Visuo-Motor Feedback Modulates Neural Activities in the Medulla of the Honeybee, Apis mellifera.

Behavioral and internal-state modulation of sensory processing has been described in several organisms. In insects, visual neurons in the optic lobe are modulated by locomotion, but the degree to which visual-motor feedback modulates these neurons remains unclear. Moreover, it also remains unknown whether self-generated and externally generated visual motion are processed differently. Here, we implemented a virtual reality system that allowed fine-scale control over visual stimulation in relation to animal motion, in combination with multichannel recording of neural activity in the medulla of a female honeybee (Apis mellifera). We found that this activity was modulated by locomotion, although, in most cases, only when the bee had behavioral control over the visual stimulus (i.e., in a closed-loop system). Moreover, closed-loop control modulated a third of the recorded neurons, and the application of octopamine (OA) evoked similar changes in neural responses that were observed in a closed loop. Additionally, in a subset of modulated neurons, fixation on a visual stimulus was preceded by an increase in firing rate. To further explore the relationship between neuromodulation and adaptive control of the visual environment of the bee, we modified motor gain sensitivity while locally injecting an OA receptor antagonist into the medulla. Whereas female honeybees were tuned to a motor gain of -2 to 2 (between the heading of the bee and its visual feedback), local disruption of the OA pathway in the medulla abolished this tuning, resulting in similar low levels of response across levels of motor gain. Our results show that behavioral control modulates neural activity in the medulla and ultimately impacts behavior.SIGNIFICANCE STATEMENT When moving, an animal generates the motion of the visual scene over its retina. We asked whether self-generated and externally generated optic flow are processed differently in the insect medulla. Our results show that closed-loop control of the visual stimulus modulates neural activity as early as the medulla and ultimately impacts behavior. Moreover, blocking octopaminergic modulation further disrupted object-tracking responses. Our results suggest that the medulla is an important site for context-dependent processing of visual information and that placing the animal in a closed-loop environment may be essential to understanding its visual cognition and processing.

Sensorimotor Perceptive Rehabilitation Integrated (SPRInt) program: exercises with augmented movement feedback associated to botulinum neurotoxin in idiopathic cervical dystonia-an observational study.

BACKGROUND: Idiopathic cervical dystonia (ICD) is a focal dystonia affecting neck muscles. Botulinum neurotoxin (BoNT) is the first-line treatment of ICD and different physical therapies (including exercise) are often proposed as adjunct treatments. However, the actual effectiveness of exercise in ICD is unclear. The aim of the current work is to assess the potential effectiveness of the Sensorimotor Perceptive Rehabilitation Integrated (SPRInt) exercise program as adjunct therapy for ICD. METHODS: Fifteen ICD patients received BoNT injections in the neck muscles and, 12 weeks later, received BoNT a second time and SPRInt started. SPRInt consists in 18 exercise sessions in which augmented feedback of movement (including visual and acoustic feedback) is extensively used. Dystonia burden was measured by the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). Patients were evaluated immediately before, 6 and 12 weeks after each BoNT injection. RESULTS: Six weeks after the first BoNT injection (i.e., at BoNT peak effect), TWSTRS total score was better than baseline and remained improved at 12 weeks. TWSTRS disability domain slightly improved 6 weeks after the first BoNT injection, but after 6 more weeks returned to its baseline level. Disability improved more at SPRInt end (i.e., 6 weeks after the second BoNT injection), being even lower than after toxin alone. With a single-subject analysis, 4/10 patients who did not improve disability after BoNT improved after SPRInt plus BoNT. CONCLUSIONS: SPRInt plus BoNT can be more effective than BoNT alone in improving cervical dystonia patients' difficulties in the activities of daily living. TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT03247868 (https://register.clinicaltrials.gov).

Successful and unsuccessful attempts to swallow in a reduced Aplysia preparation regulate feeding responses and produce memory at different neural sites.

