Relapse to cocaine-seeking behavior requires an increase in nucleus accumbens (NAc) core glutamate transmission. Decreased expression of glutamate type I transporter (GLT1), which is responsible for >90% of glutamate clearance, occurs in the core of rats withdrawn from cocaine self-administration, while treatment with ceftriaxone, a beta-lactam antibiotic previously shown to increase GLT1 expression and function in rodents, up-regulates GLT1 and attenuates cue-induced cocaine reinstatement. Here, we tested the effects of increasing GLT1 expression on cue-induced cocaine seeking in rats exposed to either limited (2 h/d) or extended (6 h/d) cocaine access followed by short (2 d) or long (45 d) withdrawal periods. Treatment with ceftriaxone (200 mg/kg, ip), up-regulated core GLT1 expression and attenuated cue-induced cocaine-seeking behavior only in rats exposed to long withdrawal periods, with a greater effect in the extended access condition. Pearson's correlation revealed GLT1 expression in core to be inversely correlated with cue-induced cocaine-seeking behavior. To localize the effects of GLT1 up-regulation within NAc, we tested the hypothesis that blockade of GLT1 in NAc core, but not shell, would reverse the ceftriaxone-mediated effect. Rats withdrawn from cocaine self-administration were treated with the same dose of ceftriaxone followed by intra-core or intra-shell infusions of one of two GLT1 blockers, dihydrokainic acid (500 μM) or DL-threo-beta-benzyloxyaspartate (250 μM), or saline. Our results reveal that the ceftriaxone-mediated attenuation of cue-induced cocaine reinstatement is reversed by GLT1 blockade in core, but not shell, and further implicate core GLT1 as a potential therapeutic target for cocaine relapse.
Cocaine addiction is characterized by compulsive drug seeking, including relapse after a period of withdrawal. The relapse response requires increased glutamate transmission in the nucleus accumbens (NAc). Consistent with this view, GLT1, the transporter responsible for >90% of glutamate uptake, is down-regulated in NAc after several days of withdrawal in rats previously trained to self-administer cocaine under limited access conditions (1–2 hr/day). Human addiction, however, appears to be better modeled by extending daily drug access (6–8 hr/day) and introducing long periods of withdrawal. Here, we determined the combined effects of manipulating cocaine access and withdrawal on GLT1 expression in NAc core and shell. Rats were trained to self-administer cocaine (0.25 mg per intravenous infusion) in daily limited or extended access sessions for 11 days followed by a period of short (1 day) or long (40–45 days) withdrawal. We found that although cocaine withdrawal decreases GLT1 expression in both core and shell, only in core is GLT1 down-regulation sensitive to both access and withdrawal. In fact, after long withdrawal, GLT1 in core is down-regulated more than in shell in either the limited or extended access condition. Thus, glutamate regulation in core appears to be a critical factor in the drug-seeking behavior that follows relatively long periods of cocaine withdrawal.
cocaine; GLT1; nucleus accumbens; self-administration; withdrawal; glutamate
Huntington’s disease (HD) is an inherited neurodegenerative disorder that causes neurological pathology in the basal ganglia and related circuitry. A key site of HD pathology is striatum, the principal basal ganglia input structure; striatal pathology likely changes basal ganglia output but no existing studies address this issue. In this report, we characterize single-neuron activity in the substantia nigra reticulata (SNr) of awake, freely-behaving 140 CAG knock-in (KI) mice at 16 to 40 weeks. KI mice are a well characterized model of adult HD and are mildly symptomatic in this age range. As the primary basal ganglia output nucleus in rodents, the SNr receives direct innervation from striatum, as well as indirect influence via polysynaptic inputs. We analyzed 32 single neurons recorded from KI animals and 44 from wild-type (WT) controls. We found increased burst rates, without a concordant change in spike discharge rate, in KI animals relative to WTs. Furthermore, although metrics of burst structure, such as the inter-spike interval in bursts, do not differ between groups, burst rate increases with age in KI, but not WT, animals. Our findings suggest that altered basal ganglia output is a physiological feature of early HD pathology.
