Optogenetic and chemogenetic approaches reveal differences in neuronal circuits that mediate initiation and maintenance of social interaction.

For social interaction to be successful, two conditions must be met: the motivation to initiate it and the ability to maintain it. This study uses both optogenetic and chemogenetic approaches to reveal the specific neural pathways that selectively influence those two social interaction components.

Brain state-dependent responses of midbrain dopaminergic neurons to footshock under urethane anaesthesia.

For a long time, it has been assumed that dopaminergic (DA) neurons in both the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc) uniformly respond to rewarding and aversive stimuli by either increasing or decreasing their activity, respectively. This response was believed to signal information about the perceived stimuli's values. The identification of VTA&SNc DA neurons that are excited by both rewarding and aversive stimuli has led to the categorisation of VTA&SNc DA neurons into two subpopulations: one signalling the value and the other signalling the salience of the stimuli. It has been shown that the general state of the brain can modulate the electrical activity of VTA&SNc DA neurons, but it remains unknown whether this factor may also influence responses to aversive stimuli, such as a footshock (FS). To address this question, we have recorded the responses of VTA&SNc DA neurons to FSs across cortical activation and slow wave activity brain states in urethane-anaesthetised rats. Adding to the knowledge of aversion signalling by midbrain DA neurons, we report that significant proportion of VTA&SNc DA neurons can change their responses to an aversive stimulus in a brain state-dependent manner. The majority of these neurons decreased their activity in response to FS during cortical activation but switched to increasing it during slow wave activity. It can be hypothesised that this subpopulation of DA neurons may be involved in the 'dual signalling' of both the value and the salience of the stimuli, depending on the general state of the brain.

Acute stress modulates noradrenergic signaling in the ventral tegmental area-amygdalar circuit.

Noradrenergic neurotransmission is a critical mediator of stress responses. In turn, exposure to stress induces noradrenergic system adaptations, some of which are implicated in the etiology of stress-related disorders. Adrenergic receptors (ARs) in the ventral tegmental area (VTA) have been demonstrated to regulate phasic dopamine (DA) release in the forebrain, necessary for behavioral responses to conditional cues. However, the impact of stress on noradrenergic modulation of the VTA has not been previously explored. We demonstrate that ARs in the VTA regulate dopaminergic activity in the VTA-BLA (basolateral amygdala) circuit, a key system for processing stress-related stimuli; and that such control is altered by acute stress. We utilized fast-scan cyclic voltammetry to assess the effects of intra-VTA microinfusion of α1 -AR and α2 -AR antagonists (terazosin and RX-821002, respectively), on electrically evoked phasic DA release in the BLA in stress-naïve and stressed (unavoidable electric shocks - UES) anesthetized male Sprague-Dawley rats. In addition, we used western blotting to explore UES-induced alterations in AR protein level in the VTA. Intra-VTA terazosin or RX-821002 dose-dependently attenuated DA release in the BLA. Interestingly, UES decreased the effects of intra-VTA α2 -AR blockade on DA release (24 h but not 7 days after stress), while the effects of terazosin were unchanged. Despite changes in α2 -AR physiological function in the VTA, UES did not alter α2 -AR protein levels in either intracellular or membrane fractions. These findings demonstrate that NA-ergic modulation of the VTA-BLA circuit undergoes significant alterations in response to acute stress, with α2 -AR signaling indicated as a key target.

Recruitment of inhibitory neuronal pathways regulating dopaminergic activity for the control of cocaine seeking.

