| 1. |
- Domi, Ana, et al.
(författare)
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Pre- and postsynaptic signatures in the prelimbic cortex associated with "alcohol use disorder" in the rat
- 2024
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Ingår i: Neuropsychopharmacology. - : SPRINGERNATURE. - 0893-133X .- 1740-634X.
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Tidskriftsartikel (refereegranskat)abstract
- The transition to alcohol use disorder (AUD) involves persistent neuroadaptations in executive control functions primarily regulated by the medial prefrontal cortex. However, the neurophysiological correlates to behavioral manifestations of AUD are not fully defined. The association between cortical neuroadaptations and behavioral manifestations of addiction was studied using a multi-symptomatic operant model based on the DSM-5 diagnostic criteria for AUD. This model aimed to characterize an AUD-vulnerable and AUD-resistant subpopulation of outbred male Wistar rats and was combined with electrophysiological measurements in the prelimbic cortex (PL). Mirroring clinical observations, rats exhibited individual variability in their vulnerability to develop AUD-like behavior, including motivation to seek for alcohol (crit 1), increased effort to obtain the substance (crit 2), and continued drinking despite negative consequences (crit 3). Only a small subset of rats met all the aforementioned AUD criteria (3 crit, AUD-vulnerable), while a larger fraction was considered AUD-resilient (0 crit). The development of AUD-like behavior was characterized by disruptions in glutamatergic synaptic activity, involving decreased frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and heightened intrinsic excitability in layers 2/3 PL pyramidal neurons. These alterations were concomitant with a significant impairment in the ability of mGlu2/3 receptors to negatively regulate glutamate release in the PL but not in downstream regions like the basolateral amygdala or nucleus accumbens core. In conclusion alterations in PL synaptic activity were strongly associated with individual addiction scores, indicating their role as potential markers of the behavioral manifestations linked to AUD psychopathology.
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| 2. |
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| 3. |
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| 4. |
- Pietrzak, Michal, 1987-, et al.
(författare)
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Ghrelin decreases sensitivity to negative feedback and increases prediction-error related caudate activity in humans, a randomized controlled trial
- 2024
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Ingår i: Neuropsychopharmacology. - : Springer Science+Business Media B.V.. - 0893-133X .- 1740-634X. ; 49, s. 1042-1049
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Tidskriftsartikel (refereegranskat)abstract
- The stomach-derived hormone ghrelin plays not only a role in feeding, starvation, and survival, but it has been suggested to also be involved in the stress response, in neuropsychiatric conditions, and in alcohol and drug use disorders. Mechanisms related to reward processing might mediate ghrelin's broader effects on complex behaviors, as indicated by animal studies and mostly correlative human studies. Here, using a within-subject double-blind placebo-controlled design with intravenous ghrelin infusion in healthy volunteers (n = 30), we tested whether ghrelin alters sensitivity to reward and punishment in a reward learning task. Parameters were derived from a computational model of participants' task behavior. The reversal learning task with monetary rewards was performed during functional brain imaging to investigate ghrelin effects on brain signals related to reward prediction errors. Compared to placebo, ghrelin decreased punishment sensitivity (t = -2.448, p = 0.021), while reward sensitivity was unaltered (t = 0.8, p = 0.43). We furthermore found increased prediction-error related activity in the dorsal striatum during ghrelin administration (region of interest analysis: t-values >= 4.21, p-values <= 0.044). Our results support a role for ghrelin in reward processing that extends beyond food-related rewards. Reduced sensitivity to negative outcomes and increased processing of prediction errors may be beneficial for food foraging when hungry but could also relate to increased risk taking and impulsivity in the broader context of addictive behaviors.
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| 5. |
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| 6. |
- Augier, Gaëlle, et al.