Sensory feedback shapes ongoing behavior and may produce learning and memory. Motor responses to edible or inedible food in a reduced Aplysia preparation were examined to test how sensory feedback affects behavior and memory. Feeding patterns were initiated by applying a cholinomimetic onto the cerebral ganglion. Feedback from buccal muscles increased the response variability and response rate. Repeated application of the cholinomimetic caused decreased responses, expressed in part by lengthening protractions. Swallowing strips of "edible" food, which in intact animals induces learning that enhances ingestion, increased the response rate, and shortened the protraction length, reflecting more swallowing. Testing memory by repeating the procedure prevented the decrease in response rate observed with the cholinomimetic alone, and shortened protractions. Training with "inedible" food that in intact animals produces learning expressed by decreased responses caused lengthened protractions. Testing memory by repeating the procedure did not cause decreased responses or lengthened protractions. After training and testing with edible or inedible food, all preparations were exposed to the cholinomimetic alone. Preparations previously trained with edible food displayed memory expressed as decreased protraction length. Preparations previously trained with inedible food showed decreases in many response parameters. Memory for inedible food may arise in part via a postsynaptic decrease in response to acetylcholine released by afferents sensing food. The lack of change in response number, and in the time that responses are maintained during the two training sessions preceding application of the cholinomimetic alone suggests that memory expression may differ from behavioral changes during training.

Attenuated beta rebound to proprioceptive afferent feedback in Parkinson's disease.

Motor symptoms are defining traits in the diagnosis of Parkinson's disease (PD). A crucial component in motor function is the integration of afferent proprioceptive sensory feedback. Previous studies have indicated abnormal movement-related cortical oscillatory activity in PD, but the role of the proprioceptive afference on abnormal oscillatory activity in PD has not been elucidated. We examine the cortical oscillations in the mu/beta-band (8-30 Hz) in the processing of proprioceptive stimulation in PD patients, ON/OFF levodopa medication, as compared to that of healthy controls (HC). We used a proprioceptive stimulator that generated precisely controlled passive movements of the index finger and measured the induced cortical oscillatory responses following the proprioceptive stimulation using magnetoencephalography. Both PD patients and HC showed a typical beta-band desynchronization during the passive movement. However, the subsequent beta rebound after the passive movement that was almost absent in PD patients compared to HC. Furthermore, we found no difference in the degree of beta rebound attenuation between patients ON and OFF levodopa medication. The results demonstrate a disease-related deterioration in cortical processing of proprioceptive afference in PD.

Muscle, a conduit to brain for hormonal control of behavior.

SBN Elsevier Lecture Investigation into mechanisms whereby hormones control behavior often starts with actions on central nervous system (CNS) motivation and motor systems and is followed by assessment of CNS drive of coordinated striated muscle contractions. Here we turn this perspective on its head by discussing ways in which hormones might first act on muscle that then secondarily drive upstream the evolution and function of the CNS. While there is a lengthy history for consideration of this perspective, newly discovered properties of muscle signaling reveal novel mechanisms that may well be captured by endocrine systems and thus of interest to behavioral endocrinologists.

Haptic Feedback Manipulation During Botulinum Toxin Injection Therapy for Focal Hand Dystonia Patients: A Possible New Assistive Strategy.

Abnormality of sensorimotor integration in the basal ganglia and cortex has been reported in the literature for patients with task-specific focal hand dystonia (FHD). In this study, we investigate the effect of manipulation of kinesthetic input in people living with writer's cramp disorder (a major form of FHD). For this purpose, severity of dystonia is studied for 11 participants while the symptoms of seven participants have been tracked during five sessions of assessment and Botulinum toxin injection (BoNT-A) therapy (one of the current suggested therapies for dystonia). BoNT-A therapy is delivered in the first and the third session. The goal is to analyze the effect of haptic manipulation as a potential assistive technique during BoNT-A therapy. The trial includes writing, hovering, and spiral/sinusoidal drawing subtasks. In each session, the subtasks are repeated twice when (a) a participant uses a normal pen, and (b) when the participant uses a robotics-assisted system (supporting the pen) which provides a compliant virtual writing surface and manipulates the kinesthetic sensory input. The results show (p-value using one-sample t-tests) that reducing the writing surface rigidity significantly decreases the severity of dystonia and results in better control of grip pressure (an indicator of dystonic cramping). It is also shown that (p-value based on paired-samples t-test) using the proposed haptic manipulation strategy, it is possible to augment the effectiveness of BoNT-A therapy. The outcome of this study is then used in the design of an actuated pen as a writing-assistance tool that can provide compliant haptic interaction during writing for FHD patients.

