Search

Abstract Background Identification of potentially harmful stimuli is necessary for the well-being and self-preservation of all organisms. However, the neural substrates involved in the processing of aversive stimuli are not well understood. For instance, painful and non-painful aversive stimuli are largely thought to activate different neural networks. However, it is presently unclear whether there is a common aversion-related network of brain regions responsible for the basic processing of aversive stimuli. To help clarify this issue, this report used a cross-species translational approach in humans (i.e. meta-analysis) and rodents (i.e. systematic review of functional neuroanatomy). Results Animal and human data combined to show a core aversion-related network, consisting of similar cortical (i.e. MCC, PCC, AI, DMPFC, RTG, SMA, VLOFC; see results section or abbreviation section for full names) and subcortical (i.e. Amyg, BNST, DS, Hab, Hipp/Parahipp, Hyp, NAc, NTS, PAG, PBN, raphe, septal nuclei, Thal, LC, midbrain) regions. In addition, a number of regions appeared to be more involved in pain-related (e.g. sensory cortex) or non-pain-related (e.g. amygdala) aversive processing. Conclusions This investigation suggests that aversive processing, at the most basic level, relies on similar neural substrates, and that differential responses may be due, in part, to the recruitment of additional structures as well as the spatio-temporal dynamic activity of the network. This network perspective may provide a clearer understanding of why components of this circuit appear dysfunctional in some psychiatric and pain-related disorders.

Awareness is an essential feature of the human mind that can be directed internally, that is, toward our self, or externally, that is, toward the environment. The combination of internal and external information is crucial to constitute our sense of self. Although the underlying neuronal networks, the so-called intrinsic and extrinsic systems, have been well-defined, the associated biochemical mechanisms still remain unclear. We used a well-established functional magnetic resonance imaging (fMRI) paradigm for internal (heartbeat counting) and external (tone counting) awareness and combined this technique with [18F]FMZ-PET imaging in the same healthy subjects. Focusing on cortical midline regions, the results showed that both stimuli types induce negative BOLD responses in the mPFC and the precuneus. Carefully controlling for structured noise in fMRI data, these results were also confirmed in an independent data sample using the same paradigm. Moreover, the degree of the GABAA receptor binding potential within these regions was correlated with the neuronal activity changes associated with external, rather than internal awareness when compared to fixation. These data support evidence that the inhibitory neurotransmitter GABA is an influencing factor in the differential processing of internally and externally guided awareness. This in turn has implications for our understanding of the biochemical mechanisms underlying awareness in general and its potential impact on psychiatric disorders. Hum Brain Mapp 35:173-184, 2014. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The perception of aversive stimuli is essential for human survival and depends largely on environmental context. Although aversive brain processing has been shown to involve the sensorimotor cortex, the neural and biochemical mechanisms underlying the interaction between two independent aversive cues are unclear. Based on previous work indicating ventromedial prefrontal cortex (vmPFC) involvement in the mediation of context-dependent emotional effects, we hypothesized a central role for the vmPFC in modulating sensorimotor cortex activity using a GABAergic mechanism during an aversive-aversive stimulus interaction. This approach revealed differential activations within the aversion-related network (eg, sensorimotor cortex, midcingulate, and insula) for the aversive-aversive, when compared with the aversive-neutral, interaction. Individual differences in sensorimotor cortex signal changes during the aversive-aversive interaction were predicted by GABAA receptors in both vmPFC and sensorimotor cortex. Together, these results demonstrate the central role of GABA in mediating context-dependent effects in aversion-related processing. [ABSTRACT FROM AUTHOR]

Recent imaging studies have demonstrated that levels of resting γ-aminobutyric acid (GABA) in the visual cortex predict the degree of stimulus-induced activity in the same region. These studies have used the presentation of discrete visual stimulus; the change from closed eyes to open also represents a simple visual stimulus, however, and has been shown to induce changes in local brain activity and in functional connectivity between regions. We thus aimed to investigate the role of the GABA system, specifically GABAA receptors, in the changes in brain activity between the eyes closed (EC) and eyes open (EO) state in order to provide detail at the receptor level to complement previous studies of GABA concentrations. We conducted an fMRI study involving two different modes of the change from EC to EO: an EO and EC block design, allowing the modeling of the haemodynamic response, followed by longer periods of EC and EO to allow the measuring of functional connectivity. The same subjects also underwent [18F]Flumazenil PET to measure GABAA receptor binding potentials. It was demonstrated that the local-to-global ratio of GABAA receptor binding potential in the visual cortex predicted the degree of changes in neural activity from EC to EO. This same relationship was also shown in the auditory cortex. Furthermore, the local-to-global ratio of GABAA receptor binding potential in the visual cortex also predicted the change in functional connectivity between the visual and auditory cortex from EC to EO. These findings contribute to our understanding of the role of GABAA receptors in stimulus-induced neural activity in local regions and in inter-regional functional connectivity. [ABSTRACT FROM AUTHOR]