(författare)
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Wistar rats choose alcohol over social interaction in a discrete-choice model
- 2023
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Ingår i: Neuropsychopharmacology. - : SPRINGERNATURE. - 0893-133X .- 1740-634X. ; 48, s. 1098-1107
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Tidskriftsartikel (refereegranskat)abstract
- Animal models of substance use disorders have been criticized for their limited translation. One important factor behind seeking and taking that has so far been largely overlooked is the availability of alternative non-drug rewards. We recently reported that only about 15% of outbred Wistar rats will choose alcohol over a sweet solution of saccharin. It was also shown using a novel operant model of choice of drugs over social rewards that social interaction consistently attenuates self-administration and incubation of craving for stimulants and opioids. Whether this is also true for alcohol and choice of alcohol over a sweet reward translates to social rewards is currently unknown. We therefore evaluated choice between alcohol and a social reward in different experimental settings in both male and female Wistar rats. We found, in contrast to prior work that employed discrete choice of drugs vs. social reward, that rats almost exclusively prefer alcohol over social interaction, irrespective of the nature of the social partner (cagemate vs. novel rat), the length of interaction, housing conditions and sex. Alcohol choice was reduced when the response requirement for alcohol was increased. However, rats persisted in choosing alcohol, even when the effort required to obtain it was 10-16 times higher (for females and males respectively) than the one for the social reward. Altogether, these results indicate that the social choice model may not generalize to alcohol, pointing to the possibility that specific interactions between alcohol and social reward, not seen when a sweet solution is used as an alternative to the drug, may play a crucial role in alcohol vs. social choice experiments.
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| 7. |
- de Wit, Harriet, et al.
(författare)
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Does acute stress play a role in the lasting therapeutic effects of psychedelic drugs?
- 2023
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Ingår i: Neuropsychopharmacology. - : SPRINGERNATURE. - 0893-133X .- 1740-634X. ; 48:10, s. 1422-1424
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Tidskriftsartikel (refereegranskat)abstract
- Psychedelic drugs, when used in the context of psychotherapy, can produce significant and long-lasting memories with enduring beneficial effects. Yet, the behavioral and neurobiological mechanisms that underlie these beneficial effects remain a mystery. Here, we suggest that both the quality and durability of memories of the drug-facilitated therapeutic experience may be mediated, in part, by the acute stress responses induced by the drugs. It is known that high doses of psychedelic drugs activate autonomic and hormonal stress responses. For evolutionarily adaptive reasons, acute stress is known to i) instill meaning to the immediate context in which it is experienced, and ii) lead to the formation of salient and lasting memories of the events surrounding the stress. Thus, the stress-inducing effect of psychedelic drugs may contribute to the reported sense of meaning, as well as the durability of the memory of the drug experience. When used in a therapeutic context these actions may i) enhance the salience of insights gained during the experience and ii) strengthen the memories formed by these experiences. Future empirical studies will help to determine whether acute stress contributes to the emotional significance and lasting effects of psychedelic-assisted psychotherapy.
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| 8. |
- Domi, Esi, et al.
(författare)
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Activation of GABA(B) receptors in central amygdala attenuates activity of PKC delta plus neurons and suppresses punishment-resistant alcohol self-administration in rats
- 2023
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Ingår i: Neuropsychopharmacology. - : SPRINGERNATURE. - 0893-133X .- 1740-634X. ; 48, s. 1386-1395
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol use despite negative consequences is a core phenomenon of alcohol addiction. We recently used alcohol self-administration that is resistant to footshock punishment as a model of this behavior, and found that activity of PKC delta + GABAergic neurons in the central amygdala (CeA) is a determinant of individual susceptibility for punishment resistance. In the present study, we examined whether activation of GABA(B) receptors in CeA can attenuate the activity of PKC delta + neurons in this region, and whether this will result in suppression of punishment- resistant alcohol self-administration in the minority of rats that show this behavior. Systemic administration of the clinically approved GABA(B) agonist baclofen (1 and 3 mg/kg) dose- dependently reduced punishment-resistant alcohol self-administration. Bilateral microinjections of baclofen into CeA (64 ng in 0.3 mu l/side) reduced the activity of PKC delta + neurons, as measured by Fos expression. This manipulation also selectively suppressed punished alcohol self-administration in punishment-resistant rats. Expression analysis indicated that virtually all CeA PKC delta + neurons express the GABA(B) receptor. Using in vitro electrophysiology, we found that baclofen induced hyperpolarization of CeA neurons, reducing their firing rate in response to depolarizing current injections. Together, our findings provide a potential mechanism that contributes to the clinical efficacy of baclofen in alcohol addiction. Therapeutic use of baclofen itself is limited by problems of tolerance and need for dose escalation. Our findings support a mechanistic rationale for developing novel, improved alcohol addiction medications that target GABA(B) receptors, and that lack these limitations, such as e.g., GABA(B) positive allosteric modulators (PAM:s).
