Mechanizmy uzależnienia od analgetyków opioidowych

Opioid addiction (opioid use disorder) is a chronic, relapsing disease of brain. Opioids induced persisting changes at the cellular and molecular levels resulted in dysregulation and remodeling of the reward system. These changes depend on genetic and environmental factors. Therapy of opioid addiction is limited and require both pharmacological therapy and psychotherapy. Understanding the neurobiological mechanisms of opioid addiction is essential for a better treatment of this disease.Uzależnienie opioidowe (zaburzenie używania opioidów) jest przewlekłą i nawracającą chorobą ośrodko­wego układu nerwowego. Opioidy wywołują w mózgu utrzymujące się zmiany na poziomie komórkowym i molekularnym, co prowadzi do zaburzenia równowagi i strukturalnego przebudowania układu nagrody. Możliwości leczenia uzależnienia opioidowego są ograniczone i wymagają kompleksowej terapii zarówno farmakologicznej, jak i psychoterapeutycznej. Poznanie neurobiologicznych mechanizmów leżących u pod­staw uzależnienia opioidowego ma zasadnicze znaczenie dla lepszego zrozumienia i leczenia tej choroby

PSDRS, BDI, MoCA and MMSE as screening tools for the evaluation of mood and cognitive functions in patients at the early stage of cerebral stroke

Aims. To evaluate the suitability of the Post-Stroke Depression Scale (PSDRS) for detecting affective disorders, to examine the correlation of depressed mood states with cognitive disorders in patients at an early stage of cerebral stroke, and to attempt a comparison of the effectiveness of detecting depressive and cognitive disorders with the selected clinical scales. Material and methods. The examination involved 43 patients within the first week after cerebral stroke. It was carried out with the application of two screening scales, the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), and two scales for the evaluation of the degree of depressiveness: PSDRS and Beck Depression Inventory (BDI). Results. A significant negative correlation of the results of the PSDRS and MoCA scales was shown. Depressed mood in patients post-cerebral stroke was statistically significantly correlated with the disorders in selected cognitive skills: visual and spatial functions, memory, attention functions and abstracting ability. Conclusions. The PSDRS and MoCA scales proved to be more effective tools for the evaluation of depressive and cognitive disorders in patients at an early stage after cerebral stroke than the conventionally applied MMSE and BDI scales. The examination results additionally show a significant dependence between mood and the cognitive impairment in this group of patients. With the weakening of cognitive functioning, the patients’ mood also became depressed

GABA-A receptor genes do not play a role in genetics of Lesch's typology in Caucasian subjects

Lesch's typology differentiates alcoholics into different treatment response subgroups. The effects of ethanol are mediated, to an important extent, via the GABA-ergic system. We have evaluated the linkage disequilibrium patterns and haplotype frequencies of GABRG1 and GABRA2 genes in 133 alcoholics divided according to Lesch's typology and in 145 matched controls. Besides several relationships at a threshold of statistical significance, we found no significant differences in the haplotype distribution of these genes between alcoholics and controls. Lesch's typology may not be related with the genotype of alcoholics – at least in terms of genes with an established role in the development of dependency

Zastosowanie Testu Łączenia Punktów do oceny elastyczności poznawczej u chorych z zaburzeniami mowy po udarze mózgu

Nadrzędnym celem pracy było określenie poziomu elastyczności poznawczej za pomocą Testu Łączenia Punktów (Trail Making Test, TMT) u chorych z zaburzeniami mowy po udarze mózgu. Badaniem objęto 43 chorych (18 kobiet oraz 25 mężczyzn) z niedokrwiennym udarem mózgu. Badanych przydzielono do trzech grup w zależności od rodzaju zaburzenia mowy: chorych z afazją, brakiem afazji i dyzartrią. Do oceny ogólnej sprawności funkcji poznawczych zastosowano Krótką Skalę Oceny Stanu Psychicznego (Mini-Mental State Examination, MMSE) oraz Test Rysowania Zegara (Clock Drawing Test, CDT). Elastyczność poznawcza była badana przy użyciu Testu Łączenia Punktów. Uzyskane wyniki wykazały, że chorzy z afazją wykazują najniższy poziom elastyczności poznawczej. Zaburzenia elastyczności poznawczej mogą być związane z dysfunkcją kory przedczołowej, która uległa uszkodzeniu w wyniku niedokrwiennego udaru mózgu. Przypuszczalnie dla umiejętności językowych i komponentów funkcji wykonawczych istnieją wspólne neuroanatomiczne obwody funkcjonalne. Stąd w przypadku uszkodzenia kluczowych dla obu zdolności struktur dysfunkcje językowe i wykonawcze mogą występować paralelnie. Współwystępowanie deficytów poznawczych u chorych z afazją może dodatkowo utrudniać funkcjonowanie chorego, a także mieć negatywny wpływ na proces rehabilitacji sprawności porozumiewania się.The main aim of this study was to evaluate the level of cognitive flexibility in patients with speech disorders after ischaemic cerebral stroke. The study was conducted in a group of 43 patients (18 women and 25 men) who had experienced cerebral ischaemic stroke. The patients under study were divided into groups based on the type of speech disorders, i.e.: aphasia, lack of speech disorders and dysarthria. A Mini-Mental State Examination (MMSE) and a Clock Drawing Test (CDT) were applied for the general evaluation of the efficiency of cognitive functions. Cognitive flexibility – a component of executive functions, was evaluated with the use of a Trail Making Test (TMT). The results obtained prove that patients with aphasia show the lowest level of cognitive flexibility. Disorders of executive functions can be related to the dysfunction of the prefrontal cortex which has been damaged as a result of ischaemic cerebral stroke. Presumably, there are common functional neuroanatomical circuits for both language skills and components of executive functions. In the case of damage to the structures that are of key importance for both skills, language and executive dysfunctions can therefore occur in parallel. The presence of executive dysfunctions in patients with aphasia can additionally impede the functioning of the patient, and also negatively influence the process of rehabilitation the aim of which is to improve the efficiency of communication

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 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

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 (AR) 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) anaesthetized 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

Alpha1_{1}-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 cocainereinforced 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 echanism. 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 erting/orienting functions, originating from bottom-up information processing to guide behaviors

The dissection of transcriptional modules regulated by various drugs of abuse in the mouse striatum

BACKGROUND: Various drugs of abuse activate intracellular pathways in the brain reward system. These pathways regulate the expression of genes that are essential to the development of addiction. To reveal genes common and distinct for different classes of drugs of abuse, we compared the effects of nicotine, ethanol, cocaine, morphine, heroin and methamphetamine on gene expression profiles in the mouse striatum. RESULTS: We applied whole-genome microarray profiling to evaluate detailed time-courses (1, 2, 4 and 8 hours) of transcriptome alterations following acute drug administration in mice. We identified 42 drug-responsive genes that were segregated into two main transcriptional modules. The first module consisted of activity-dependent transcripts (including Fos and Npas4), which are induced by psychostimulants and opioids. The second group of genes (including Fkbp5 and S3-12), which are controlled, in part, by the release of steroid hormones, was strongly activated by ethanol and opioids. Using pharmacological tools, we were able to inhibit the induction of particular modules of drug-related genomic profiles. We selected a subset of genes for validation by in situ hybridization and quantitative PCR. We also showed that knockdown of the drug-responsive genes Sgk1 and Tsc22d3 resulted in alterations to dendritic spines in mice, possibly reflecting an altered potential for plastic changes. CONCLUSIONS: Our study identified modules of drug-induced genes that share functional relationships. These genes may play a critical role in the early stages of addiction