Huntington’s disease; knock-in mice; basal ganglia; substantia nigra reticulata; spike burst
An expansion of glutamine repeats in the N-terminal domain of the huntingtin protein leads to Huntington's disease (HD), a neurodegenerative condition characterized by the presence of involuntary movements, dementia, and psychiatric disturbances. Evaluation of postmortem HD tissue indicates that the most prominent cell loss occurs in cerebral cortex and striatum, forebrain regions in which cortical pyramidal neurons (CPNs) and striatal medium spiny neurons (MSNs) are the most affected. Subsequent evidence obtained from HD patients and especially from transgenic mouse models of HD indicates that long before neuronal death, patterns of communication between CPNs and MSNs become dysfunctional. In fact, electrophysiological signaling in transgenic HD mice is altered even before the appearance of the HD behavioral phenotype, suggesting that dysfunctional cortical input to the striatum sets the stage for the emergence of HD neurological signs. Striatal MSNs, moreover, project back to cortex via multi-synaptic connections, allowing for even further disruptions in cortical processing. An effective therapeutic strategy for HD, therefore, may lie in understanding the synaptic mechanisms by which it dysregulates the corticostriatal system. Here, we review literature evaluating the molecular, morphological, and physiological alterations in the cerebral cortex, a key component of brain circuitry controlling motor behavior, as they occur in both patients and transgenic HD models.
basal ganglia; glutamate transmission; huntingtin; neuronal processing
Prefrontal cortex (PFC) dysfunction is common in patients with Huntington’s disease (HD), a dominantly inherited neurological disorder, and has been linked to cognitive disruption. We previously reported alterations in neuronal firing patterns recorded from PFC of the R6/2 mouse model of HD. To determine if PFC dysfunction results in behavioral impairments, we evaluated performance of wild-type (WT) and R6/2 mice in a fear conditioning and extinction behavioral task. Fear conditioning and extinction retrieval were similar in both genotypes, but R6/2s exhibited less fear during extinction by freezing less than WTs. A fear reinstatement test after extinction retrieval indicated that faster extinction was not due to poor memory for conditioning. During initial extinction and extinction retrieval training, neuronal activity was recorded from prelimbic (PL) cortex, a subregion of PFC known to be important for fear expression. In WTs, a large number of neurons were activated by the conditioned stimulus during initial extinction and this activation was significantly impaired in R6/2s. Notably, there was no genotype difference in PFC activity during extinction retrieval. Thus, altered extinction is likely a result of reduced fear expression due to impairments in PL activation. Collectively, our results suggest that PFC dysfunction may play a key role in R6/2 cognitive impairments.
fear extinction; Huntington’s disease; prefrontal cortex; electrophysiology; R6/2
The R6/2 mouse is a popular model of Huntington’s disease (HD) because of its rapid progression and measurable behavioral phenotype. Yet current behavioral phenotyping methods are usually univariate (e.g., latency to fall from a rotarod) and labor intensive. We used a force-plate actometer and specialized computer algorithms to partition the data into topographically specific behavioral categories that were sensitive to HD-like abnormalities. Seven R6/2 male mice and 7 wild type (WT) controls were placed in a 42 cm X 42 cm force-plate actometer for 20-min recording sessions at 6–7, 8–9, 10–11 and 12–13 weeks of age. Distance traveled, number of wall rears, and number of straight runs (traveling 175 mm or more in 1.5 s) were reduced in R6/2 relative to WT mice at all ages tested. Low mobility bouts (each defined as remaining continuously in a virtual circle of 15 mm radius for 5 s) were increased in R6/2 mice at 6–7 wk and beyond. Independent of body weight, force off-load during wall rears was reduced in R6/2 mice except at 6–7 wk. Power spectra of force variation during straight runs indicated an age-related progressive loss of rhythmicity in R6/2 compared to WT, suggesting gait dysrhythmia and dysmetria. Collectively, these data, which extend results obtained with other widely different behavioral phenotyping methods, document a multifaceted syndrome of motor abnormalities in R6/2 mice. We suggest, moreover, that the force-plate actometer offers a high-throughput tool for screening drugs that may affect symptom expression in R6/2 or other HD model mice.