Drug seeking is associated with the ventral tegmental area (VTA) dopaminergic (DA) activity. Previously, we have shown that brief optogenetic inhibition of VTA DA neurons with 1 s pulses delivered every 9 s attenuates cocaine seeking under extinction conditions in rats without producing overt signs of dysphoria or locomotor sedation. Whether recruitment of neuronal pathways inhibiting VTA neuronal activity would suppress drug seeking remains unknown. Here, we asked if optogenetic stimulation of the lateral habenula (LHb) efferents in the rostromedial tegmental nucleus (RMTg) as well as RMTg efferents in VTA would reduce drug seeking. To investigate this, we measured how recruitment of elements of this inhibitory pathway affects cocaine seeking in male rats under extinction conditions. The effectiveness of brief optogenetic manipulations was confirmed electrophysiologically at the level of electrical activity of VTA DA neurons. Real-time conditioned place aversion (RT-CPA) and open field tests were performed to control for potential dysphoric/sedating effects of brief optogenetic stimulation of LHb-RMTg-VTA circuitry. Optogenetic stimulation of either RMTg or LHb inhibited VTA DAergic neuron firing, whereas similar stimulation of RMTg efferents in VTA or LHb efferents in RMTg reduced cocaine seeking under extinction conditions. Moreover, stimulation of LHb-RMTg efferents produced an effect that was maintained 24 h later, during cocaine seeking test without stimulation. This effect was specific, as brief optogenetic stimulation did not affect locomotor activity and was not aversive. Our results indicate that defined inhibitory pathways can be recruited to inhibit cocaine seeking, providing potential new targets for non-pharmacological treatment of drug craving.

Differential regulation of phasic dopamine release in the forebrain by the VTA noradrenergic receptor signaling.

Phasic dopamine (DA) release from the ventral tegmental area (VTA) into forebrain structures is implicated in associative learning and conditional stimulus (CS)-evoked behavioral responses. Mounting evidence points to noradrenaline signaling in the VTA as an important regulatory input. Accordingly, adrenergic receptor (AR) blockade in the VTA has been shown to modulate CS-dependent behaviors. Here, we hypothesized that α1 - and α2 -AR (but not ß-AR) activity preferentially modulates phasic, in contrast to tonic, DA release. In addition, these effects could differ between forebrain targets. We used fast-scan cyclic voltammetric measurements in rats to assess the effects of intra-VTA microinfusion of terazosin, a selective α1 -AR antagonist, on electrically evoked phasic DA release in the nucleus accumbens (NAc) core and medial prefrontal cortex (mPFC). Terazosin dose-dependently attenuated phasic, but not tonic, DA release in the NAc core, but not in the mPFC. Next, we measured the effects of intra-VTA administration of the α2 -AR selective antagonist RX-821002 on evoked DA in the NAc core. Similar to the effects of α1 -AR blockade, intra-VTA α2 -AR blockade with RX-0821002 strongly and dose-dependently attenuated phasic, but not tonic, DA release. In contrast, no regulation by RX-821002 was observed in the mPFC. This effect was sensitive to intra-VTA blockade of D2 receptors with raclopride. Finally, the ß-AR antagonist propranolol ineffectively modulated DA release in the NAc core. These findings revealed both α1 - and α2 -ARs in the VTA as selective regulators of phasic DA release. Importantly, we demonstrated that AR blockade modulated mesolimbic, in contrast to mesocortical, DA release in previously unstudied heterogeneity in AR regulation of forebrain phasic DA.

Novel and effective arthroscopic extracapsular stabilization technique for anterior shoulder instability-BLS.

PURPOSE: Arthroscopic Bankart repair for the treatment of anterior shoulder instability is associated with a high rate of recurrent instability. Extracapsular stabilization of the glenohumeral joint with enhancement of anterior wall soft tissues may be an effective alternative treatment technique. The aim of this study is to retrospectively assess clinical outcomes in the treatment of anterior shoulder instability using a novel technique of anterior extracapsular stabilization-"between glenohumeral ligaments and subscapularis tendon" (BLS). METHODS: Patients with anterior shoulder instability who underwent surgical treatment with a novel arthroscopic BLS technique between 2008 and 2016 were eligible for inclusion. According to the level of glenoid bone loss, patients were separated into four groups. Group 1 comprised patients with GBL equal to or less than 5%, group 2 patients with GBL 6-10%, group 3 patients with GBL 11-15%, and group 4 patients with GBL > 15%. A positive outcome in this study was defined as full restoration of joint stability. To evaluate clinical results, preoperative range of ER and IR measured in 90 degrees of abduction were compared with ER and IR measured at final follow-up. Additional outcome instruments used consisted of the Constant Score and the Walch-Duplay Score. RESULTS: A total of 150 patients underwent arthroscopic BLS surgery. During the study period, 50 patients were lost to follow-up and 100 patients were available for final analysis. Mean patient age was 27.5 (± 10.3) years at the time of surgery. Mean duration of follow-up was 82.9 (± 29.4) months. At final assessment, 86 patients (86%) were categorized as having a positive outcome, with full restoration of joint stability. Recurrence of shoulder instability was observed in 14 (14%) patients, including 6 (6%) cases that were associated with major trauma. At final follow-up, the mean Constant Score was 88.2 ± 10.1, compared to 82.9 ± 9.1 preoperatively (p < 0.05). The mean final and mean preoperative Walch-Duplay Scores were 81.5 ± 18.9 and 52.2 ± 11.9, respectively (p < 0.05). There was no statistically significant limitation of external or internal rotation. CONCLUSIONS: The BLS technique has been shown to be an effective method to anterior shoulder instability in patients without significant glenoid bone loss. It was shown that this technique provides significant improvement in shoulder function without reducing shoulder range of motion. LEVEL OF EVIDENCE: IV.

