| 1. |
- Licheri, Valentina, et al.
(författare)
-
Nicotine-induced neuroplasticity in striatum is subregion-specific and reversed by motor training on the rotarod.
- 2020
-
Ingår i: Addiction biology. - : Wiley. - 1369-1600 .- 1355-6215. ; 25:3
-
Tidskriftsartikel (refereegranskat)abstract
- Nicotine is recognized as one of the most addictive drugs, which in part could be attributed to progressive neuroadaptations and rewiring of dorsal striatal circuits. Since motor-skill learning produces neuroplasticity in the same circuits, we postulate that rotarod training could be sufficient to block nicotine-induced rewiring and thereby prevent long-lasting impairments of neuronal functioning. To test this hypothesis, Wistar rats were subjected to 15days of treatment with either nicotine (0.36mg/kg) or vehicle. After treatment, a subset of animals was trained on the rotarod. Ex vivo electrophysiology was performed 1week after the nicotine treatment period and after up to 3months of withdrawal to define neurophysiological transformations in circuits of the striatum and amygdala. Our data demonstrate that nicotine alters striatal neurotransmission in a distinct temporal and spatial sequence, where acute transformations are initiated in dorsomedial striatum (DMS) and nucleus accumbens (nAc) core. Following 3months of withdrawal, synaptic plasticity in the form of endocannabinoid-mediated long-term depression (eCB-LTD) is impaired in the dorsolateral striatum (DLS), and neurotransmission is altered in DLS, nAc shell, and the central nucleus of the amygdala (CeA). Training on the rotarod, performed after nicotine treatment, blocks neurophysiological transformations in striatal subregions, and prevents nicotine-induced impairment of eCB-LTD. These datasets suggest that nicotine-induced rewiring of striatal circuits can be extinguished by other behaviors that induce neuroplasticity. It remains to be determined if motor-skill training could be used to prevent escalating patterns of drug use in experienced users or facilitate the recovery from addiction.
|
|
| 2. |
- Ademar, Karin, et al.
(författare)
-
Acamprosate reduces ethanol intake in the rat by a combined action of different drug components
- 2023
-
Ingår i: Scientific Reports. - 2045-2322. ; 13:1
-
Tidskriftsartikel (refereegranskat)abstract
- Alcohol misuse accounts for a sizeable proportion of the global burden of disease, and Campral (R) (acamprosate; calcium-bis-(N-acetylhomotaurinate)) is widely used as relapse prevention therapy. The mechanism underlying its effect has in some studies been attributed to the calcium moiety and not to the N-acetylhomotaurine part of the compound. We recently suggested that the dopamine elevating effect of acamprosate is mediated both by N-acetylhomotaurine and calcium in a glycine receptor dependent manner. Here we aimed to explore, by means of in vivo microdialysis, if our previous study using local administration was functionally relevant and if systemic administration of the sodium salt of N-acetylhomotaurine (sodium acamprosate; 200 mg/kg, i.p.) enhanced the effects of calcium chloride (CaCl2; 73.5 mg/kg, i.p.) on nucleus accumbens (nAc) dopamine and/or taurine levels in male Wistar rats. In addition, we investigated the impact of regular acamprosate and the combination of CaCl(2 )and N-acetylhomotaurine on the alcohol deprivation effect (ADE). Finally, we assessed if N-acetylhomotaurine potentiates the ethanol-intake reducing effect of CaCl(2 )in a two-bottle choice voluntary ethanol consumption model followed by an ADE paradigm. Systemic administration of regular acamprosate, sodium acamprosate and CaCl(2 )all trended to increase nAc dopamine whereas the combination of CaCl(2)and sodium acamprosate produced a significant increase. Sodium acamprosate elevated extracellular taurine levels without additional effects of CaCl2. Ethanol intake was significantly reduced by systemic administration of CaCl(2 )without additional effects of the combination of CaCl(2 )and sodium acamprosate. Both acamprosate and CaCl(2 )combined with sodium acamprosate blocked the ADE following acute treatment. The data presented suggest that CaCl(2 )and N-acetylhomotaurine act in concert on a neurochemical level, but calcium appears to have the predominant effect on ethanol intake.
|
|
| 3. |
- Ademar, Karin, et al.