Effect of JWH-250, JWH-073 and their interaction on "tetrad", sensorimotor, neurological and neurochemical responses in mice.

JWH-250 and JWH-073 are two synthetic cannabinoid agonists with nanomolar affinity at CB1 and CB2 receptors. They are illegally marketed within "herbal blend" for theirs psychoactive effects greater than those produced by Cannabis. Recently, we analyzed an "herbal" preparation containing a mixture of both JWH-250 and JWH-073. The present study was aimed at investigating the in vitro and in vivo pharmacological activity of JWH-250 and JWH-073 in male CD-1 mice. In vitro competition binding experiments performed on mouse and human CB1 and CB2 receptors revealed a nanomolar affinity and potency of the JWH-250 and JWH-073. In vivo studies showed that JWH-250 and JWH-073, administered separately, induced a marked hypothermia, increased pain threshold to both noxious mechanical and thermal stimuli, caused catalepsy, reduced motor activity, impaired sensorimotor responses (visual, acoustic and tactile), caused seizures, myoclonia, hyperreflexia and promote aggressiveness in mice. Moreover, microdialysis study in freely moving mice showed that systemic administration of JWH-250 and JWH-073 stimulated dopamine release in the nucleus accumbens in a dose-dependent manner. Behavioral, neurological and neurochemical effects were fully prevented by the selective CB1 receptor antagonist/inverse agonist AM 251. Co-administration of ineffective doses of JWH-250 and JWH-073 impaired visual sensorimotor responses, improved mechanical pain threshold and stimulated mesolimbic DA transmission in mice, living unchanged all other behavioral and physiological parameters. For the first time the present study demonstrates the overall pharmacological effects induced by the administration of JWH-250 and JWH-073 in mice and it reveals their potentially synergistic action suggesting that co-administration of different synthetic cannabinoids may potentiate the detrimental effects of individual compounds increasing their dangerousness and abuse potential.

Cerebrolysin dose-dependently improves neurological outcome in rats after acute stroke: A prospective, randomized, blinded, and placebo-controlled study.

BACKGROUND: Cerebrolysin is a mixture of neuropeptides and free amino acids that is clinically used for the treatment of stroke. To further standardize treatment schemes, we assessed the dose response of Cerebrolysin on sensorimotor outcome in a rat model of ischemic stroke. METHODS: This study was a prospective, blinded, placebo-controlled, preclinical experiment. Male and female Wistar rats, subjected to embolic middle cerebral artery occlusion, were randomly treated with Cerebrolysin doses of 0.8, 2.5, 5.0, 7.5 ml/kg or placebo, 4 h after middle cerebral artery occlusion for a total of 10 consecutive days. RESULTS: The primary outcome was neurologic improvement at day 28, lesion volume, mortality, and animal weight were secondary and safety outcomes, respectively. There was a significant (p < 0.001) dose effect of Cerebrolysin on neurological outcome. Cerebrolysin at a dose of ≥ 2.5 ml/kg significantly (p < 0.001) improved neurological outcome (Mean Estimate (95% CL): 0.8 ml/kg: 6.2 (-6.0/18.4), 2.5 ml/kg: -28.9 (-41.6/-16.2), 5.0 ml/kg: -33.4 (-45.0/-21.7), 7.5 ml/kg: -36.3 (-48.2/-24.4). Higher doses (≥ 2.5 ml/kg) resulted in better recovery; however, differences between effective doses were not significant. Treatment with 5 ml/kg reduced lesion volume (p = 0.016). No treatment gender interactions were found and there were no differences in death or weight loss. CONCLUSION: Collectively, these data on Cerebrolysin efficacy demonstrate the feasibility of a preclinical study setup following a randomized, placebo-controlled, and blinded design with a clinical relevant treatment scheme. Cerebrolysin at doses of ≥ 2.5 ml/kg improved functional outcome and at a dose of 5 ml/kg reduced infarct volume.