Environmental enrichment is associated with enhanced learning of complex tasks, attenuated seeking of natural and drug rewards, and altered function of the nucleus accumbens (NAcc), a brain region involved in goal-directed behavior. For example, during acquisition of a discriminative learning task, neurons in the NAcc core subregion are more responsive to discrete, goal-directed movements in rats raised in an enriched condition (EC) relative to an isolated condition (IC), but as learning materialized, this enhanced responsiveness shifts to the cues that predict these movements. Here, we report that these results do not extend to NAcc shell: neuronal responses in this subregion are similar in EC and IC rats during goal-directed movement and the presentation of associative cues both during and after task acquisition. With experience in this task, however, the overall proportion of task-related neuronal responses in NAcc shell decreases. The response pattern of shell neurons is also sensitive to the presence of contextual cues: shell neuronal firing reveals a significant shift from a predominant excitatory to a predominant inhibitory profile in probe trials when the cue that predicts sucrose availability is absent. Collectively, these data suggest that NAcc shell neurons encode cues associated with natural reward, are less responsive during appetitive behavior in familiar conditions, and are insensitive to appetitive learning differences expressed in rats reared in different environmental conditions.
Nucleus accumbens; Environmental enrichment; Social isolation; Single-unit activity; Appetitive conditioning
This paper expands on recent findings that link dynamic patterns of striatal activity with patterns of movement and exploration in wild-type and transgenic mice (R6/2) that model Huntington disease (HD), a fatally inherited neurological condition. Here, with HD as a backdrop, we further develop the concept of entropy conservation in brain and behavior. In particular, we propose that entropy conservation could serve as a rule that guides the process of redistributing brain activity dynamics in order to alter behavior, allowing the adaptation to an ever-changing external environment. This concept is further linked to recent neuroimaging studies in human aging, building a new bridge between our recent findings of entropy conservation and the extant literature.
aging; neuroimaging; entropy; Huntington disease; striatum; behavioral neuroscience
Huntington’s Disease (HD) is a fatally inherited neurodegenerative disorder caused by an expanded glutamine repeat in the N-terminal region of the huntingtin (HTT) protein. The result is a progressively worsening triad of cognitive, emotional, and motor alterations that typically begin in adulthood and end in death 10-20 years later. Autopsy of HD patients indicates massive cell loss in the striatum and its main source of input, the cerebral cortex. Further studies of HD patients and transgenic animal models of HD indicate that corticostriatal neuronal processing is altered long before neuronal death takes place. In fact, altered neuronal function appears to be the primary driver of the HD behavioral phenotype, and dysregulation of glutamate, the excitatory amino acid released by corticostriatal afferents, is believed to play a critical role. Although mutant HTT interferes with the operation of multiple proteins related to glutamate transmission, consistent evidence links the expression of mutant HTT with reduced activity of glutamate transporter 1 (rodent GLT1 or human EAAT2), the astrocytic protein responsible for the bulk of glutamate uptake. Here, we review corticostriatal dysfunction in HD and focus on GLT1 and its expression in astrocytes as a possible therapeutic target.
ascorbate; astrocytes; electrophysiology; glutamate transport; huntingtin; oxidative stress; transgenic models
We examined whether repeated exposure to the increasingly abused amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) results in long-lasting neurobehavioral changes, and further, the ability of contextual cues to modulate these changes. We focused on dorsal striatum, a brain region implicated in the formation of persistent drug-related habits. Rats were transported to a novel recording chamber and treated with once-daily injections (sc) of (±)-MDMA (5.0 mg/kg) or saline for 5 days, followed by a challenge injection 14 days later either in the same (Experiment 1) or different context (Experiment 2). Chronically implanted micro-wire bundles were used to record from populations of striatal neurons on days 1, 5, and challenge. Twenty-four h after the last injection, brains were removed and processed using a modified Golgi method to assess changes in neuronal morphology. A sensitized locomotor response was observed following MDMA challenge in 11 of 12 rats in Experiment 1 (same context), whereas only 58% of rats (7 of 12) displayed sensitization in Experiment 2 (different context). Furthermore, several alterations in striatal electrophysiology were apparent on challenge day, but only in rats that displayed sensitization. Conversely, structural changes in striatal medium spiny neurons, such as increases in spine density, were observed in MDMA-treated rats regardless of whether they displayed behavioral sensitization. Thus, it appears that reorganization of synaptic connectivity in dorsal striatum may contribute to long-lasting drug-induced behavioral alterations, but that these behavioral alterations are subject to modification depending on individual differences and the context surrounding drug administration.