(författare)
-
Sodium acamprosate and calcium exert additive effects on nucleus accumbens dopamine in the rat
- 2022
-
Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 27:5
-
Tidskriftsartikel (refereegranskat)abstract
- Acamprosate (Campral (R) - calcium-bis[N-acetylhomotaurinate]) is one of few available pharmacotherapies for individuals suffering from alcohol use disorder. Previously, we suggested that acamprosate reduces ethanol intake by increasing dopamine in the nucleus accumbens (nAc), thereby partly substituting for alcohol's dopamine releasing effect. An experimental study suggested the calcium moiety of acamprosate to be the active component of the drug and to mediate the relapse preventing effect. The aim of the present study was to, by means of reversed in vivo microdialysis, elucidate if the dopamine elevating properties of acamprosate are mediated by N-acetylhomotaurine or by the calcium moiety. Male rats were equipped with a microdialysis probe in the nAc and received acute local treatment with regular acamprosate (CaAcamp 0.5 mM), calcium chloride (CaCl2 0.5 mM), sodium acamprosate (NaAcamp 0.5-1 mM), the glycine receptor (GlyR) antagonist strychnine (Stry 20 mu M), or vehicle. In all experiments, extracellular levels of dopamine and taurine were examined. We found that local perfusion with both CaAcamp and CaCl2 increased dopamine levels in a GlyR-dependent manner. NaAcamp did not influence dopamine levels, but concomitant administration with CaCl2 resulted in an additive dopamine output compared to the drugs administrated alone. We also found CaAcamp and the combination of CaCl2 and NaAcamp to increase accumbal taurine levels, suggesting that CaAcamp may act indirectly on GlyRs via taurine release. The present results indicate that both N-acetylhomotaurine and the calcium moiety of acamprosate have dopamine elevating properties within the nAc and that, in this respect, these substances are beneficial in combination.
|
|
| 4. |
- Adermark, Louise, 1974, et al.
(författare)
-
Astrocytes modulate extracellular neurotransmitter levels and excitatory neurotransmission in dorsolateral striatum via dopamine D2 receptor signaling
- 2022
-
Ingår i: Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 0893-133X .- 1740-634X. ; 47:8, s. 1493-1502
-
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.
|
|
| 5. |
- Adermark, Louise, 1974, et al.
(författare)
-
Astrocytic Regulation of Endocannabinoid-Dependent Synaptic Plasticity in the Dorsolateral Striatum
- 2024
-
Ingår i: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - 1661-6596 .- 1422-0067. ; 25:1
-
Tidskriftsartikel (refereegranskat)abstract
- Astrocytes are pivotal for synaptic transmission and may also play a role in the induction and expression of synaptic plasticity, including endocannabinoid-mediated long-term depression (eCB-LTD). In the dorsolateral striatum (DLS), eCB signaling plays a major role in balancing excitation and inhibition and promoting habitual learning. The aim of this study was to outline the role of astrocytes in regulating eCB signaling in the DLS. To this end, we employed electrophysiological slice recordings combined with metabolic, chemogenetic and pharmacological approaches in an attempt to selectively suppress astrocyte function. High-frequency stimulation induced eCB-mediated LTD (HFS-LTD) in brain slices from both male and female rats. The metabolic uncoupler fluorocitrate (FC) reduced the probability of transmitter release and depressed synaptic output in a manner that was independent on cannabinoid 1 receptor (CB1R) activation. Fluorocitrate did not affect the LTD induced by the CB1R agonist WIN55,212-2, but enhanced CB1R-dependent HFS-LTD. Reduced neurotransmission and facilitated HFS-LTD were also observed during chemogenetic manipulation using Gi-coupled DREADDs targeting glial fibrillary acidic protein (GFAP)-expressing cells, during the pharmacological inhibition of connexins using carbenoxolone disodium, or during astrocytic glutamate uptake using TFB-TBOA. While pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonopentanoic acid (APV) failed to prevent synaptic depression induced by FC, it blocked the facilitation of HFS-LTD. While the lack of tools to disentangle astrocytes from neurons is a major limitation of this study, our data collectively support a role for astrocytes in modulating basal neurotransmission and eCB-mediated synaptic plasticity.
|
|
| 6. |
- Andersson, Marica, et al.
