14,298 research outputs found

    PPARG SIGNALING IN THE NUCLEUS ACCUMBENS REGULATES MESOLIMBIC DOPAMINE ACTIVITY

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    Background: The mesolimbic dopamine system consists of dopamine neuron projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc). The NAc regulates VTA dopamine release through inhibitory GABA projections to the VTA. Hyperactive mesolimbic dopamine signaling is implicated in anxiety. Cannabidiol, a compound found in cannabis, demonstrates promising therapeutic potential for anxiety through the regulation of the mesolimbic dopamine system. Previous studies have revealed that cannabidiol infusions into the NAc decreases mesolimbic dopamine activity - potentially through the inhibitory GABA signaling to the VTA. However, the receptor mechanism in the NAc through which CBD produces its effects is unknown. Peroxisome proliferator-activated receptor gamma (PPARG) is a nuclear transcription factor that binds to CBD and colocalizes with GABA neurons. Recent evidence suggests that PPARG activation can decrease mesolimbic dopamine activity through inhibitory GABA signaling. Considering that the NAc expresses high levels of PPARG, intra-NAc CBD may regulate mesolimbic dopamine activity through PPARG activation. Hypothesis: PPARG activation in the NAc regulates mesolimbic dopamine transmission through the modulation of the GABAergic inhibition of the VTA. Methods: In-vivo electrophysiology was used to investigate the effects of intra-NAc PPARG activation on mesolimbic dopamine activity. The anxiolytic effects of intra-NAc PPARG activation was measured using the light-dark box and elevated plus maze behavioural tests. Results: We report that PPARG activation in the NAc significantly decreases mesolimbic dopamine activity whereas PPARG antagonists block this effect. Additionally, we reveal that intra-NAc PPARG activation produces anxiolytic effects as measured in the light-dark box and elevated plus maze behavioural tests

    Acute High Fat Diet Consumption Activates the Mesolimbic Circuit and Requires Orexin Signaling in a Mouse Model

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    Overconsumption of palatable energy-dense foods has negative health implications and it is associated with obesity andseveral eating disorders. Currently, little is known about the neuronal circuitries activated by the acute ingestion of arewarding stimulus. Here, we used a combination of immunohistochemistry, pharmacology and neuronal tracing analysesto examine the role of the mesolimbic system in general, and the orexin neurons in particular, in a simple experimental testin which nańĪ Őąve mice are allowed to spontaneously eat a pellet of a high fat diet (HFD) for 2 h. We found that acute HFDactivates c-Fos expression in several reward-related brain areas, including the ventral tegmental area (VTA), nucleusaccumbens, central amygdala and lateral hypothalamic area. We also found that: i- HFD-mediated orosensory stimulationwas required for the mesolimbic pathway activation, ii- acute HFD differentially activates dopamine neurons of theparanigral, parabrachial pigmented and interfascicular sub-regions of the VTA, and iii- orexin neurons of the lateralhypothalamic area are responsive to acute HFD. Moreover, orexin signaling blockade, with the orexin 1 receptor antagonistSB-334867, reduces acute HFD consumption and c-Fos induction in the VTA but not in the other mesolimbic nuclei understudy. Finally, we found that most orexin neurons responsive to acute HFD innervate the VTA. Our results show that acuteHFD consumption recruits the mesolimbic system and that the full manifestation of this eating behavior requires theactivation of orexin signaling.Fil: Valdivia Torres, Lesly Spring. Consejo Nacional de Investigaciones Cient√≠ficas y T√©cnicas. Centro Cient√≠fico Tecnol√≥gico Conicet - La Plata. Instituto Multidisciplinario de Biolog√≠a Celular. Provincia de Buenos Aires. Gobernaci√≥n. Comisi√≥n de Investigaciones Cient√≠ficas. Instituto Multidisciplinario de Biolog√≠a Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biolog√≠a Celular; ArgentinaFil: Patrone, Anabela. Consejo Nacional de Investigaciones Cient√≠ficas y T√©cnicas. Centro Cient√≠fico Tecnol√≥gico Conicet - La Plata. Instituto Multidisciplinario de Biolog√≠a Celular. Provincia de Buenos Aires. Gobernaci√≥n. Comisi√≥n de Investigaciones Cient√≠ficas. Instituto Multidisciplinario de Biolog√≠a Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biolog√≠a Celular; ArgentinaFil: Reynaldo, Mirta Beatriz. Consejo Nacional de Investigaciones Cient√≠ficas y T√©cnicas. Centro Cient√≠fico Tecnol√≥gico Conicet - La Plata. Instituto Multidisciplinario de Biolog√≠a Celular. Provincia de Buenos Aires. Gobernaci√≥n. Comisi√≥n de Investigaciones Cient√≠ficas. Instituto Multidisciplinario de Biolog√≠a Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biolog√≠a Celular; ArgentinaFil: Perello, Mario. Consejo Nacional de Investigaciones Cient√≠ficas y T√©cnicas. Centro Cient√≠fico Tecnol√≥gico Conicet - La Plata. Instituto Multidisciplinario de Biolog√≠a Celular. Provincia de Buenos Aires. Gobernaci√≥n. Comisi√≥n de Investigaciones Cient√≠ficas. Instituto Multidisciplinario de Biolog√≠a Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biolog√≠a Celular; Argentin

