SciCombinator

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Concept: Dopamine

259

Anecdotally, both acute and chronic cannabis use have been associated with apathy, amotivation, and other reward processing deficits. To date, empirical support for these effects is limited, and no previous studies have assessed both acute effects of Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), as well as associations with cannabis dependence.

Concepts: Cannabis sativa, Dopamine, Cannabinoid receptor, Cannabinoid, Tetrahydrocannabinol, Cannabidiol, Cannabis

244

An aversion to harming others is a core component of human morality and is disturbed in antisocial behavior [1-4]. Deficient harm aversion may underlie instrumental and reactive aggression, which both feature in psychopathy [5]. Past work has highlighted monoaminergic influences on aggression [6-11], but a mechanistic account of how monoamines regulate antisocial motives remains elusive. We previously observed that most people show a greater aversion to inflicting pain on others than themselves [12]. Here, we investigated whether this hyperaltruistic disposition is susceptible to monoaminergic control. We observed dissociable effects of the serotonin reuptake inhibitor citalopram and the dopamine precursor levodopa on decisions to inflict pain on oneself and others for financial gain. Computational models of choice behavior showed that citalopram increased harm aversion for both self and others, while levodopa reduced hyperaltruism. The effects of citalopram were stronger than those of levodopa. Crucially, neither drug influenced the physical perception of pain or other components of choice such as motor impulsivity or loss aversion [13, 14], suggesting a direct and specific influence of serotonin and dopamine on the valuation of harm. We also found evidence for dose dependency of these effects. Finally, the drugs had dissociable effects on response times, with citalopram enhancing behavioral inhibition and levodopa reducing slowing related to being responsible for another’s fate. These distinct roles of serotonin and dopamine in modulating moral behavior have implications for potential treatments of social dysfunction that is a common feature as well as a risk factor for many psychiatric disorders.

Concepts: Reuptake inhibitor, Antisocial personality disorder, Morality, Serotonin, Mental disorder, Dopamine, Selective serotonin reuptake inhibitor, Neurotransmitter

193

Brain dopamine dysfunction in attention deficit/hyperactivity disorder (ADHD) could explain why stimulant medications, which increase dopamine signaling, are therapeutically beneficial. However while the acute increases in dopamine induced by stimulant medications have been associated with symptom improvement in ADHD the chronic effects have not been investigated.

Concepts: Dopaminergic, Amphetamine, Dopamine receptor, Stimulant, Methylphenidate, Hyperactivity, Dopamine, Attention-deficit hyperactivity disorder

191

We describe a disease encompassing infantile-onset movement disorder (including severe parkinsonism and nonambulation), mood disturbance, autonomic instability, and developmental delay, and we describe evidence supporting its causation by a mutation in SLC18A2 (which encodes vesicular monoamine transporter 2 [VMAT2]). VMAT2 translocates dopamine and serotonin into synaptic vesicles and is essential for motor control, stable mood, and autonomic function. Treatment with levodopa was associated with worsening, whereas treatment with direct dopamine agonists was followed by immediate ambulation, near-complete correction of the movement disorder, and resumption of development.

Concepts: Monoamine neurotransmitter, Parkinson's disease, Transport, Monoamine transporter, Dopamine, Norepinephrine, Neurotransmitter, Serotonin

191

The firing of mesolimbic dopamine neurons is important for drug-induced reinforcement, although underlying genetic factors remain poorly understood. In a recent genome-wide association metaanalysis of alcohol intake, we identified a suggestive association of SNP rs26907 in the ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) gene, encoding a protein that mediates Ca(2+)-dependent activation of the ERK pathway. We performed functional characterization of this gene in relation to alcohol-related phenotypes and mesolimbic dopamine function in both mice and adolescent humans. Ethanol intake and preference were decreased in Rasgrf2(-/-) mice relative to WT controls. Accordingly, ethanol-induced dopamine release in the ventral striatum was blunted in Rasgrf2(-/-) mice. Recording of dopamine neurons in the ventral tegmental area revealed reduced excitability in the absence of Ras-GRF2, likely because of lack of inhibition of the I(A) potassium current by ERK. This deficit provided an explanation for the altered dopamine release, presumably linked to impaired activation of dopamine neurons firing. Functional neuroimaging analysis of a monetary incentive-delay task in 663 adolescent boys revealed significant association of ventral striatal activity during reward anticipation with a RASGRF2 haplotype containing rs26907, the SNP associated with alcohol intake in our previous metaanalysis. This finding suggests a link between the RASGRF2 haplotype and reward sensitivity, a known risk factor for alcohol and drug addiction. Indeed, follow-up of these same boys at age 16 y revealed an association between this haplotype and number of drinking episodes. Together, these combined animal and human data indicate a role for RASGRF2 in the regulation of mesolimbic dopamine neuron activity, reward response, and alcohol use and abuse.