Feedback from visual cortical area 7 to areas 17 and 18 in cats: How neural web is woven during feedback.

To investigate the feedback effect from area 7 to areas 17 and 18, intrinsic signal optical imaging combined with pharmacological, morphological methods and functional magnetic resonance imaging (fMRI) was employed. A spatial frequency-dependent decrease in response amplitude of orientation maps was observed in areas 17 and 18 when area 7 was inactivated by a local injection of GABA, or by a lesion induced by liquid nitrogen freezing. The pattern of orientation maps of areas 17 and 18 after the inactivation of area 7, if they were not totally blurred, paralleled the normal one. In morphological experiments, after one point at the shallow layers within the center of the cat's orientation column of area 17 was injected electrophoretically with HRP (horseradish peroxidase), three sequential patches in layers 1, 2 and 3 of area 7 were observed. Employing fMRI it was found that area 7 feedbacks mainly to areas 17 and 18 on ipsilateral hemisphere. Therefore, our conclusions are: (1) feedback from area 7 to areas 17 and 18 is spatial frequency modulated; (2) feedback from area 7 to areas 17 and 18 occurs mainly ipsilaterally; (3) histological feedback pattern from area 7 to area 17 is weblike.

Cortical Feedback Decorrelates Olfactory Bulb Output in Awake Mice.

The olfactory bulb receives rich glutamatergic projections from the piriform cortex. However, the dynamics and importance of these feedback signals remain unknown. Here, we use multiphoton calcium imaging to monitor cortical feedback in the olfactory bulb of awake mice and further probe its impact on the bulb output. Responses of feedback boutons were sparse, odor specific, and often outlasted stimuli by several seconds. Odor presentation either enhanced or suppressed the activity of boutons. However, any given bouton responded with stereotypic polarity across multiple odors, preferring either enhancement or suppression. Feedback representations were locally diverse and differed in dynamics across bulb layers. Inactivation of piriform cortex increased odor responsiveness and pairwise similarity of mitral cells but had little impact on tufted cells. We propose that cortical feedback differentially impacts these two output channels of the bulb by specifically decorrelating mitral cell responses to enable odor separation.

Ten Mistakes To Avoid When Injecting Botulinum Toxin.

Injection of botulinum toxin is currently the most common cosmetic procedure in the United States, and in recent years it has become-together with dermal fillers-the mainstay of therapy for the prevention and treatment of facial aging. However, in some cases the treatment may lead to a somewhat unnatural appearance, usually caused by loss of facial expression or other telltale signs. In the present article, we review the 10 mistakes that should be avoided when injecting botulinum toxin. We also reflect on how treatment with botulinum toxin influences us through our facial expressions, both in terms of how we feel and what others perceive.

Adolescents with Type 1 diabetes mellitus experience psychosensorial symptoms during hypoglycaemia.