DENDRITIC SPINES; ELECTROPHYSIOLOGY; MDMA; MORPHOLOGY; STRIATUM; SENSITIZATION
A corticostriatal-dependent deficit in the release of ascorbate (AA), an antioxidant vitamin and neuromodulator, occurs concurrently in striatum with dysfunctional GLT1-dependent uptake of glutamate in the R6/2 mouse model of Huntington's disease (HD), an autosomal dominant condition characterized by overt corticostriatal dysfunction. To determine if deficient striatal AA release into extracellular fluid is related to altered GLT1 activity in HD, symptomatic R6/2 mice between 6 and 9 weeks of age and age-matched wild-type (WT) mice received single daily injections of 200 mg/kg ceftriaxone, a β-lactam antibiotic that elevates the functional expression of GLT1, or saline vehicle for 5 consecutive days. On the following day, in vivo voltammetry was coupled with corticostriatal afferent stimulation to monitor evoked release of AA into striatum. In saline-treated mice, we found a marked decrease in evoked extracellular AA in striatum of R6/2 relative to WT. Ceftriaxone, in contrast, restored striatal AA in R6/2 mice to WT levels. In addition, intra-striatal infusion of either the GLT1 inhibitor dihydrokainic acid (DHK) or DL-threo-beta-benzyloxyaspartate (TBOA) blocked evoked striatal AA release. Collectively, our results provide compelling evidence for a link between GLT1 activation and release of AA into the striatal extracellular fluid, and suggest that dysfunction of this system is a key component of HD pathophysiology.
Huntington's disease; ceftriaxone; ascorbate; glutamate uptake; striatum
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that targets the corticostriatal system and results in progressive deterioration of cognitive, emotional, and motor skills. Although cortical and striatal neurons are widely studied in animal models of HD, there is little information on neuronal function during expression of the HD behavioral phenotype. To address this knowledge gap, we used chronically implanted micro-wire bundles to record extracellular spikes and local field potentials (LFPs) in truncated (R6/1 and R6/2) and full-length (knock-in, KI) mouse models as well as in transgenic HD rats (tgHD rats) behaving in an open-field arena. Spike activity was recorded in the striatum of all models and in prefrontal cortex (PFC) of R6/2 and KI mice, and in primary motor cortex (M1) of R6/2 mice. We also recorded LFP activity in R6/2 striatum. All HD models exhibited altered neuronal activity relative to wild-type (WT) controls. Although there was no consistent effect on firing rate across models and brain areas, burst firing was reduced in striatum, PFC, and M1 of R6/2 mice, and in striatum of KI mice. Consistent with a decline in bursting, the inter-spike-interval coefficient of variation was reduced in all regions of all models, except PFC of KI mice and striatum of tgHD rats. Among simultaneously recorded neuron pairs, correlated firing was reduced in all brain regions of all models, while coincident bursting, which measures the temporal overlap between bursting pairs, was reduced in striatum of all models as well as in M1 of R6/2s. Preliminary analysis of striatal LFPs revealed aberrant behavior-related oscillations in the delta to theta range and in gamma activity. Collectively, our results indicate that disrupted corticostriatal processing occurs across multiple HD models despite differences in the severity of the behavioral phenotype. Efforts aimed at normalizing corticostriatal activity may hold the key to developing new HD therapeutics.
mouse models of Huntington's disease; behavioral electrophysiology; striatal local field potentials; spike synchrony; bursting
Repeated, intermittent exposure to the psychomotor stimulants amphetamine and cocaine induces a progressive and enduring augmentation of their locomotor-activating effects, known as behavioral sensitization, which is accompanied by similarly stable adaptations in the dendritic structure of cortico-striatal neurons. We examined whether repeated exposure to the increasingly abused amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) also results in long-lasting behavioral and morphological changes in mesocortical (medial prefrontal cortex) and ventral striatal (nucleus accumbens) neurons. Rats received 2 daily injections of either 5.0 mg/kg (±)-MDMA or saline vehicle, ~6 hr apart, for 3 consecutive days, followed by 4 drug-free days for a total of 3 weeks. Following a 4-week drug-free period, MDMA-pretreated rats displayed behavioral sensitization, as well as large increases in spine density and the number of multiple-headed spines on medium spiny neurons in core and shell subregions of nucleus accumbens. In medial prefrontal cortex, the prelimbic subregion showed increased spine density on distal dendrites of layer V pyramidal neurons, while the anterior cingulate subregion showed a change in the distribution of dendritic material instead. Collectively, our results show that long-lasting locomotor sensitization to MDMA is accompanied by reorganization of synaptic connectivity in limbic-cortico-striatal circuitry. The differential plasticity in cortical subregions, moreover, suggests that drug-induced structural changes are not homogeneous and may be specific to the circuitry underlying long-term changes in drug-seeking and drug-taking behavior.