    EFFECTS OF OPTOGENETIC ACTIVATION AND PHARMACOLOGICAL MODULATION OF DOPAMINE NEURONS

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    This study explored the use of optogenetic tools to better understand treatments used for schizophrenia. The ‚Äúpositive‚ÄĚ symptoms (e.g., hallucinations, paranoia, etc.) of schizophrenia may come from overexpression of dopamine in mesolimbic dopamine neurons. Positive symptoms can be produced in healthy volunteers treated with amphetamine, a psychostimulant drug and dopamine releaser. Conversely, antipsychotic drugs may reduce positive symptoms by blocking dopamine receptors. This study used optogenetics to explore how drugs that alter neurotransmission, might alter behaviors occurring from activation of mesolimbic dopamine (DA) neurons in the ventral tegmental area (VTA). Light-induced activation of DA neurons in the VTA in male rats produced a significant increase in total distance traveled in an open field and body temperature. Animals treated with amphetamine, a dopamine releaser, also had a significant increase in total distance travelled and body temperature. No significant change was found between trials of amphetamine; it would be logical to think amphetamine depleted neurons of dopamine. However, A D2/3 receptor antagonist did block these effects. These results demonstrate that selective activation of mesolimbic dopamine neurons produces effects similar to amphetamine. Further, they coincide with previous findings that used different research techniques to link amphetamine‚Äôs effects to mesolimbic dopamine neurons

    Alcohol-related expectancies are associated with the D2 dopamine receptor and GABAa receptor B3 subunit genes

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    Molecular genetic research has identified promising markers of alcohol dependence, including alleles of the D2 dopamine receptor (DRD2) and the GABAA receptor ÔŅĘ3 subunit (GABRB3) genes. Whether such genetic risk manifests itself in stronger alcohol-related outcome expectancies, or in difficulty resisting alcohol, is unknown. In the present study, A1+ (A1A1 and A1A2 genotypes) and A1- (A2A2 genotype) alleles of the DRD2 and G1+ (G1G1 and G1 non-G1 genotypes) and G1- (non-G1 non-G1 genotype) alleles of the GABRB3 were determined in a group of 56 medically-ill patients diagnosed with alcohol dependence. Mood-related Alcohol Expectancy (AE) and Drinking Refusal Self-Efficacy (DRSE) were assessed using the Drinking Expectancy Profile (Young and Oei, 1996). Patients with the DRD2 A1+ allele, compared to those with the DRD2 A1- allele, reported lower DRSE in situations of social pressure (p=. 009). Similarly, lower DRSE was reported under social pressure by patients with the GABRB3 G1+ allele when compared to those with the GABRB3 G1- allele (p=.027). Patients with the GABRB3 G1+ allele also revealed reduced DRSE in situations characterized by negative affect than patients with the GABRB3 G1- alleles (p=. 037). Patients carrying the GABRB3 G1+ allele showed stronger AE relating to negative affective change (for example, increased depression) than their GABRB3 G1- counterparts (p=. 006). Biological influence in the development of some classes of cognitions is hypothesized. The clinical implications, particularly with regard to patient-treatment matching and the development of an integrated psychological and pharmacogenetic approach are discussed