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| 9. |
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| 10. |
- Lee, Mary R., et al.
(författare)
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Corticotropin-Releasing Factor receptor 1 (CRF1) antagonism in patients with alcohol use disorder and high anxiety levels: effect on neural response during Trier Social Stress Test video feedback
- 2023
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Ingår i: Neuropsychopharmacology. - : SPRINGERNATURE. - 0893-133X .- 1740-634X. ; 48:5, s. 816-820
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Tidskriftsartikel (refereegranskat)abstract
- In preclinical models of alcohol use disorder, the corticotropin-releasing factor (CRF) receptor is upregulated, particularly in the extended amygdala. This upregulation is thought to play a role in stress-induced relapse to drinking by a mechanism that is independent of the hypothalamic-pituitary-adrenal axis. As part of a double-blind, placebo-controlled clinical study with pexacerfont, a selective, orally available, and brain-penetrant CRF1 receptor antagonist which has anti-anxiety effects in preclinical studies, we examined the effect of pexacerfont on the neural response to a social stress task adapted to fMRI. Subjects were 39 individuals (4 women) with high trait anxiety and moderate to severe alcohol use disorder randomized to receive pexacerfont or placebo. The task involved feedback of videoclips of an individual performing the Trier Social Stress Test. Pexacerfont had no effect on the neural response to self-observation under stress. The neural response to viewing oneself under stress vs an unknown other under stress activated prefrontal brain regions including insula, inferior frontal gyrus as well as medial, superior frontal gyri. These regions of activation overlap with those found in studies using similar paradigms. Potential applications of this task to probe neurocircuitry that is disrupted in addiction is discussed.
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| 11. |
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| 12. |
- Sayalı, Ceyda, et al.
(författare)
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Methylphenidate undermines or enhances divergent creativity depending on baseline dopamine synthesis capacity
- 2023
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Ingår i: Neuropsychopharmacology. - : Springer Nature. - 0893-133X .- 1740-634X. ; 48:13, s. 1849-1858
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Tidskriftsartikel (refereegranskat)abstract
- Catecholamine-enhancing psychostimulants, such as methylphenidate have long been argued to undermine creative thinking. However, prior evidence for this is weak or contradictory, stemming from studies with small sample sizes that do not consider the well-established large variability in psychostimulant effects across different individuals and task demands. We aimed to definitively establish the link between psychostimulants and creative thinking by measuring effects of methylphenidate in 90 healthy participants on distinct creative tasks that measure convergent and divergent thinking, as a function of individuals’ baseline dopamine synthesis capacity, indexed with 18F-FDOPA PET imaging. In a double-blind, within-subject design, participants were administered methylphenidate, placebo or selective D2 receptor antagonist sulpiride. The results showed that striatal dopamine synthesis capacity and/or methylphenidate administration did not affect divergent and convergent thinking. However, exploratory analysis demonstrated a baseline dopamine-dependent effect of methylphenidate on a measure of response divergence, a creativity measure that measures response variability. Response divergence was reduced by methylphenidate in participants with low dopamine synthesis capacity but enhanced in those with high dopamine synthesis capacity. No evidence of any effect of sulpiride was found. These results show that methylphenidate can undermine certain forms of divergent creativity but only in individuals with low baseline dopamine levels.
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| 13. |
- Vazquez-Juarez, Erika, et al.