DENDRITIC SPINES; MEDIAL PREFRONTAL CORTEX; MORPHOLOGY; NUCLEUS ACCUMBENS; SENSITIZATION
Although the core region of the nucleus accumbens (NAcc) has been implicated in motor control and the acquisition of appetitive learning, these processes are altered by environmental experience. To assess how environment influences neuronal processing in NAcc core, we recorded single-unit activity during acquisition of an appetitive learning task in which rats reared in an environmentally enriched condition (EC) learned the operant response (nosepoke into a lit hole) for sucrose reinforcement faster than rats reared in an isolated condition (IC). In the first training session, even before the emergence of learning differences, core neurons were more likely to respond (increase or decrease activity) during the operant and consummatory responses in EC than IC rats. By the third training session, when learning differences emerged, EC neurons continued to be more responsive than IC neurons, but in very different ways: the response shifted to the cues that signaled trial onset (1900 Hz tone and green LED) and reward availability (4500 Hz tone and yellow LED). Cue-related responding, moreover, was dominated by neuronal excitations. In contrast, post-acquisition recordings revealed no EC-IC differences. Collectively, these results suggest that core neurons are initially more responsive to discrete, goal-directed movements in EC rats, but as learning materializes, the neuronal response shifts to the cues that predict these movements. Thus, environmental experience alters core neuronal processing of both motor- and sensory-related events but at different stages over the course of learning.
nucleus accumbens; environmental enrichment; social isolation; single-unit activity; appetitive conditioning; goal-directed behavior
Relapse to cocaine-seeking behavior depends on increased glutamate transmission in key regions of the mesocorticolimbic motive circuit, including prefrontal cortex (PFC) and nucleus accumbens (NAcc). Because GLT1 is responsible for the uptake of ≥90% of extracellular glutamate, we tested the hypothesis that increased GLT1 expression attenuates cocaine relapse. Rats were trained to self-administer cocaine (0.125 mg per iv infusion) in a lever-pressing task in a daily two-hour session for 10–14 days followed by five days of extinction training. Immediately after each extinction session, rats received ceftriaxone (ip), a β-lactam antibiotic believed to increase GLT1 expression, or vehicle. On the following day, presentation of the cue (light and tone) previously associated with cocaine self-administration reinstated lever-pressing in rats treated with vehicle, whereas 100 or 200, but not 50 mg/kg ceftriaxone blocked this response. Immunoblotting confirmed that the ceftriaxone-induced blockade of cocaine relapse was associated with an increase in GLT1 expression in both PFC and NAcc. In separate groups of rats, 200 mg/kg ceftriaxone failed to block cue-induced food seeking, arguing against a ceftriaxone-induced effect unique to extinction training or lever pressing. Our results suggest that glutamate plays a key role in cue-induced relapse to cocaine-seeking behavior, implicating GLT1 as a potential therapeutic target for cocaine addiction.
ceftriaxone; cocaine; GLT1; glutamate; prefrontal cortex; nucleus accumbens
Understanding cortical information processing in Huntington’s disease (HD), a genetic neurological disorder characterized by prominent motor and cognitive abnormalities, is key to understanding the mechanisms underlying the HD behavioral phenotype. We recorded extracellular spike activity in two symptomatic, freely behaving mouse models: R6/2 transgenics, which are based on a CBAxC57BL/6 background and show robust behavioral symptoms, and HD knock-in (KI) mice, which have a 129sv background and express relatively mild behavioral signs. We focused on prefrontal cortex and assessed firing patterns of individually recorded neurons as well as the amount of synchrony between simultaneously recorded neuronal pairs. At the single-unit level, spike trains in R6/2 transgenics were less variable and had a faster rate than their corresponding wild-type (WT) littermates but showed significantly less bursting. In contrast, KI and WT firing patterns were closely matched. An assessment of both WTs revealed that the R6/2 and KI difference could not be explained by a difference in WT electrophysiology. Thus, the altered pattern of individual spike trains in R6/2 mice appears to parallel their aggressive form of symptom expression. Both WT lines, however, showed a high proportion of synchrony between neuronal pairs (>85%) that was significantly attenuated in both corresponding HD models (decreases of ~20% and ~30% in R6/2s and knock-ins, respectively). The loss of spike synchrony, regardless of symptom severity, suggests a population-level deficit in cortical information processing that underlies HD progression.
