-induced higher exercise output in adult males was associated with hyperactivation of CaMKII in the dorsal striatum, indicating a mechanistic role for CaMKII in running output. Together, the present results indicate sexually dimorphic adaptive biochemical changes in the dorsal striatum in rats that had escalated running activity, and highlight the importance of including sex as a biological variable in exploring neuroplasticity changes that predict enhanced exercise output in a voluntary physical activity paradigm.

Behavioral changes after nicotine challenge are associated with α7 nicotinic acetylcholine receptor stimulated glutamate release in the rat dorsal striatum

Behavioral changes after nicotine challenge are associated with α7 nicotinic acetylcholine receptor stimulated glutamate release in the rat dorsal striatum

Behavioral cross-sensitization between cocaine and ethanol is accompanied by parallel changes in the activity of AMPK system

Behavioral sensitization is thought to be relevant to the psychopathology of drug addiction. A previous study from our research group demonstrated cross-sensitization between cocaine and ethanol. Although these findings suggest a common mechanism of action between these two drugs, little is known about the molecular or cellular aspects of this commonality. The AMPK pathway functions as an intracellular energy sensor and plays a critical role in maintaining cellular energy homeostasis. Thus, the present study examined AMPK signaling following reciprocal cross-sensitization between cocaine and ethanol in the rat prefrontal cortex and dorsal striatum. Male Sprague–Dawley rats were repeatedly treated with either cocaine (15 mg/kg, 5 times) or ethanol (0.5 g/kg, 15 times) and then challenged reciprocally with the other drug. When sensitized to either cocaine or ethanol, the phosphorylation in response to additional challenges with the same drug was enhanced, indicating the development of sensitization. However, responses to the cocaine challenge were enhanced in the ethanol-sensitized state, whereas the responses to the ethanol challenge were not apparently enhanced in the cocaine-sensitized state. This was likely due to the ceiling effect of cocaine sensitization, which suggested that cocaine had more robust effects than ethanol. Although the same changes were found for two upstream kinases of AMPK (LKB1 and CaMK4), TAK1 responded differently and was not affected by acute challenges from either cocaine or ethanol. In the prefrontal cortex, there was an increase in activity, whereas there was a decrease in activity in the dorsal striatum. This difference might be due to dopamine D1 receptor dominance in the prefrontal cortex and D2 receptor dominance in the dorsal striatum. Taken together, these results suggest that both cocaine and ethanol may share overlapping molecular pathways in the process of behavioral sensitization. However, the action of cocaine was stronger than that of ethanol.

Molecular Adaptations in the Rat Dorsal Striatum and Hippocampus Following Abstinence-Induced Incubation of Drug Seeking After Escalated Oxycodone Self-Administration

Repeated exposure to the opioid agonist, oxycodone, can lead to addiction. Here, we sought to identify potential neurobiological consequences of withdrawal from escalated and non-escalated oxycodone self-administration in rats. To reach these goals, we used short-access (ShA) (3 h) and long-access (LgA) (9 h) exposure to oxycodone self-administration followed by protracted forced abstinence. After 31 days of withdrawal, we quantified mRNA and protein levels of opioid receptors in the rat dorsal striatum and hippocampus. Rats in the LgA, but not the ShA, group exhibited escalation of oxycodone SA, with distinction of two behavioral phenotypes of relatively lower (LgA-L) and higher (LgA-H) oxycodone takers. Both LgA, but not ShA, phenotypes showed time-dependent increases in oxycodone seeking during the 31 days of forced abstinence. Rats from both LgA-L and LgA-H groups also exhibited decreased levels of striatal mu opioid receptor protein levels in comparison to saline and ShA rats. In contrast, mu opioid receptor mRNA expression was increased in the dorsal striatum of LgA-H rats. Moreover, hippocampal mu and kappa receptor protein levels were both increased in the LgA-H phenotype. Nevertheless, hippocampal mu receptor mRNA levels were decreased in the two LgA groups whereas kappa receptor mRNA expression was decreased in ShA and LgA oxycodone groups. Decreases in striatal mu opioid receptor protein expression in the LgA rats may serve as substrates for relapse to drug seeking because these changes occur in rats that showed incubation of oxycodone seeking.