Brain γ-aminobutyric acid (GABA) and 5-hydroxytryptamine (5-HT)2C receptors are implicated in the neuronal regulation of reward- and aversion-related behaviour. Within the mesocorticolimbic pathways of the brain, relationships between GABA containing neurons and 5-HT2C receptor activity may be important in this context. The primary aim of this study was to investigate the role of NAc shell GABA receptors on ventral tegmental area intracranial self-stimulation (ICSS) and to examine the systemic effects of GABAergic ligands in this context. The second aim was to investigate the relationship between GABA receptor- and 5-HT2C receptor-related ICSS behaviour, using systemic administration of the selective agonist WAY 161503. Locomotor activity was assessed to compare the potential motor effects of drugs; feeding behaviour and intra-NAc injections of amphetamine (1.0 µg/side) were used as positive controls. When administered systemically the GABAA receptor agonist muscimol and antagonist picrotoxin did not selectively change ICSS reward thresholds, although the 5-HT2C receptor agonist WAY 161503 (1.0 mg/kg) decreased reward measures. Intra-NAc shell administration of muscimol (225 ng/side) and picrotoxin (125 ng/side), respectively, decreased and increased measures of reward. Intra-NAc shell baclofen (0-225 ng/side; GABAB receptor agonist) did not affect any ICSS measures although it increased feeding. Combining picrotoxin and WAY 161503 attenuated the effects of each. These results suggest that a 5-HT2C and GABAA receptor-mediated neuronal relationship in the NAc shell may be relevant for the regulation of brain reward pathways. [ABSTRACT FROM PUBLISHER]

Abstract: Serotonin 1B (5-HT1B) receptors may play a role in regulating motivation and reward-related behaviours. To date, no studies have investigated the effects of the highly selective 5-HT1B receptor agonist CP 94253, on the reward model of ventral tegmental area intracranial self-stimulation. The current study investigated the hypothesis that 5-HT1B receptors play an inhibitory role in ventral tegmental area ICSS. Using Sprague–Dawley rats, the effects of the selective 5-HT1B receptor agonist CP 94253 (0–5.0 mg/kg) and the 5-HT1B/1D receptor antagonist GR 127935 (10.0 mg/kg) were investigated in rats trained to respond for ventral tegmental area ICSS; results were compared using rate-frequency threshold analysis. The highest dose of CP 94253 (5.0 mg/kg) tested in ventral tegmental area ICSS produced an increase in rate-frequency thresholds without affecting maximal response rates. This effect was attenuated by GR 127935 which did not show any effects when administered alone. These results suggest that 5-HT1B receptors play an inhibitory role in regulating ventral tegmental area ICSS. [Copyright &y& Elsevier]

Abstract: Rationale: Numerous studies indicate a role for both the serotonin 2C receptor (5-HT2C) and the nicotinic acetylcholine receptor in locomotion, reinforcement and motivated behaviours. Nicotine, a potent nicotinic acetylcholine receptor agonist, interacts with the dopaminergic and serotonergic systems and is known to positively affect reward-related behaviours. Objectives: The current study examined the effects of 5-HT2C receptor activation on nicotine-induced (0.6mg/kg) place conditioning and spontaneous locomotion. Methods: Using Sprague–Dawley rats, the effects of the selective 5-HT2C receptor agonist WAY 161503 (0–1.0mg/kg) and the selective 5-HT2C receptor antagonist SB 242084 (1.0mg/kg) alone, in combination, and on nicotine-induced (0.6mg/kg) spontaneous locomotor activity were assessed. The effects of WAY 161503 (1.0, 3.0mg/kg) were also investigated in nicotine-induced place conditioning using a two-compartment biased design; amphetamine (1.0mg/kg) served as a positive control. As differential effects were observed between place conditioning and locomotor activity, the subjects used in the place conditioning experiments were also tested for effects on locomotor activity. Results: WAY 161503 decreased baseline and nicotine-induced locomotor activity at the highest dose tested (1.0mg/kg) and these effects were attenuated by SB 242084. Amphetamine and nicotine both induced robust place preferences and WAY 161503 did not have any effects in the context of place conditioning. In contrast, WAY 161503 (1.0mg/kg) blocked nicotine-induced locomotor activity. Conclusions: These results suggest that 5-HT2C receptors may play an inhibitory role in nicotine-induced locomotor activity, but do not appear to influence place conditioning under the current conditions. [Copyright &y& Elsevier]