bursting; spike synchrony; electrophysiology; transgenic; knock-in; corticostriatal pathway
To assess the role of dopamine input to the nucleus accumbens core in anticipatory learning, fast-scan cyclic voltammetry was combined with appetitive Pavlovian conditioning. One group of rats (Paired) received 16 tone-food pairings for at least four daily sessions while the control group (Unpaired) received the same number of unpaired tone and food presentations. Both groups showed transient dopamine responses during food presentation throughout training, confirming dopamine involvement in reward processing. Only the Paired Group, however, showed consistently timed dopamine transients during the 10-s tone presentation. Transients first appeared near the end of the tone period as each animal acquired the tone-food association and then occurred progressively sooner on subsequent sessions. Later sessions also revealed a consistently timed dopamine response soon after food delivery in Paired animals. Collectively, these results implicate phasic dopamine release in the acquisition of Pavlovian learning and also suggest an early dopamine response to the unconditioned stimulus as training continues.
dopamine transients; nucleus accumbens core; Pavlovian conditioning; voltammetry
The striatum, which processes cortical information for behavioral output, is a key target of Huntington's disease (HD), an autosomal dominant condition characterized by cognitive decline and progressive loss of motor control. Increasing evidence implicates deficient glutamate uptake caused by a down-regulation of GLT1, the primary astroglial glutamate transporter. To test this hypothesis, we administered ceftriaxone, a β-lactam antibiotic known to elevate GLT1 expression (200 mg/kg, ip, for 5 days), to symptomatic R6/2 mice, a widely studied transgenic model of HD. Relative to vehicle, ceftriaxone attenuated several HD behavioral signs: paw clasping and twitching were reduced, while motor flexibility, as measured in a plus maze, and open-field climbing were increased. Assessment of GLT1 expression in striatum confirmed a ceftriaxone-induced increase relative to vehicle. To determine if the change in behavior and GLT1 expression represented a change in striatal glutamate handling, separate groups of behaving mice were evaluated with no-net-flux microdialysis. Vehicle treatment revealed a glutamate uptake deficit in R6/2 mice relative to wild-type controls that was reversed by ceftriaxone. Vehicle-treated animals, however, did not differ in GLT1 expression, suggesting that the glutamate uptake deficit in R6/2 mice reflects dysfunctional rather than missing GLT1. Our results indicate that impaired glutamate uptake is a major factor underlying HD pathophysiology and symptomology. The glutamate uptake deficit, moreover, is present in symptomatic HD mice and reversal of this deficit by up-regulating the functional expression of GLT1 with ceftriaxone attenuates the HD phenotype.
Huntington's disease; ceftriaxone; R6/2; striatum; microdialysis; glutamate
The widely used recreational drug MDMA (ecstasy) supports self-administration in animals, but it is not known whether MDMA-associated cues are able to reinstate drug seeking in a relapse model of drug addiction. To assess this possibility, drug-naïve rats were trained to press a lever for MDMA infusions (0.30 mg/kg/infusion, i.v.) paired with a compound cue (light and tone) in daily 2 hr sessions. Responding was reinforced contingent on a modified fixed-ratio 5 schedule of reinforcement. Conditioned cue-induced reinstatement tests were conducted after lever pressing was extinguished in the absence of MDMA and the conditioned cues. Conditioned cues reinstated lever pressing after extinction, and the magnitude of reinstatement was positively correlated with the level of responding during MDMA self-administration. These results show for the first time that conditioned cues can trigger reinstatement of MDMA-seeking behavior in rats, and that individual differences in the pattern of MDMA self-administration can predict the magnitude of reinstatement responding.