Noradrenergic signaling in the VTA modulates cocaine craving.

Exposure to drug-associated cues evokes drug-seeking behavior and is regarded as a major cause of relapse. Conditional stimulus upregulates noradrenaline (NA) system activity, but the drug-seeking behavior depends particularly on phasic dopamine signaling downstream from the ventral tegmental area (VTA). The VTA dopamine-ergic activity is regulated via the signaling of alpha1 -adrenergic and alpha2 -adrenergic receptors (α1 -ARs and α2 -ARs); thus, the impact of the conditional stimulus on drug-seeking behavior might involve NAergic signaling in the VTA. To date, the role of VTA ARs in regulating cocaine seeking was not studied. We found that cocaine seeking under extinction conditions in male Sprague-Dawley rats was attenuated by intra-VTA prazosin or terazosin-two selective α1 -AR antagonists. In contrast, cocaine seeking was facilitated by intra-VTA administration of the selective α1 -AR agonist phenylephrine as well as α2 -AR antagonist RX 821002, whereas the selective ß-AR antagonist propranolol had no effects. In addition, blockade of α1 -AR in the VTA prevented α2 -AR antagonist-induced enhancement of cocaine seeking. Importantly, the potential non-specific effects of the VTA AR blockade on cocaine seeking could be excluded, because none of the AR antagonists influenced sucrose seeking under extinction conditions or locomotor activity in the open field test. These results demonstrate that NAergic signaling potently and selectively regulates cocaine seeking during early cocaine withdrawal via VTA α1 -AR and α2 -AR but not ß-AR. Our findings provide new insight into the NAergic mechanisms that underlie cocaine craving.

Results of arthroscopic treatment of rotator cuff tear with the resection of symptomatic acromioclavicular joint with degenerative changes.

BACKGROUND: Rotator cuff (RC) tear is one of the most common disorders affecting the shoulder. Acromioclavicular (AC) joint arthritis is an equally common pathology of the shoulder. The coexistence of both disorders is common, although RC tear is more frequently the cause of shoulder pain than AC joint arthritis. The purpose of this study was to compare the results of arthroscopic treatment of RC tear and simultaneous resection of symptomatic AC joint with arthritis. MATERIAL/METHODS: We retrospectively evaluated 40 patients who underwent arthroscopic RC repair between January 2008 and December 2009. Patients were divided into two groups. The first group consisted of 20 patients with symptomatic arthritis of AC joint, specifically painful joint palpation test and painful cross-body adduction test. The control group included 20 patients with asymptomatic degenerative changes of AC joint. The first group of patients underwent RC resection and AC joint repair; the second group had an isolated RC repair. Follow-up period lasted from 44 to 68 months, an average of 54.4 months. RESULTS: Analysis using chi-squared test for independence has shown no statistically significant difference in terms of subjects' gender or age in both groups. No significant difference in terms of pain intensity (VAS) was observed before and after surgery in either group. Significant reduction in pain intensity after surgery was observed in both groups, the AC joint resection group (p<0.001) and the without joint resection group (p<0.001). An increase in Constant's scale score was recorded in both groups after the surgery. Analysis has shown that patients who had undergone AC joint resection, had lower scores on a Constant's scale (p<0.022) before the surgery than those who were not resected. There were no statistically significant differences between the two groups after the surgery. CONCLUSIONS: Supplementary resection of a painful AC joint with arthritis during RC tear repair provides good, long-term outcomes. In contrast to patients with asymptomatic AC joint arthritis, the coexistence of a torn RC and symptomatic AC joint with arthritis, can worsen shoulder function in the preoperative period.