(författare)
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The effect of ketamine on synaptic mistuning induced by impaired glutamate reuptake
- 2023
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Ingår i: Neuropsychopharmacology. - : Springer Nature. - 0893-133X .- 1740-634X. ; 48:13, s. 1859-1868
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Tidskriftsartikel (refereegranskat)abstract
- Mistuning of synaptic transmission has been proposed to underlie many psychiatric disorders, with decreased reuptake of the excitatory neurotransmitter glutamate as one contributing factor. Synaptic tuning occurs through several diverging and converging forms of plasticity. By recording evoked field postsynaptic potentials in the CA1 area in hippocampal slices, we found that inhibiting glutamate transporters using DL-TBOA causes retuning of synaptic transmission, resulting in a new steady state with reduced synaptic strength and a lower threshold for inducing long-term synaptic potentiation (LTP). Moreover, a similar reduced threshold for LTP was observed in a rat model of depression with decreased levels of glutamate transporters. Most importantly, we found that the antidepressant ketamine counteracts the effects of increased glutamate on the various steps involved in synaptic retuning. We, therefore, propose that ketamine's mechanism of action as an antidepressant is to restore adequate synaptic tuning.
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| 14. |
- Adermark, Louise, 1974, et al.
(författare)
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Astrocytes modulate extracellular neurotransmitter levels and excitatory neurotransmission in dorsolateral striatum via dopamine D2 receptor signaling
- 2022
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Ingår i: Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 0893-133X .- 1740-634X. ; 47:8, s. 1493-1502
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Tidskriftsartikel (refereegranskat)abstract
- Astrocytes provide structural and metabolic support of neuronal tissue, but may also be involved in shaping synaptic output. To further define the role of striatal astrocytes in modulating neurotransmission we performed in vivo microdialysis and ex vivo slice electrophysiology combined with metabolic, chemogenetic, and pharmacological approaches. Microdialysis recordings revealed that intrastriatal perfusion of the metabolic uncoupler fluorocitrate (FC) produced a robust increase in extracellular glutamate levels, with a parallel and progressive decline in glutamine. In addition, FC significantly increased the microdialysate concentrations of dopamine and taurine, but did not modulate the extracellular levels of glycine or serine. Despite the increase in glutamate levels, ex vivo electrophysiology demonstrated a reduced excitability of striatal neurons in response to FC. The decrease in evoked potentials was accompanied by an increased paired pulse ratio, and a reduced frequency of spontaneous excitatory postsynaptic currents, suggesting that FC depresses striatal output by reducing the probability of transmitter release. The effect by FC was mimicked by chemogenetic inhibition of astrocytes using G(i)-coupled designer receptors exclusively activated by designer drugs (DREADDs) targeting GFAP, and by the glial glutamate transporter inhibitor TFB-TBOA. Both FC- and TFB-TBOA-mediated synaptic depression were inhibited in brain slices pre-treated with the dopamine D2 receptor antagonist sulpiride, but insensitive to agents acting on presynaptic glutamatergic autoreceptors, NMDA receptors, gap junction coupling, cannabinoid 1 receptors, mu-opioid receptors, P2 receptors or GABA(A) receptors. In conclusion, our data collectively support a role for astrocytes in modulating striatal neurotransmission and suggest that reduced transmission after astrocytic inhibition involves dopamine.
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| 15. |
- Karlsson, Hanna, et al.
(författare)
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Acute effects of alcohol on social and personal decision making
- 2022
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Ingår i: Neuropsychopharmacology. - : SPRINGERNATURE. - 0893-133X .- 1740-634X. ; 47:4, s. 824-831
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Tidskriftsartikel (refereegranskat)abstract
- Social drinking is common, but it is unclear how moderate levels of alcohol influence decision making. Most prior studies have focused on adverse long-term effects on cognitive and executive function in people with alcohol use disorders (AUD). Some studies have investigated the acute effects of alcohol on decision making in healthy people, but have predominantly used small samples and focused on a narrow selection of tasks related to personal decision making, e.g., delay or probability discounting. Here, we conducted a large (n = 264), preregistered randomized placebo-controlled study (RCT) using a parallel group design, to systematically assess the acute effects of alcohol on measures of decision making in both personal and social domains. We found a robust effect of a 0.6 g/kg dose of alcohol on both moral judgment and altruistic behavior, but no effects on several measures of risk taking or waiting impulsivity. These findings suggest that alcohol at low to moderate doses selectively moderates decision making in the social domain, and promotes utilitarian decisions over those dictated by rule-based ethical principles (deontological). This is consistent with existing theory that emphasizes the dual roles of shortsighted information processing and salient social cues in shaping decisions made under the influence of alcohol. A better understanding of these effects is important to understand altered social functioning during alcohol intoxication.