AIM: To describe mood and psychosensorial symptoms of hypoglycaemia in adolescents with Type 1 diabetes mellitus in two countries with different cultures, Turkey and the USA. METHODS: We developed a 68-item questionnaire assessing physical, behavioural, mood and psychosensorial symptom frequency and ratings ['good', 'bad', or 'both' (sometimes good, sometimes bad)]. Adolescents with Type 1 diabetes were recruited from paediatric diabetes clinics at the University of North Carolina at Chapel Hill in the USA and Kocaeli University in Turkey. The percentages of participants at each clinic who endorsed individual symptoms, symptom categories and symptom ratings were calculated and compared. RESULTS: Cronbach's α values were > 0.7 for each real symptom category. No symptom items were excluded from the questionnaire analysis based on item-total correlation results which were all > 0.2. Data were collected from 132 participants (69 from University of North Carolina, 63 from Kocaeli University, 54% male). The mean (SD) age of the participants was 14.9 (1.9) years, HbA1c level was 8.7 (1.8) % and duration of Type 1 diabetes was 5.8 (3.7) years. On average, each physical symptom was experienced by 65.2% of participants, each behavioural symptom by 46.5%, each mood symptom by 42.8%, and each psychosensorial symptom by 48.9%. On average, each physical, behavioral, mood and psychosensorial symptom was rated as 'good' or 'both' by 23.0, 29.1, 36.9 and 37.2% of participants, respectively. There were no symptom differences between the groups in each country. CONCLUSIONS: In addition to the classic physical symptoms experienced during hypoglycaemia, adolescents with Type 1 diabetes report psychosensorial, mood and behavioral symptoms, and some describe them as positive experiences. Symptom experiences were similar in these two countries with different cultures.

Wide-field feedback neurons dynamically tune early visual processing.

An important strategy for efficient neural coding is to match the range of cellular responses to the distribution of relevant input signals. However, the structure and relevance of sensory signals depend on behavioral state. Here, we show that behavior modifies neural activity at the earliest stages of fly vision. We describe a class of wide-field neurons that provide feedback to the most peripheral layer of the Drosophila visual system, the lamina. Using in vivo patch-clamp electrophysiology, we found that lamina wide-field neurons respond to low-frequency luminance fluctuations. Recordings in flying flies revealed that the gain and frequency tuning of wide-field neurons change during flight, and that these effects are mimicked by the neuromodulator octopamine. Genetically silencing wide-field neurons increased behavioral responses to slow-motion stimuli. Together, these findings identify a cell type that is gated by behavior to enhance neural coding by subtracting low-frequency signals from the inputs to motion detection circuits.

Nasal deposition of ciclesonide nasal aerosol and mometasone aqueous nasal spray in allergic rhinitis patients.

BACKGROUND: Sensory attributes of intranasal corticosteroids, such as rundown to the back of the throat, may influence patient treatment preferences. This study compares the nasal deposition and nasal retention of a radiolabeled solution of ciclesonide nasal aerosol (CIC-hydrofluoroalkane [HFA]) with a radiolabeled suspension of mometasone furoate monohydrate aqueous nasal spray (MFNS) in subjects with either perennial allergic rhinitis (AR) or seasonal AR. METHODS: In this open-label, single-dose, randomized, crossover scintigraphy study, 14 subjects with symptomatic AR received a single dose of radiolabeled 74-µg CIC-HFA (37 µg/spray, 1 spray/each nostril) via a nasal metered-dose inhaler or a single dose of radiolabeled 200-µg MFNS (50 µg/spray, 2 sprays/each nostril), with a minimum 5-day washout period between treatments. Initial deposition (2 minutes postdose) of radiolabeled CIC-HFA and MFNS in the nasal cavity, nasopharynx, and on nasal wipes, and retention of radioactivity in the nasal cavity and nasal run-out on nasal wipes at 2, 4, 6, 8, and 10 minutes postdose were quantified with scintigraphy. RESULTS: At 2 and 10 minutes postdose, deposition of radiolabeled CIC-HFA was significantly higher in the nasal cavity versus radiolabeled MFNS (99.42% versus 86.50% at 2 minutes, p = 0.0046; and 81.10% versus 54.31% at 10 minutes, p < 0.0001, respectively; p values unadjusted for multiplicity). Deposition of radioactivity on nasal wipes was significantly higher with MFNS versus CIC-HFA at all five time points, and posterior losses of radiolabeled formulation were significantly higher with MFNS at 6, 8, and 10 minutes postdose. CONCLUSION: In this scintigraphic study, significantly higher nasal deposition and retention of radiolabeled aerosol CIC-HFA were observed versus radiolabeled aqueous MFNS in subjects with AR.

[Effect of course intake of bio-active flavonoids-containing plant preparation Extralife on the level of anxiety and sensorimotor reactivity in rats].