Arm Function After Arthroscopic Decompression of the Suprascapular Nerve at the Spinoglenoid Notch and Suprascapular Notch in Volleyball Players.

Background: Suprascapular nerve (SSN) entrapment in volleyball players leads to infraspinatus (ISP) muscle atrophy and weakness of abduction and external rotation (ER) of the shoulder. Purpose: To assess functional outcome after arthroscopic extended decompression of SSN in the spinoglenoid notch and suprascapular notch in a group of volleyball athletes. Study Design: Case series; Level of evidence, 4. Methods: Volleyballers who underwent arthroscopic SSN decompression were analyzed retrospectively. Assessment tools consisted of range of motion and ER strength on Lovett scale and postoperative ER strength measured by dynamometer, Constant-Murley score (CMS), and visual evaluation of ISP muscle recovery by assessing muscle bulk. Results: The study included 10 patients (9 male and 1 female). The mean age was 25.9 years (range, 19-33) and mean follow-up was 77.9 months (range, 7-123). The mean range of postoperative ER at 90° of abduction (ER2) was 105.6° (88°-126°) and 108.5° (93°-124°) for the contralateral side, while ER2 strength was 8 ± 2.6 and 12.65 ± 2.8 kg (P < .01) respectively. Mean CMS was 89.9 (84-100). In 5 cases, there was complete recovery of ISP muscle atrophy whereas 2 patients had partial recovery and 3 had none. Conclusion: Arthroscopic SSN decompression in volleyball players improves shoulder function, but results of ISP recovery and ER strength are variable.

Return to Preinjury-Level Sports After Arthroscopic Latarjet for Recurrent Anterior Shoulder Instability in Professional Athletes.

Background: The Latarjet procedure is recommended to treat recurrent anterior shoulder instability with glenoid bone loss. Longer return-to-sport (RTS) times have been reported after the open Latarjet when compared with the arthroscopic Latarjet. Purpose: To assess the clinical outcomes and RTS in athletes who underwent an arthroscopic Latarjet. Study Design: Case series; Level of evidence, 4. Methods: This study included 46 professional athletes with recurrent anterior shoulder instability who underwent an arthroscopic Latarjet between 2010 and 2016. Patients were divided by type of sport: noncollision and nonoverhead (n = 22), collision and martial arts (n = 13), and overhead (n = 11). Sport activity was evaluated with the Kerlan-Jobe Orthopaedic Clinic (KJOC) score, Subjective Patient Outcome for Return to Sports score, and RTS time. Clinical results were evaluated by Constant-Murley score, Walch-Duplay score, and range of external and internal rotation. Complication rates, recurrence of shoulder instability, and number of revision procedures were recorded. Correlation tests were used to assess the relationship between measured parameters. Results: The mean ± SD patient age was 27.1 ± 7.3 years, and the mean follow-up was 50.7 ± 18 months. Overall, 44 patients (95.7%) returned to their previously practiced sports, and 40 (87%) returned to their preinjury levels. The RTS time was 5 ± 1.4 months, with no significant difference among sport types. KJOC and Subjective Patient Outcome for Return to Sports scores were 95.2 ± 5.6 and 9.5 ± 1, respectively. Significant pre- to postoperative improvement was seen on the Constant-Murley score (from 54.3 ± 9.4 to 87.9 ± 8.2; P = .001) and Walch-Duplay score (from 53.7 ± 7.3 to 88.1 ± 10.7; P = .001). Mean postoperative external and internal rotation was 72.8° ± 18.6° and 81.3° ± 11.3°. Procedure-related complications occurred in 10 patients (21.7%); recurrence of shoulder instability was observed in 4 (8.7%); and 4 (8.7%) underwent revision surgery. A worse Walch-Duplay score was significantly associated with longer RTS time (r = -0.39; P = .019) and lower KJOC score (r = 0.29; P = .03). Conclusion: There was a 95.7% RTS rate after the arthroscopic Latarjet procedure, although the procedure was not free from complications.

Glutamate input to noradrenergic neurons plays an essential role in the development of morphine dependence and psychomotor sensitization.