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| 16. |
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| 17. |
- Lagerberg, T, et al.
(författare)
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Selective serotonin reuptake inhibitors and suicidal behaviour: a population-based cohort study
- 2022
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Ingår i: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 1740-634X. ; 47:4, s. 817-823
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Tidskriftsartikel (refereegranskat)abstract
- There is concern that selective serotonin reuptake inhibitor (SSRI) treatment may increase the risk of suicide attempts or deaths, particularly among children and adolescents. However, debate remains regarding the nature of the relationship. Using nationwide Swedish registers, we identified all individuals aged 6–59 years with an incident SSRI dispensation (N = 538,577) from 2006 to 2013. To account for selection into treatment, we used a within-individual design to compare the risk of suicide attempts or deaths (suicidal behaviour) in time periods before and after SSRI-treatment initiation. Within-individual incidence rate ratios (IRRs) of suicidal behaviour were estimated. The 30 days before SSRI-treatment initiation was associated with the highest risk of suicidal behaviour compared with the 30 days 1 year before SSRI initiation (IRR = 7.35, 95% CI 6.60–8.18). Compared with the 30 days before SSRI initiation, treatment periods after initiation had a reduced risk—the IRR in the 30 days after initiation was 0.62 (95% CI 0.58–0.65). The risk then declined over treatment time. These patterns were similar across age strata, and when stratifying on history of suicide attempts. Initiation with escitalopram was associated with the greatest risk reduction, though CIs for the IRRs of the different SSRI types were overlapping. The results do not suggest that SSRI-treatment increases the risk for suicidal behaviour in either youths or adults; rather, it may reduce the risk. Further research with different study designs and in different populations is warranted.
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| 18. |
- Nassan, M, et al.
(författare)
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Genetic evidence for a potential causal relationship between insomnia symptoms and suicidal behavior: a Mendelian randomization study
- 2022
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Ingår i: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 1740-634X. ; 47:9, s. 1672-1679
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Tidskriftsartikel (refereegranskat)abstract
- Insomnia and restless leg syndrome (RLS) are associated with increased risk for suicidal behavior (SB), which is often comorbid with mood or thought disorders; however, it is unclear whether these relationships are causal. We performed a two-sample Mendelian randomization study using summary-level genetic associations with insomnia symptoms and RLS against the outcomes of risk of major depressive disorder (MDD), bipolar disorder (BP), schizophrenia (SCZ), and SB. The inverse-variance weighted method was used in the main analysis. We performed replication and sensitivity analyses to examine the robustness of the results. We identified outcome cohorts for MDD (n = 170,756 cases/329,443 controls), BP (n = 20,352/31,358), SCZ (n = 69,369/236,642), SB-Cohort-2019 (n = 6569/14,996 all with MDD, BP or SCZ; and SB within individual disease categories), and SB-Cohort-2020 (n = 29,782/519,961). Genetically proxied liability to insomnia symptoms significantly associated with increased risk of MDD (odds ratio (OR) = 1.23, 95% confidence interval (CI) = 1.2–1.26, P = 1.37 × 10–61), BP (OR = 1.15, 95% CI = 1.07–1.23, P = 5.11 × 10–5), SB-Cohort-2019 (OR = 1.17, 95% CI = 1.07–1.27, P = 2.30 × 10–4), SB-Cohort-2019 in depressed patients (OR = 1.34, 95% CI = 1.16–1.54, P = 5.97 × 10–5), and SB-Cohort-2020 (OR = 1.24, 95% CI = 1.18–1.3, P = 1.47 × 10–18). Genetically proxied liability to RLS did not significantly influence the risk of any of the outcomes (all corrected P > 0.05). Results were replicated for insomnia with MDD and SB in Mass General Brigham Biobank and were consistent in multiple lines of sensitivity analyses. In conclusion, human genetic evidence supports for the first time a potentially independent and causal effect of insomnia on SB and encourages further clinical investigation of treatment of insomnia for prevention or treatment of SB.