(författare)
-
Low Holding Densities Increase Stress Response and Aggression in Zebrafish
- 2022
-
Ingår i: Biology. - : MDPI AG. - 2079-7737. ; 11:5
-
Tidskriftsartikel (refereegranskat)abstract
- Simple Summary Zebrafish are used as experimental animals in labs all around the world. To ensure that the health of zebrafish is maintained at the highest level, it is important to know the optimal housing conditions of the animals, including the housing density. Guidelines for housing densities of zebrafish can then be spread and followed globally, making it possible to compare research data from different facilities. To investigate the optimal housing densities of zebrafish and to better understand how holding density affects zebrafish behaviour and physiology, we evaluated the welfare of zebrafish housed at different densities for nine weeks. We observed that fish housed at the lowest holding density of 1 fish/L stood out from the rest of the experimental fish, showing higher levels of aggression, secreting more of the stress hormone cortisol in the water, and spending more time in the top zone of the tank, possibly reflecting the fact that fish in this density were hiding more behind the floating plants. Our data indicate that zebrafish should not be kept at 1 fish/L, or lower, to ensure good welfare of the animals. With laboratory zebrafish (Danio rerio) being an established and popular research model, there is a need for universal, research-based husbandry guidelines for this species, since guidelines can help promote good welfare through providing appropriate care. Despite the widespread use of zebrafish in research, it remains unclear how holding densities affect their welfare. Previous studies have mainly evaluated the effects of holding densities on a single parameter, such as growth, reproductive output, or social interactions, rather than looking at multiple welfare parameters simultaneously. Here we investigated how chronic (nine weeks) exposure to five different holding densities (1, 4, 8, 12, and 16 fish/L) affected multiple welfare indicators. We found that fish in the 1 fish/L density treatment had higher free water cortisol concentrations per fish, increased vertical distribution, and displayed aggressive behaviour more frequently than fish held at higher densities. On the other hand, density treatments had no effect on anxiety behaviour, whole-brain neurotransmitter levels, egg volume, or the proportion of fertilised eggs. Our results demonstrate that zebrafish can be held at densities between 4 and 16 fish/L without compromising their welfare. However, housing zebrafish in the density of 1 fish/L increased their stress level and aggressive behaviour.
|
|
| 7. |
- Danielsson, Klara, et al.
(författare)
-
Differential dopamine release by psychosis-generating and non-psychosis-generating addictive substances in the nucleus accumbens and dorsomedial striatum
- 2021
-
Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is associated with three main categories of symptoms; positive, negative and cognitive. Of these, only the positive symptoms respond well to treatment with antipsychotics. Due to the lack of effect of antipsychotics on negative symptoms, it has been suggested that while the positive symptoms are related to a hyperdopaminergic state in associative striatum, the negative symptoms may be a result of a reduced dopamine (DA) activity in the nucleus accumbens (nAc). Drug abuse is common in schizophrenia, supposedly alleviating negative symptomatology. Some, but not all, drugs aggravate psychosis, tentatively due to differential effects on DA activity in striatal regions. Here this hypothesis was tested in rats by using a double-probe microdialysis technique to simultaneously assess DA release in the nAc and associative striatum (dorsomedial striatum; DMS) following administration of the psychosis-generating substances amphetamine (0.5 mg/kg), cocaine (15 mg/kg) and Delta(9)-tetrahydrocannabinol (THC, 3 mg/kg), and the generally non-psychosis-generating substances ethanol (2.5 g/kg), nicotine (0.36 mg/kg) and morphine (5 mg/kg). The data show that amphetamine and cocaine produce identical DA elevations both in the nAc and DMS, whereas nicotine increases DA in nAc only. Ethanol and morphine both increased DMS DA, but weaker and in a qualitatively different way than in nAc, suggesting that the manner in which DA is increased might be important to the triggering of psychosis. THC elevated DA in neither region, indicating that the pro-psychotic effects of THC are not related to DA release. We conclude that psychosis-generating substances affect striatal DA release differently than non-psychosis-generating substances.
|
|
| 8. |
- Danielsson, Klara, et al.