The brain's noradrenergic system is involved in the development of behaviours induced by drugs of abuse, e.g. dependence and withdrawal, and also reward or psychomotor effects. To investigate how noradrenergic system activity is controlled in the context associated with drug-induced behaviours, we generated a Cre/loxP mouse model in which the essential glutamate NMDA receptor subunit NR1 is ablated in cells expressing dopamine ß-hydroxylase (Dbh). As a result, the noradrenergic cells in NR1DbhCre mice lack the NMDA receptor-dependent component of excitatory post-synaptic currents. The mutant mice displayed no obvious behavioural alterations, had unchanged noradrenaline content and mild increase in dopamine levels in the nucleus accumbens. Interestingly, NR1DbhCre animals did not develop morphine-induced psychomotor sensitization. However, when the morphine injections were preceded by treatment with RX821002, an antagonist of α2-adrenergic receptors, the development of sensitization was restored. Conversely, pretreatment with clonidine, an agonist of α2-adrenergic receptors, blocked development of sensitization in wild-type mice. We also found that while the development of tolerance to morphine was normal in mutant mice, withdrawal symptoms were attenuated. These data reveal that NMDA receptors on noradrenergic neurons regulate development of opiate dependence and psychomotor sensitization, by controlling drug-induced noradrenaline signalling.

Arthroscopic Latarjet Procedure With 2-Screw Stabilization: Results of Treatment of 156 Cases with a Minimum of 2-Year Follow-Up. Multicenter Study.

BACKGROUND: Various arthroscopic stabilization procedures are associated with recurrence rates ranging from 10.8% to 21.1%. Recurrences occur especially in young male patients participating in contact sport activities. Bony defects of the humeral head and the glenoid predispose not only to subsequent dislocations but also to failure of surgical treatment. This is the group where "bony" procedures such as arthroscopic Latarjet are recommended to provide better stability as the primary treatment. MATERIAL AND METHODS: Patients with traumatic unidirectional anterior shoulder instability treated from 2009 to 2016 with an arthroscopic Latarjet procedure operated on in two centres. Clinical results, including range of motion, Subjective Shoulder Value and Walch-Duplay score, and postpoperative complications were evaluated. RESULTS: 156 patients were available for follow-up at a minimum of 2 years after surgery. The mean follow-up was 4318 months. Mean age at the time of surgery was 27.9 (16-53) years. At final follow-up, 8 cases of recurrent instability were identified, including 6 cases of recurrent dislocation and two cases of recurrent subluxation. Mean Walch-Duplay score increased from 3019 preoperatively to 8316 (p<0.05) at the last follow-up. An average loss of external rotation of 11.8 (0-70) (p<0.05) when compared with the contralateral shoulder was observed at the last follow-up. Mean Subjective Shoulder Value score was 92.89.4%. 8 (5%) patients presented with loss of shoulder stability. 25 (15.8%) patients reported subjective return to sport anxiety. Eleven (7%) patients complained of anterior compartment pain. The total number of revision surgeries was 14 (8.9%). CONCLUSIONS: 1. The arthroscopic Latarjet procedure can achieve satisfactory clinical outcomes for the treatment of anterior shoulder instability 2. The rate of complications and recurrence does not increase with time and is comparable at a minimum of 2 years follow-up to early results described in literature.

Optogenetic stimulation of medial prefrontal cortex excites GABAergic cells in the nucleus accumbens and hippocampus of Wistar-Kyoto rats exposed to chronic mild stress.

BACKGROUND: High frequency optogenetic stimulation (OGS) of prelimbic cortex (PLC) has been reported to exert antidepressant-like effects in the chronic mild stress model of depression in Wistar Kyoto (WKY) rats, which are non-responsive to antidepressant drugs. Here we have examined the effect of OGS on activity in the PLC and in two other regions implicated in depression, the nucleus accumbens (NAc) and hippocampus (HPC). METHOD: OGS was applied to the PLC of WKY rats using the same stress schedule, and the identical placement, virus infection and stimulation parameters, used in the earlier behavioural experiments. Confocal microscopy was used to identify cells co-expressing the immediate early gene c-Fos and markers of GABAergic (GAD) and glutamatergic (CaMKII) neurons. RESULTS: Stress decreased sucrose intake, which was restored by OGS. Stress also caused an overall decrease in Fos expression in the structures examined. In stressed animals, but not in non-stressed controls, OGS in mPFC increased the number of Fos+ cells in both the core and shell of the NAc (where the vast majority of cells are GABAergic), and increased the number and proportion of active GABAergic, but not glutamatergic, cells in dorsal and ventral HPC and dentate gyrus. CONCLUSIONS: We conclude that OGS of PLC has a net excitatory effect on outputs from the PLC, leading to an overall inhibitory effect in structures innervated (NAc and HPC).