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| 19. |
- Saarinen, Marcus, et al.
(författare)
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TAAR1 dependent and independent actions of the potential antipsychotic and dual TAAR1/5-HT1A receptor agonist SEP-383856
- 2022
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Ingår i: Neuropsychopharmacology. - : Springer Nature. - 0893-133X .- 1740-634X. ; 47, s. 2319-2329
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Tidskriftsartikel (refereegranskat)abstract
- SEP-383856 (SEP-856) is a novel antipsychotic under clinical development. It displays a unique pattern of receptor interaction, with only weak (partial agonist) activity at dopamine D2 receptors, yet more potent agonist activity at the trace amine associated receptor (TAAR1) and 5-hydroxytryptamine 1 A receptor (5-HT1A). Nonetheless, these observations await independent confirmation and more detailed characterization of the in vitro and in vivo actions of SEP-856 at TAAR1 and 5-HT1A receptors would be instructive. Herein, we employed luminescence complementation technology in heterologous live cell systems, confocal microscopy, voltage clamp electrophysiology, behavioral readouts and TAAR1 knockout (KO) mice to study SEP-856 in further detail. We provide evidence for the ability of SEP-856 to activate TAAR1 at the surface plasma membrane, and show that this interaction results in Gαs recruitment (pEC50: 6.08 ± 0.22 EMAX: 96.41% ± 15.26) and by extension, to G-protein inwardly rectifying potassium (GIRK) channel activation. Using TAAR1-KO mice, we find TAAR1 to be indispensable for SEP-856 control of body temperature, baseline locomotion reduction and for “antipsychotic-like” efficacy as characterized by a reversal of dizocilipine (MK-801) mediated disruption of pre-pulse inhibition. Conversely, the inhibition by SEP-856 of MK-801 induced locomotion was unaffected in TAAR1 KO mice. SEP-856 behaved as a low-potency, partial agonist at the 5-HT1A receptor, while it partially inhibited recruitment of D2 receptor-coupled Gα and GIRK by DA and acted as a weak partial agonist with low potency at the same receptor when applied alone. Our findings corroborate and extend previous observations on the molecular substrates engaged by this unique, dual TAAR1/5-HT1A receptor agonist and potential antipsychotic that could prove to have major advantages in the treatment of schizophrenia and other psychotic disorders.
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| 20. |
- Svensson, JE, et al.
(författare)
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In vivo correlation of serotonin transporter and 1B receptor availability in the human brain: a PET study
- 2022
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Ingår i: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 1740-634X. ; 47:10, s. 1863-1868
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Tidskriftsartikel (refereegranskat)abstract
- Synaptic serotonin levels in the brain are regulated by active transport into the bouton by the serotonin transporter, and by autoreceptors, such as the inhibitory serotonin (5-HT) 1B receptor which, when activated, decreases serotonin release. Animal studies have shown a regulatory link between the two proteins. Evidence of such coupling could translate to an untapped therapeutic potential in augmenting the effect of selective serotonin reuptake inhibitors through pharmacological modulation of 5-HT1B receptors. Here we will for the first time in vivo examine the relationship between 5-HT1B receptors and serotonin transporters in the living human brain. Seventeen healthy individuals were examined with PET twice, using the radioligands [11C]AZ10419369 and [11C]MADAM for quantification of the 5-HT1B receptor and the 5-HT transporter, respectively. The binding potential was calculated for a set of brain regions, and the correlations between the binding estimates of the two radioligands were studied. [11C]AZ10419369 and [11C]MADAM binding was positively correlated in all examined brain regions. In most cortical regions the correlation was strong, e.g., frontal cortex, r(15) = 0.64, p = 0.01 and parietal cortex, r(15) = 0.8, p = 0.0002 while in most subcortical regions, negligible correlations was observed. Though the correlation estimates in cortex should be interpreted with caution due to poor signal to noise ratio of [11C]MADAM binding in these regions, it suggests a link between two key proteins involved in the regulation of synaptic serotonin levels. Our results indicate a need for further studies to address the functional importance of 5-HT1B receptors in treatment with drugs that inhibit serotonin reuptake.