    Dysfunctional play and dopamine physiology in the Fischer 344 rat

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    Juvenile Fischer 344 rats are known to be less playful than other inbred strains, although the neurobiological substrate(s) responsible for this phenotype is uncertain. In the present study, Fischer 344 rats were compared to the commonly used outbred Sprague-Dawley strain on several behavioral and physiological parameters in order to ascertain whether the lack of play may be related to compromised activity of brain dopamine (DA) systems. As expected, Fischer 344 rats were far less playful than Sprague-Dawley rats, with Fischer 344 rats less likely to initiate playful contacts with a playful partner and less likely to respond playfully to these contacts. We also found that Fischer 344 rats showed less of a startle response and greater pre-pulse inhibition (PPI), especially at higher prepulse intensities. The increase in PPI seen in the Fischer 344 rat could be due to reduced DA modulation of sensorimotor gating and neurochemical measures were consistent with Fischer 344 rats releasing less DA than Sprague-Dawley rats. Fast scan cyclic voltammetry (FSCV) revealed Fischer 344 rats had less evoked DA release in dorsal and ventral striatal brain slices and high-performance liquid chromatography revealed Fischer 344 rats to have less DA turnover in the striatum and prefrontal cortex. We also found DA-dependent forms of cortical plasticity were deficient in the striatum and prefrontal cortex of the Fischer 344 rat. Taken together, these data indicate that deficits in play and enhanced PPI of Fischer 344 rats may be due to reduced DA modulation of corticostriatal and mesolimbic/mesocortical circuits critical to the execution of these behaviors

    Effects of hippocampal damage on reward threshold and response rate during self-stimulation of the ventral tegmental area in the rat

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    The main purpose of this study was to explore the role of the hippocampus in motivated behavior. Rats with bilateral excitotoxic lesions of the hippocampus and controls were trained to lever press for electrical stimulation of the ventral tegmental area. Rate intensity functions were generated from an ascending and descending series of current intensities. Lesion-induced changes in sensitivity to reward were distinguished from enhancements in motor output by calculating reward thresholds and maximal response rates from the rate-intensity functions. Rats with hippocampal damage showed lower reward thresholds and higher maximal response rates than controls. These results provide further evidence of hippocampal modulation of the nucleus accumbens, suggesting that lesions of this structure enhance sensitivity to reward and increase motor output

    Orexinergic Input to Dopaminergic Neurons of the Human Ventral Tegmental Area

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    The mesolimbic reward pathway arising from dopaminergic (DA) neurons of the ventral tegmental area (VTA) has been strongly implicated in reward processing and drug abuse. In rodents, behaviors associated with this projection are profoundly influenced by an orexinergic input from the lateral hypothalamus to the VTA. Because the existence and significance of an analogous orexigenic regulatory mechanism acting in the human VTA have been elusive, here we addressed the possibility that orexinergic neurons provide direct input to DA neurons of the human VTA. Dual-label immunohistochemistry was used and orexinergic projections to the VTA and to DA neurons of the neighboring substantia nigra (SN) were analyzed comparatively in adult male humans and rats. Orexin B-immunoreactive (IR) axons apposed to tyrosine hydroxylase (TH)-IR DA and to non-DA neurons were scarce in the VTA and SN of both species. In the VTA, 15.062.8% of TH-IR perikarya in humans and 3.260.3% in rats received orexin B-IR afferent contacts. On average, 0.2460.05 and 0.0560.005 orexinergic appositions per TH-IR perikaryon were detected in humans and rats, respectively. The majority(86‚Äď88%) of randomly encountered orexinergic contacts targeted the dendritic compartment of DA neurons. Finally, DA neurons of the SN also received orexinergic innervation in both species. Based on the observation of five times heavierorexinergic input to TH-IR neurons of the human, compared with the rat, VTA, we propose that orexinergic mechanism acting in the VTA may play just as important roles in reward processing and drug abuse in humans, as already established well in rodents
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