Alpha1-adrenergic receptor blockade in the ventral tegmental area attenuates acquisition of cocaine-induced pavlovian associative learning.

Activity of the alpha1-adrenergic receptor (α1-AR) in the ventral tegmental area (VTA) modulates dopaminergic activity, implying its modulatory role in the behavioral functions of the dopamine (DA) system. Indeed, intra-VTA α1-AR blockade attenuates conditioned stimulus dependent behaviors such as drug seeking responses signifying a role of the noradrenergic signaling in the VTA in conditioned behaviors. Importantly, the role of the VTA α1-AR activity in Pavlovian associative learning with positive outcomes remains unknown. Here, we aimed to examine how intra-VTA α1-AR blockade affects acquisition of cocaine-induced Pavlovian associative learning in the conditioned place preference (CPP) paradigm. The impact of α1-AR blockade on cocaine-reinforced operant responding and cocaine-evoked ultrasonic vocalizations (USVs) was also studied. In addition, both α1-AR immunoreactivity in the VTA and its role in phasic DA release in the nucleus accumbens (NAc) were assessed. We demonstrated cellular localization of α1-AR expression in the VTA, providing a neuroanatomical substrate for the α1-AR mechanism. We showed that prazosin (α1-AR selective antagonist; 1 µg/0.5 µl) microinfusion attenuated electrically evoked DA transients in the NAc and dose-dependently (0.1-1 µg/0.5 µl) prevented the acquisition of cocaine CPP but did not affect cocaine-reinforced operant responding nor cocaine-induced positive affective state (measured as USVs). We propose that the VTA α1-AR signaling is necessary for the acquisition of Pavlovian associative learning but does not encode hedonic value. Thus, α1-AR signaling in the VTA might underlie salience encoding of environmental stimuli and reflect an ability of alerting/orienting functions, originating from bottom-up information processing to guide behaviors.

Regulation of cocaine seeking behavior by locus coeruleus noradrenergic activity in the ventral tegmental area is time- and contingency-dependent.

Substance use disorder is linked to impairments in the ventral tegmental area (VTA) dopamine (DA) reward system. Noradrenergic (NA) inputs from locus coeruleus (LC) into VTA have been shown to modulate VTA neuronal activity, and are implicated in psychostimulant effects. Phasic LC activity controls time- and context-sensitive processes: decision making, cognitive flexibility, motivation and attention. However, it is not yet known how such temporally-distinct LC activity contributes to cocaine seeking. In a previous study we demonstrated that pharmacological inhibition of NA signaling in VTA specifically attenuates cocaine-seeking. Here, we used virally-delivered opsins to target LC neurons for inhibition or excitation, delivered onto afferents in VTA of male rats seeking cocaine under extinction conditions. Optogenetic stimulation or inhibition was delivered in distinct conditions: upon active lever press, contingently with discreet cues; or non-contingently, i.e., throughout the cocaine seeking session. Non-contingent inhibition of LC noradrenergic terminals in VTA attenuated cocaine seeking under extinction conditions. In contrast, contingent inhibition increased, while contingent stimulation reduced cocaine seeking. These findings were specific for cocaine, but not natural reward (food) seeking. Our results show that NA release in VTA drives behavior depending on timing and contingency between stimuli - context, discreet conditioned cues and reinforcer availability. We show that, depending on those factors, noradrenergic signaling in VTA has opposing roles, either driving CS-induced drug seeking, or contributing to behavioral flexibility and thus extinction.

Effectiveness of conservative treatment of multidirectional instability of the shoulder joint. Literature review and meta-analysis.