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| 21. |
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| 22. |
- Heilig, Markus, et al.
(författare)
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Addiction as a brain disease revised : why it still matters, and the need for consilience
- 2021
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Ingår i: Neuropsychopharmacology. - : Springer Nature. - 0893-133X .- 1740-634X. ; 46:10, s. 1715-1723
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Forskningsöversikt (refereegranskat)abstract
- The view that substance addiction is a brain disease, although widely accepted in the neuroscience community, has become subject to acerbic criticism in recent years. These criticisms state that the brain disease view is deterministic, fails to account for heterogeneity in remission and recovery, places too much emphasis on a compulsive dimension of addiction, and that a specific neural signature of addiction has not been identified. We acknowledge that some of these criticisms have merit, but assert that the foundational premise that addiction has a neurobiological basis is fundamentally sound. We also emphasize that denying that addiction is a brain disease is a harmful standpoint since it contributes to reducing access to healthcare and treatment, the consequences of which are catastrophic. Here, we therefore address these criticisms, and in doing so provide a contemporary update of the brain disease view of addiction. We provide arguments to support this view, discuss why apparently spontaneous remission does not negate it, and how seemingly compulsive behaviors can co-exist with the sensitivity to alternative reinforcement in addiction. Most importantly, we argue that the brain is the biological substrate from which both addiction and the capacity for behavior change arise, arguing for an intensified neuroscientific study of recovery. More broadly, we propose that these disagreements reveal the need for multidisciplinary research that integrates neuroscientific, behavioral, clinical, and sociocultural perspectives.
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| 23. |
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| 24. |
- Kaltsouni, Elisavet, et al.
(författare)
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Brain reactivity during aggressive response in women with premenstrual dysphoric disorder treated with a selective progesterone receptor modulator
- 2021
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Ingår i: Neuropsychopharmacology. - : Springer Nature. - 0893-133X .- 1740-634X. ; 46:8, s. 1460-1467
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Tidskriftsartikel (refereegranskat)abstract
- Premenstrual dysphoric disorder (PMDD) is a psychiatric condition characterized by late luteal phase affective, cognitive, and physical impairment. The disorder causes significant suffering in about 5% of women in their reproductive age. Altered sensitivity of cognitive-affective brain circuits to progesterone and its downstream metabolite allopregnanolone is suggested to underlie PMDD symptomatology. Core mood symptoms include irritability and anger, with aggression being the behavioral outcome of these symptoms. The present study sought to investigate the neural correlates of reactive aggression during the premenstrual phase in women with PMDD, randomized to a selective progesterone receptor modulator (SPRM) or placebo. Self-reports on the Daily Record of Severity of Problems were used to assess PMDD symptoms and gonadal hormone levels were measured by liquid chromatography tandem mass spectrometry. Functional magnetic resonance imaging was performed in 30 women with PMDD, while performing the point subtraction aggression paradigm. Overall, a high SPRM treatment response rate was attained (93%), in comparison with placebo (53.3%). Women with PMDD randomized to SPRM treatment had enhanced brain reactivity in the dorsal anterior cingulate cortex and dorsomedial prefrontal cortex during the aggressive response condition. The fronto-cingulate reactivity during aggressive responses depended on treatment, with a negative relationship between brain reactivity and task-related aggressiveness found in the placebo but not the SPRM group. The findings contribute to define the role of progesterone in PMDD symptomatology, suggesting a beneficial effect of progesterone receptor antagonism, and consequent anovulation, on top-down emotion regulation, i.e., greater fronto-cingulate activity in response to provocation stimuli.
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| 25. |
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