Concepts: Striatum, Mesolimbic pathway, Nucleus accumbens, Drug addiction, Addiction, Ventral tegmental area, Reward system, Dopamine

190

Dopamine has a central role in motivation and reward. Dopaminergic neurons in the ventral tegmental area (VTA) signal the discrepancy between expected and actual rewards (that is, reward prediction error), but how they compute such signals is unknown. We recorded the activity of VTA neurons while mice associated different odour cues with appetitive and aversive outcomes. We found three types of neuron based on responses to odours and outcomes: approximately half of the neurons (type I, 52%) showed phasic excitation after reward-predicting odours and rewards in a manner consistent with reward prediction error coding; the other half of neurons showed persistent activity during the delay between odour and outcome that was modulated positively (type II, 31%) or negatively (type III, 18%) by the value of outcomes. Whereas the activity of type I neurons was sensitive to actual outcomes (that is, when the reward was delivered as expected compared to when it was unexpectedly omitted), the activity of type II and type III neurons was determined predominantly by reward-predicting odours. We ‘tagged’ dopaminergic and GABAergic neurons with the light-sensitive protein channelrhodopsin-2 and identified them based on their responses to optical stimulation while recording. All identified dopaminergic neurons were of type I and all GABAergic neurons were of type II. These results show that VTA GABAergic neurons signal expected reward, a key variable for dopaminergic neurons to calculate reward prediction error.

Concepts: Neuron, Mesolimbic pathway, American films, Game theory, Ventral tegmental area, Reward system, Nervous system, Dopamine

188

The majority of individuals evaluate themselves as superior to average. This is a cognitive bias known as the “superiority illusion.” This illusion helps us to have hope for the future and is deep-rooted in the process of human evolution. In this study, we examined the default states of neural and molecular systems that generate this illusion, using resting-state functional MRI and PET. Resting-state functional connectivity between the frontal cortex and striatum regulated by inhibitory dopaminergic neurotransmission determines individual levels of the superiority illusion. Our findings help elucidate how this key aspect of the human mind is biologically determined, and identify potential molecular and neural targets for treatment for depressive realism.

Concepts: Schizophrenia, Thought, Human brain, Cognitive science, Cognition, Psychology, Dopamine, Brain

182

The ventral subiculum (vSUB) plays a key role in addiction, and identifying the neuronal circuits and synaptic mechanisms by which vSUB alters the excitability of dopamine neurons is a necessary step to understand the motor changes induced by cocaine. Here, we report that high-frequency stimulation of the vSUB (HFSvSUB) over-activates ventral tegmental area (VTA) dopamine neurons in vivo and triggers long-lasting modifications of synaptic transmission measured ex vivo. This potentiation is caused by NMDA-dependent plastic changes occurring in the bed nucleus of the stria terminalis (BNST). Finally, we report that the modification of the BNST-VTA neural circuits induced by HFSvSUB potentiates locomotor activity induced by a sub-threshold dose of cocaine. Our findings unravel a neuronal circuit encoding behavioral effects of cocaine in rats and highlight the importance of adaptive modifications in the BNST, a structure that influences motivated behavior as well as maladaptive behaviors associated with addiction.

Concepts: Psychology, Motivation, Human behavior, Ventral tegmental area, Neuron, Nicotine, Nervous system, Dopamine

180

The human voice is a critical social cue, and listeners are extremely sensitive to the voices in their environment. One of the most salient voices in a child’s life is mother’s voice: Infants discriminate their mother’s voice from the first days of life, and this stimulus is associated with guiding emotional and social function during development. Little is known regarding the functional circuits that are selectively engaged in children by biologically salient voices such as mother’s voice or whether this brain activity is related to children’s social communication abilities. We used functional MRI to measure brain activity in 24 healthy children (mean age, 10.2 y) while they attended to brief (<1 s) nonsense words produced by their biological mother and two female control voices and explored relationships between speech-evoked neural activity and social function. Compared to female control voices, mother's voice elicited greater activity in primary auditory regions in the midbrain and cortex; voice-selective superior temporal sulcus (STS); the amygdala, which is crucial for processing of affect; nucleus accumbens and orbitofrontal cortex of the reward circuit; anterior insula and cingulate of the salience network; and a subregion of fusiform gyrus associated with face perception. The strength of brain connectivity between voice-selective STS and reward, affective, salience, memory, and face-processing regions during mother's voice perception predicted social communication skills. Our findings provide a novel neurobiological template for investigation of typical social development as well as clinical disorders, such as autism, in which perception of biologically and socially salient voices may be impaired.

Concepts: Sociology, Ventral tegmental area, Temporal lobe, Neuroanatomy, Dopamine, Brain, Limbic system, Cerebrum

176

Dopamine signaling is implicated in reinforcement learning, but the neural substrates targeted by dopamine are poorly understood. We bypassed dopamine signaling itself and tested how optogenetic activation of dopamine D1 or D2 receptor–expressing striatal projection neurons influenced reinforcement learning in mice. Stimulating D1 receptor–expressing neurons induced persistent reinforcement, whereas stimulating D2 receptor–expressing neurons induced transient punishment, indicating that activation of these circuits is sufficient to modify the probability of performing future actions.

Concepts: Reinforcement, Reinforcement learning, Dopamine, Neurotransmitter, Operant conditioning, Nervous system, Neuron, Dopamine receptor