ADDICTION; CUE; MDMA; REINSTATEMENT; RELAPSE; SELF-ADMINISTRATION
Ethological assessment of murine models of Huntington’s disease (HD), an inherited neurodegenerative disorder, enables correlation between phenotype and pathophysiology. Currently, the most characterized model is the R6/2 line that develops a progressive behavioral and neurological phenotype by six weeks of age. A recently developed knock-in model with 140 CAG repeats (KI) exhibits a subtle phenotype with a longer progressive course, more typical of adult-onset HD in humans. We evaluated rotarod performance, open-field behavior, and motor activity across the diurnal cycle in KI mice during early to mid-adulthood. Although we did not observe any effects of age, relative to wild-type (WT) mice, KI mice showed significant deficits in both open-field climbing behavior and home-cage running wheel activity during the light phase of the diurnal cycle. An interesting sex difference also emerged. KI females spent more time in the open-field grooming and more time running during the diurnal dark phase than KI males and WT mice of both sexes. In striatum, the primary site of HD pathology, we measured behavior-related changes in extracellular ascorbate (AA), which is abnormally low in the R6/2 line, consistent with a loss of antioxidant protection in HD. KI males exhibited a 20–40% decrease in striatal AA from anesthesia baseline to behavioral activation that was not observed in other groups. Collectively, our results indicate behavioral deficits in KI mice that may be specific to the diurnal cycle. Furthermore, sex differences observed in behavior and striatal AA release suggest sex-dependent variation in the phenotype and neuropathology of HD.
Huntington’s disease; sex; rotarod; open-field; diurnal cycle; ascorbate; voltammetry; oxidative stress
We previously demonstrated that prenatal alcohol exposure results in brain defects at different embryonic stages. This study is aimed at characterizing the influence of prenatal alcohol exposure on the levels of several neurotransmitters at early embryonic stage 13 (E13). Pregnant C57BL/6 mice were exposed to either a 25% ethanol derived calorie diet (ALC) or pair-fed (PF) liquid diet from E7 to E13. At E13, fetal brains were collected from dams of the ALC and PF groups. Liquid chromatography/tandem mass spectrometry (LC-MS) was then used to evaluate neurotransmitter levels. This approach involved the use of an LC column in conjunction with multiple-reaction monitoring mass spectrometry. Quantitative analyses of catecholamines, idolamine, and amino acid neurotransmitters revealed significant reductions in the levels of dopamine (p=0.004), norepinephrine (p=0.0009), epinephrine (p=0.0002), serotonin (p=0.004), and GABA (p=0.002) in the ALC group compared to the PF group. However, there was no significant change in the levels of glutamate in E13 fetal brains. These findings demonstrate that prenatal alcohol exposure reduces the concentrations of some catecholamines, idolamine, and amino acid neurotransmitters in E13 fetal brains. This study suggests that alterations of selective neurotransmitters may be the cause of abnormalities in brain function and behavior found in fetal alcohol spectrum disorders.
fetal alcohol exposure; serotonin; dopamine; norepinephrine; GABA; LC-MS
The return to drug seeking, even after prolonged periods of abstinence, is a defining feature of cocaine addiction. The neural circuitry underlying relapse has been identified in neuropharmacological studies of experimental animals, typically rats, and supported in brain imaging studies of human addicts. Although the nucleus accumbens (NAcc), which has long been implicated in goal-directed behavior, plays a critical role in this circuit, the prefrontal cortex (PFC) appears to process the events that directly trigger relapse: exposure to acute stress, cues previously associated with the drug, and the drug itself. In this paper, we review animal models of relapse and what they have revealed about the mechanisms underlying the involvement of the NAcc and PFC in cocaine-seeking behavior. We also present electrophysiological data from PFC illustrating how the hedonic, motor, motivational, and reinforcing effects of cocaine can be analyzed at the neuronal level. Our preliminary findings suggest a role for PFC in processing information related to cocaine seeking but not the hedonic effects of the drug. Further use of this recording technology can help dissect the functions of PFC and other components of the neural circuitry underlying relapse.