Clinical and epidemiological data evidence the need to search for new substances for treatment and prevention of increased anxiety associated with emotional and neurotic breakdown and worsening clinical prognosis of psychosomatic diseases. Of particular interest are the drugs of plant origin, which are generally well tolerated under prolonged use, and treat- ment is cheaper as compared with modem anxiolytics. The purpose of this study was to investigate the effects of course taking a flavonoid-containing plant preparation Extralife (water-soluble extract Pentaphylloides fruticosa, 40 mg/kg per day for 1 month) in <> and <> inbred albino rats sampled in the population using a multi-parameter method for evaluating anxiety-phobic states. This method was also used for evaluating the severity of anxiety (state anxiety) in rats in the dynamics of the survey. Sensorimotor reactivity (emotionality) was assessed by the parameters of the acoustic startle response. Extralife did not prevent the increase in state anxiety in <> rats and did not change the level of anxiety in the <> animals. However, the drug reduced the amplitude of the acoustic startle response in the <> animals and increased startle response latency in both <> and <> rats, that is reduced the symptoms of anxiety caused by alarm sound stimuli in terms of sensorimotor reactivity. The data testify to the anxiolytic and sedative effects of Extralife more pronounced in the <> animals. In a course intake of Extralife <> rats demonstrated transient decrease in the pre-pulse inhibition of the acoustic startle response, probably associated with the occurrence of transient disturbances in the psycho-emotional sphere. The findings suggest that Extralife in a course taking may have negative side effects on the emotionality of animals that determines the need to incorporate the features of mental and emotional status of the individual in the development of therapeutic approaches to the correction of high anxiety with the inclusion of the drug.

Children with heavy prenatal alcohol exposure experience reduced control of isotonic force.

BACKGROUND: Heavy prenatal alcohol exposure can result in diverse and extensive damage to the central nervous system, including the cerebellum, basal ganglia, and cerebral cortex. Given that these brain regions are involved in the generation and maintenance of motor force, we predicted that prenatal alcohol exposure would adversely affect this parameter of motor control. We previously reported that children with gestational alcohol exposure experience significant deficits in regulating isometric (i.e., constant) force. The purpose of this study was to determine whether these children exhibit similar deficits when producing isotonic (i.e., graded) force. METHODS: Children with heavy prenatal alcohol exposure and typically developing children completed a series of isotonic force contractions by exerting force on a load cell to match a criterion target force displayed on a computer monitor. Two levels of target force (5 or 20% of maximum voluntary force) were investigated in combination with varying levels of visual feedback. RESULTS: Compared with control children, children with heavy prenatal alcohol exposure generated isotonic force signals that were less accurate, more variable, and less complex in the time domain. Specifically, interactions were found between group and visual feedback for response accuracy and signal complexity, suggesting that these children have greater difficulty altering their motor output when visual feedback is low. CONCLUSIONS: These data suggest that prenatal alcohol exposure produces deficits in regulating isotonic force, which presumably result from alcohol-related damage to developing brain regions involved in motor control. These children will most likely experience difficulty performing basic motor skills and daily functional skills that require coordination of finely graded force. Therapeutic strategies designed to increase feedback and, consequently, facilitate visual-motor integration could improve isotonic force production in these children.

The impact of oxytocin administration and maternal love withdrawal on event-related potential (ERP) responses to emotional faces with performance feedback.

This is the first experimental study on the effect of oxytocin administration on the neural processing of facial stimuli conducted with female participants that uses event-related potentials (ERPs). Using a double-blind, placebo-controlled within-subjects design, we studied the effects of 16 IU of intranasal oxytocin on ERPs to pictures combining performance feedback with emotional facial expressions in 48 female undergraduate students. Participants also reported on the amount of love withdrawal they experienced from their mothers. Vertex positive potential (VPP) and late positive potential (LPP) amplitudes were more positive after oxytocin compared to placebo administration. This suggests that oxytocin increased attention to the feedback stimuli (LPP) and enhanced the processing of emotional faces (VPP). Oxytocin heightened processing of the happy and disgusted faces primarily for those reporting less love withdrawal. Significant associations with LPP amplitude suggest that more maternal love withdrawal relates to the allocation of attention toward the motivationally relevant combination of negative feedback with a disgusted face.