(författare)
-
Subregion-specific effects on striatal neurotransmission and dopamine-signaling by acute and repeated amphetamine exposure
- 2021
-
Ingår i: Neuropharmacology. - : Elsevier BV. - 0028-3908. ; 194
-
Tidskriftsartikel (refereegranskat)abstract
- Repeated administration of psychostimulants, such as amphetamine, is associated with a progressive increased sensitivity to some of the drug's effects, but tolerance towards others. We hypothesized that these adaptations in part could be linked to differential effects by amphetamine on dopaminergic signaling in striatal subregions. To test this theory, acute and long-lasting changes in dopaminergic neurotransmission were assessed in the nucleus accumbens (nAc) and the dorsomedial striatum (DMS) following amphetamine exposure in Wistar rats. By means of in vivo microdialysis, dopamine release induced by local administration of amphetamine was monitored in nAc and DMS of amphetamine naïve rats, and in rats subjected to five days of systemic amphetamine administration (2.0 mg/kg/day) followed by two weeks of withdrawal. In parallel, ex vivo electrophysiology was conducted to outline the effect of acute and repeated amphetamine exposure on striatal neurotransmission. The data shows that amphetamine increases dopamine in a concentration-dependent and subregion-specific manner. Furthermore, repeated administration of amphetamine followed by abstinence resulted in a selective decrease in baseline dopamine in the nAc, and a potentiation of the relative dopamine elevation after systemic amphetamine in the same area. Ex vivo electrophysiology demonstrated decreased excitatory neurotransmission in brain slices from amphetamine-treated animals, and a nAc selective shift in the responsiveness to the dopamine D2-receptor agonist quinpirole. These selective effects on dopamine signaling seen in striatal subregions after repeated drug exposure may partially explain why tolerance develops to the rewarding effects, but not towards the psychosis inducing properties of amphetamine. © 2021 The Author(s)
|
|
| 9. |
- Ericson, Mia, 1970, et al.
(författare)
-
Different dopamine tone in ethanol high- and low-consuming Wistar rats
- 2020
-
Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 2019
-
Tidskriftsartikel (refereegranskat)abstract
- - Excessive alcohol use causes considerable morbidity and mortality worldwide. Changes in the mesolimbic dopamine system have been postulated as a neurobiological underpinning of excessive alcohol consumption, and recent research also suggests that the amino acid taurine plays a central role in ethanol-induced dopamine elevation. The aim of this study was to further outline the role of dopamine and taurine in regulating alcohol consumption. In this study, a choice between ethanol (20%) and water was administered to Wistar rats in an intermittent manner (three times/week) for seven consecutive weeks. In vivo microdialysis was used to explore baseline levels as well as ethanol-induced increases of extracellular dopamine and taurine, in the nucleus accumbens (nAc) of Wistar rats voluntarily consuming large or small amounts of ethanol. Basal levels of taurine were also measured in cerebrospinal fluid (CSF) and serum in a subset of rats. Ethanol-induced increases in nAc dopamine and taurine did not differ between alcohol-consuming and naïve rats. However, when categorized based on ethanol intake, rats consuming larger amounts of ethanol exhibited a lower dopamine tone in the nucleus accumbens and responded to ethanol with a slower elevation of extracellular taurine levels, as compared with low-consuming animals. Basal levels of taurine in nAc, CSF, or serum did not differ between ethanol high- and low-consuming rats. Our data support previous studies claiming an association between low endogenous dopamine levels and excessive alcohol intake. © 2019 Society for the Study of Addiction
|
|
| 10. |
- Lagström, Oona, et al.
(författare)
-
Subregion specific neuroadaptations in the female rat striatum during acute and protracted withdrawal from nicotine
- 2024
-
Ingår i: Journal of Neural Transmission. - 0300-9564. ; 131:1, s. 83-94
-
Tidskriftsartikel (refereegranskat)abstract
- Epidemiological studies and clinical observations suggest that nicotine, a major contributor of the global burden of disease, acts in a partially sex specific manner. Still, preclinical research has primarily been conducted in males. More research is thus required to define the effects displayed by nicotine on the female brain. To this end, female rats received 15 injections of either nicotine (0.36mg/kg) or saline, over a 3-week period and were then followed for up to 3 months. Behavioral effects of nicotine were assessed using locomotor activity measurements and elevated plus maze, while neurophysiological changes were monitored using ex vivo electrophysiological field potential recordings conducted in subregions of the dorsal and ventral striatum. Behavioral assessments demonstrated a robust sensitization to the locomotor stimulatory properties of nicotine, but monitored behaviors on the elevated plus maze were not affected during acute (24 h) or protracted (3 months) withdrawal. Electrophysiological recordings revealed a selective increase in excitatory neurotransmission in the nucleus accumbens shell and dorsomedial striatum during acute withdrawal. Importantly, accumbal neuroadaptations in nicotine-treated rats correlated with locomotor behavior, supporting a role for the nucleus accumbens in behavioral sensitization. While no sustained neuroadaptations were observed following 3 months withdrawal, there was an overall trend towards reduced inhibitory tone. Together, these findings suggest that nicotine produces selective transformations of striatal brain circuits that may drive specific behaviors associated with nicotine exposure. Furthermore, our observations suggest that sex-specificity should be considered when evaluating long-term effects by nicotine on the brain.
|
|