cocaine seeking; prefrontal cortex (PFC); nucleus accumbens (NAcc); drug self-administration; reinstatement; single-unit; electrophysiology; rat
Aims: Changes in glutamatergic transmission affect many aspects of neuroplasticity associated with ethanol and drug addiction. For instance, ethanol- and drug-seeking behavior is promoted by increased glutamate transmission in key regions of the motive circuit. We hypothesized that because glutamate transporter 1 (GLT1) is responsible for the removal of most extracellular glutamate, up-regulation or activation of GLT1 would attenuate ethanol consumption. Methods: Alcohol-preferring (P) rats were given 24 h/day concurrent access to 15 and 30% ethanol, water and food for 7 weeks. During Week 6, P rats received either 25, 50, 100 or 200 mg/kg ceftriaxone (CEF, i.p.), a β-lactam antibiotic known to elevate GLT1 expression, or a saline vehicle for five consecutive days. Water intake, ethanol consumption and body weight were measured daily for 15 days starting on Day 1 of injections. We also tested the effects of CEF (100 and 200 mg/kg, i.p.) on daily sucrose (10%) consumption as a control for motivated behavioral drinking. Results: Statistical analyses revealed a significant reduction in daily ethanol, but not sucrose, consumption following CEF treatment. During the post treatment period, there was a recovery of ethanol intake across days. Dose-dependent increases in water intake were manifest concurrent with the CEF-induced decreases in ethanol intake. Nevertheless, CEF did not affect body weight. An examination of a subset of the CEF-treated ethanol-drinking rats, on the third day post CEF treatment, revealed increases in GTL1 expression levels within the prefrontal cortex and nucleus accumbens. Conclusions: These results indicate that CEF effectively reduces ethanol intake, possibly through activation of GLT1, and may be a potential therapeutic drug for alcohol addiction treatment.
Relapse is a hallmark of cocaine addiction. Cocaine-induced neuroplastic changes in the mesocorticolimbic circuits critically contribute to this phenomenon. Preclinical evidence indicates that relapse to cocaine-seeking behavior depends on activation of dopamine neurons in the ventral tegmental area. Thus, blocking such activation may inhibit relapse. Because activity of dopamine neurons are regulated by D2-like autoreceptors expressed on somatodendritic sites, this study, using the reinstatement model, aimed to determine whether activation of D2-like receptors in the ventral tegmental area can inhibit cocaine-induced reinstatement of extinguished cocaine-seeking behavior. Rats were trained to self-administer intravenous cocaine (0.25 mg/infusion) under a modified fixed-ratio 5 schedule. After such behavior was well learned, rats went through extinction training to extinguish cocaine-seeking behavior. Then the effect of quinpirole, a selective D2-like receptor agonist microinjected into the ventral tegmental area on cocaine-induced reinstatement was assessed. Quinpirole (0 – 3.2 μg/side) dose-dependently decreased cocaine-induced reinstatement and such effects were reversed by the selective D2-like receptor antagonist eticlopride when co-microinjected with quinpirole into the ventral tegmental area. The effect appeared to be specific to the ventral tegmental area because quinpirole microinjected into the substantia nigra had no effect. Because D2-like receptors are expressed on rat ventral tegmental area dopamine neurons projecting to the prefrontal cortex and nucleus accumbens, our data suggest that these dopamine circuits may play a critical role in cocaine-induced reinstatement. The role of potential changes in D2-like receptors and related signaling molecules of dopamine neurons in the vulnerability to relapse was discussed.
dorsal prefrontal cortex; nucleus accumbens; relapse; neuroplasticity
Chronic restraint stress produces morphological changes in medial prefrontal cortex and disrupts a prefrontally mediated behavior, retrieval of extinction. To assess potential physiological correlates of these alterations, we compared neural activity in infralimbic and prelimbic cortex of unstressed versus stressed rats during fear conditioning and extinction. After implantation of microwire bundles into infralimbic or prelimbic cortex, rats were either unstressed or stressed via placement in a plastic restrainer (3 h/day for 1 week). Rats then underwent fear conditioning and extinction while activity of neurons in infralimbic or prelimbic cortex was recorded. Percent freezing and neural activity were assessed during all phases of training. Chronic stress enhanced freezing during acquisition of conditioned fear, and altered both prelimbic and infralimbic activity during this phase. Stress did not alter initial extinction or conditioned stimulus (CS)-related activity during this phase. However, stress impaired retrieval of extinction assessed 24 h later, and this was accompanied by alterations in neuronal activity in both prelimbic and infralimbic cortex. In prelimbic cortex, unstressed rats showed decreased activity in response to CS presentation, whereas stressed rats showed no change. In infralimbic cortex, neurons in unstressed rats exhibited increased firing in response to the CS, whereas stressed rats showed no increase in infralimbic firing during the tone. Finally, CS-related firing in infralimbic but not prelimbic cortex was correlated with extinction retrieval. Thus, the stress-induced alteration of neuronal activity in infralimbic cortex may be responsible for the stress-induced deficit in retrieval of extinction.
Stress; Medial prefrontal cortex; Infralimbic cortex; Prelimbic cortex; Extracellular Recording; Extinction Retrieval