[Copper nanoparticles as modulators of apoptosis and structural changes in some organs].

The effect of repeated intramuscular injection into the organism of copper nanoparticles (CNP) with the diameter of 103 nm on the index of cell readiness to apoptosis and the structure of liver, spleen, kidney, as well as sensomotor cerebral cortex, was studied in 78 male Wistar rats. CNP were injected once per week for 12 weeks. The organs were studied using histological, immunohistochemical and morphometric methods. It was found that after the injections, CNP were distributed into organs and tissues of animals causing structural changes that were specific for eaach tissue. Toxicity of CNP in respect to microgliocytes was demonstrated at a dose of 2 mg/kg, hepatotoxicity and nephrotoxicity--at 6 mg/kg. The increase of CNP load on the organism up to toxic threshold (maximum tolerated dose) resulted in the appearance of signs of dystrophy and tissue necrosis. The data obtained suggest the application of an index of cell readiness to apoptosis, as assessed by caspase 3 expression, as a criterion for evaluation of CNP injection safety.

Dysregulation of D2-mediated dopamine transmission in monkeys after chronic escalating methamphetamine exposure.

Compulsive drug-seeking and drug-taking are important substance-abuse behaviors that have been linked to alterations in dopaminergic neurotransmission and to impaired inhibitory control. Evidence supports the notions that abnormal D2 receptor-mediated dopamine transmission and inhibitory control may be heritable risk factors for addictions, and that they also reflect drug-induced neuroadaptations. To provide a mechanistic explanation for the drug-induced emergence of inhibitory-control deficits, this study examined how a chronic, escalating-dose regimen of methamphetamine administration affected dopaminergic neurochemistry and cognition in monkeys. Dopamine D2-like receptor and dopamine transporter (DAT) availability and reversal-learning performance were measured before and after exposure to methamphetamine (or saline), and brain dopamine levels were assayed at the conclusion of the study. Exposure to methamphetamine reduced dopamine D2-like receptor and DAT availability and produced transient, selective impairments in the reversal of a stimulus-outcome association. Furthermore, individual differences in the change in D2-like receptor availability in the striatum were related to the change in response to positive feedback. These data provide evidence that chronic, escalating-dose methamphetamine administration alters the dopamine system in a manner similar to that observed in methamphetamine-dependent humans. They also implicate alterations in positive-feedback sensitivity associated with D2-like receptor dysfunction as the mechanism by which inhibitory control deficits emerge in stimulant-dependent individuals. Finally, a significant degree of neurochemical and behavioral variation in response to methamphetamine was detected, indicating that individual differences affect the degree to which drugs of abuse alter these processes. Identification of these factors ultimately may assist in the development of individualized treatments for substance dependence.

Sensory feedback modulates quipazine-induced stepping behavior in the newborn rat.

Research has shown that sensory feedback modulates locomotor behavior in intact as well as spinal adult animals. Here we examined if locomotor activity ("stepping") in newborn rats is influenced by cutaneous and proprioceptive feedback. One-day-old rats were treated with the serotonergic receptor agonist quipazine (3.0mg/kg) to induce air-stepping behavior or with saline (vehicle control). During stepping, a substrate/floor (elastic, stiff, or none) was placed beneath their limbs so that the feet could make plantar surface contact with a substrate. Pups treated with quipazine showed significantly more alternated fore- and hindlimb steps and plantar paw contact with the substrate, compared to pups treated with saline. Pups also made proportionately less contact with the stiff substrate versus the elastic substrate during stepping. Different types of movements made on the substrate (paw pushes, taps, swipes, and stances) were also characterized. These results indicate that sensory feedback modulates locomotor mechanisms and behavior in perinatal rats.