<br><b>Introduction:</b> Multidirectional shoulder instability (MDI) occurs when the shoulder is dislocating in at least two directions. The patient usually experiences pain with apprehension and a clicking sensation inside the joint. So far, a few classification scales of shoulder instability have been made. Despite this fact, MDI is highly problematic for clinicians in diagnosis and treating.</br> <br><b>Aim:</b> This article presents the current trends in the conservative treatment of multidirectional instability, assess effectiveness of rehabilitation and indicates the directions of MDI research.</br> <br><b>Material and methods:</b> In order to find current literature and conduct a critical analysis, the following scientific database was used: Cochrane Library, Physiotherapy Evidence Database (PEDro), MEDLINE and PubMed. We chose four articles which included a comparison of conservative and operative treatment, and four which evaluate the effectiveness of rehabilitation.</br> <br><b>Results:</b> Low quality evidence shows priority of surgical treatment over conservative treatment. The protocol developed by Watson obtains a statistically significant advantage over the Burkhead and Rockwood protocol. Discussion: The effectiveness of rehabilitation reaches different levels. Rehabilitation should last from 3 to 12 months. If rehabilitation does not achieve a sufficient effect, arthroscopic methods of reducing the volume of the articular capsule should be considered. Due to the small number of scientific reports and their quality, the obtained data should be interpreted with caution. Much further research is required to create a precise and most effective algorithm.</br> <br><b>Conclusion:</b> Rehabilitation exercises play an important role in the treatment of multidirectional instability of the shoulder joint, especially when the patient has not had an injury. Exercise types and load should be dosed individually. At present, the protocol described by Watson is the most effective.</br>.

Insufficiency of ventral hippocampus to medial prefrontal cortex transmission explains antidepressant non-response.

BACKGROUND: There is extensive evidence that antidepressant drugs restore normal brain function by repairing damage to ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC). While the damage is more extensive in hippocampus, the evidence of treatments, such as deep brain stimulation, suggests that functional changes in prefrontal cortex may be more critical. We hypothesized that antidepressant non-response may result from an insufficiency of transmission from vHPC to mPFC. METHOD: Antidepressant non-responsive Wistar Kyoto (WKY) rats were subjected to chronic mild stress (CMS), then treated with chronic daily administration of the antidepressant drug venlafaxine (VEN) and/or repeated weekly optogenetic stimulation (OGS) of afferents to mPFC originating from vHPC or dorsal HPC (dHPC). RESULTS: As in many previous studies, CMS decreased sucrose intake, open-arm entries on the elevated plus maze (EPM), and novel object recognition (NOR). Neither VEN nor vHPC-mPFC OGS alone was effective in reversing the effects of CMS, but the combination of chronic VEN and repeated OGS restored normal behaviour on all three measures. dHPC-mPFC OGS restored normal behaviour in the EPM and NOR test irrespective of concomitant VEN treatment, and had no effect on sucrose intake. CONCLUSIONS: The synergism between VEN and vHPC-mPFC OGS supports the hypothesis that the antidepressant non-responsiveness of WKY rats results from a failure of antidepressant treatment fully to restore transmission in the vHPC-mPFC pathway.

AMPA receptors mediate the pro-cognitive effects of electrical and optogenetic stimulation of the medial prefrontal cortex in antidepressant non-responsive Wistar-Kyoto rats.

BACKGROUND: The chronic mild stress (CMS) procedure is a widely used animal model of depression, and its application in Wistar-Kyoto (WKY) rats has been validated as a model of antidepressant-refractory depression. While not responding to chronic treatment with antidepressant drugs, WKY rats do respond to acute deep brain stimulation (DBS) of the medial prefrontal cortex (mPFC). In antidepressant-responsive strains there is evidence suggesting a role for AMPA subtype of glutamate receptor in the action mechanism of both antidepressants and DBS. METHODS: Animals were subjected to CMS for 6 to 8 weeks; sucrose intake was monitored weekly and novel object recognition (NOR) test was conducted following recovery from CMS. Wistars were treated chronically with venlafaxine (VEN), while WKY were treated acutely with either DBS, optogenetic stimulation (OGS) of virally-transduced (AAV5-hSyn-ChR2-EYFP) mPFC or ventral hippocampus, or acute intra-mPFC injection of the AMPA receptor positive allosteric modulator CX-516. The AMPA receptor antagonist NBQX was administered, at identical sites in mPFC, immediately following the exposure trial in the NOR. RESULTS: Sucrose intake and NOR were suppressed by CMS, and restored by VEN in Wistars and by DBS, OGS, or CX-516 in WKY. However, OGS of the ventral hippocampal afferents to mPFC was ineffective. A low dose of NBQX selectively blocked the procognitive effect of VEN, DBS and OGS. CONCLUSIONS: These results suggest that activation of AMPA receptors in the mPFC represents a common pathway for the antidepressant effects of both conventional (VEN) and novel (DBS, OGS) antidepressant modalities, in both antidepressant responsive (Wistar) and antidepressant-resistant (WKY) rats.

Noradrenergic and corticosteroid receptors regulate somatic and motivational symptoms of morphine withdrawal.

Somatic and motivational symptoms accompanying opiate withdrawal are considered one of the major reasons for relapse to opiate-seeking and opiate-taking behaviors. These symptoms are accompanied by the activation of stress-related processes including hypothalamic-pituitary-adrenal axis activity and noradrenergic (NA) signaling. In particular, the NA system plays an important role in the expression of somatic signs of opiate withdrawal, whereas glucocorticoid (GR) and mineralocorticoid receptors (MR) are activated during opiate abstinence. The purpose of our study was to examine the roles of α1-, α2-, and ß-adrenoceptors (ARs) as well as GR and MR, in the formation and expression of physiological and motivational symptoms of morphine withdrawal. We showed that systemic pretreatment with the selective α1-AR antagonist prazosin (0-1 mg/kg), the selective α2-AR antagonist RX821002 (0-2 mg/kg), the selective ß-adrenergic antagonist, propranolol (0-10 mg/kg), or the selective MR antagonist spironolactone (0-50 mg/kg), but not the selective GR antagonist mifepristone (0-40 mg/kg), decreased somatic symptoms of naloxone-precipitated morphine withdrawal in mice chronically treated with morphine. In contrast, only propranolol pretreatment attenuated the dysphoric affective state accompanying naloxone-precipitated morphine withdrawal as assessed in the conditioned place aversion (N-CPA) paradigm. Together, our results demonstrate the important roles of noradrenergic receptors in the modulation of somatic, but not motivational/affective, symptoms of morphine withdrawal. In addition MR but not GR regulates the expression of only somatic symptoms of morphine withdrawal.

Alpha1-adrenergic receptor blockade in the ventral tegmental area modulates conditional stimulus-induced cocaine seeking.

Exposure to drug-associated cues evokes drug-craving and upregulates noradrenaline (NA) and dopamine (DA) system activity. Importantly, conditional stimulus-induced drug-seeking behavior depends particularly on phasic DA signaling downstream from the ventral tegmental area (VTA), a midbrain structure key for the regulation of cocaine seeking. In particular, the activity of the alpha1-adrenergic receptor (α1-AR), which has recently been hypothesized to modulate salience encoding, is capable of bidirectional regulation of VTA dopaminergic activity. Thus, the impact of the conditional stimuli (CSs) on drug-seeking behavior might involve α1-AR signaling in the VTA. To date, the role of VTA α1-ARs in regulating CS-induced cocaine seeking has not been studied. In male Sprague-Dawley rats, we found that intra-VTA terazosin, a selective α1-AR antagonist, attenuated CS-induced cocaine seeking in a novel context and under extinction conditions, as well as CS-induced reinstatement of cocaine seeking. In contrast, terazosin microinfusion in a dose that attenuated CS-induced cocaine seeking had no effects on CS-induced food seeking or stress (2 mg/kg yohimbine)-evoked reinstatement of cocaine seeking. The potential nonspecific effects (sedative, anxiogenic) of α1-AR blockade of the VTA were also measured in the open-field test. Finally, using immunostaining, we demonstrated dopamine ß-hydroxylase (DBH)-positive afferents in the VTA of cocaine-abstinent rats, providing a neuroanatomical substrate for the α1-AR mechanism. These results demonstrated for the first time that NAergic signaling via VTA α1-ARs potently and selectively regulates CS-induced cocaine seeking. Our findings provide new neuronal mechanisms that regulate cocaine craving.