Alessandra Lintas

Identification of a Dopamine Receptor-Mediated Opiate Reward Memory Switch in the Basolateral Amygdala–Nucleus Accumbens Circuit

The basolateral amygdala (BLA), ventral tegmental area (VTA), and nucleus accumbens (NAc) play central roles in the processing of opiate-related associative reward learning and memory. The BLA receives innervation from dopaminergic fibers originating in the VTA, and both dopamine (DA) D1 and D2 receptors are expressed in this region. Using a combination of in vivo single-unit extracellular recording in the NAc combined with behavioral pharmacology studies, we have identified a double dissociation in the functional roles of DA D1 versus D2 receptor transmission in the BLA, which depends on opiate exposure state; thus, in previously opiate-naive rats, blockade of intra-BLA D1, but not D2, receptor transmission blocked the acquisition of associative opiate reward memory, measured in an unbiased conditioned place preference procedure. In direct contrast, in rats made opiate dependent and conditioned in a state of withdrawal, intra-BLA D2, but not D1, receptor blockade blocked opiate reward encoding. This functional switch was dependent on cAMP signaling as comodulation of intra-BLA cAMP levels reversed or replicated the functional effects of intra-BLA D1 or D2 transmission during opiate reward processing. Single-unit in vivo extracellular recordings performed in neurons of the NAc confirmed an opiate-state-dependent role for BLA D1/D2 transmission in NAc neuronal response patterns to morphine. Our results characterize and identify a novel opiate addiction switching mechanism directly in the BLA that can control the processing of opiate reward information as a direct function of opiate exposure state via D1 or D2 receptor signaling substrates.

Acetaldehyde sequestering prevents ethanol-induced stimulation of mesolimbic dopamine transmission.

Acetaldehyde (ACD) has been postulated to mediate some of the neurobehavioral effects of ethanol (EtOH). In this study we sought to evaluate whether the stimulatory effects of EtOH on mesolimbic dopamine (DA) transmission are affected by the administration of ACD-sequestering agent D-penicillamine (Dp). To this end we studied the effect of EtOH and ACD in the rat mesoaccumbens pathway by in vivo microdialysis in the nucleus accumbens shell (NAccs), and by single cell extracellular recordings from antidromically identified mesoaccumbens DA neurons in the ventral tegmental area (VTA). Both EtOH (1g/kg) and ACD (20mg/kg) administration increased DA levels in the NAccs and increased the activity of mesoaccumbens DA neurons. Pretreatment with Dp (50mg/kg i.p. 1h before drug challenge) prevented both EtOH- and ACD-induced stimulation of the DA mesolimbic system without affecting morphine stimulatory actions. These observations add further support to the notion that EtOH-derived ACD stimulates the mesolimbic DA system and is essential in EtOH-induced stimulation of the DA mesoaccumbens system. We conclude that modulation of ACD bioavailability may influence the addictive profile of EtOH by decreasing its psychotropic effects and possibly leading the way to new pharmacological treatments of alcoholism.

Inputs from the basolateral amygdala to the nucleus accumbens shell control opiate reward magnitude via differential dopamine D1 or D2 receptor transmission

The basolateral amygdala (BLA), ventral tegmental area and nucleus accumbens (NAc) form a functionally connected neural circuit involved in the processing of opiate‐related reward and memory. Dopamine (DA) projections from the ventral tegmental area to the BLA modulate associative plasticity mechanisms within the BLA. However, the role of DA receptor signaling in the BLA and its functional outputs to the NAc during opiate reward processing is not currently understood. Using an unbiased place conditioning procedure, we measured the rewarding effects of morphine following intra‐BLA microinfusions of specific DA D1 or D2 receptor agonists in either opiate‐naive or opiate‐dependent/withdrawn rats. Activation of intra‐BLA D1 receptors strongly potentiated the behaviorally rewarding effects of opiates, only in the opiate‐naive state. However, once opiate dependence and withdrawal occurred, the intra‐BLA DA‐mediated potentiation of opiate reward salience switched to a D2 receptor‐dependent substrate. We next performed single‐unit, in‐vivo extracellular neuronal recordings in the NAc shell (NA shell), to determine if intra‐BLA D1/D2 receptor activation may modulate the NA shell neuronal response patterns to morphine. Consistent with our behavioral results, intra‐BLA D1 or D2 receptor activation potentiated NAc ‘shell’ (NA shell) neuronal responses to sub‐reward threshold opiate administration, following the same functional boundary between the opiate‐naive and opiate‐dependent/withdrawn states. Finally, blockade of N‐methyl‐d‐aspartate transmission within the NA shell blocked intra‐BLA DA D1 or D2 receptor‐mediated opiate reward potentiation. Our findings demonstrate a novel and functional DA D1/D2 receptor‐mediated opiate reward memory switch within the BLA→NA shell circuit that controls opiate reward magnitude as a function of opiate exposure state.

Crucial role of acetaldehyde in alcohol activation of the mesolimbic dopamine system.

Ethyl alcohol (EtOH), the main psychoactive ingredient of alcoholic drinks, is widely considered responsible for alcohol abuse and alcoholism through its positive motivational properties, which depend, at least partially, on the activation of the mesolimbic dopaminergic system. On the other hand, acetaldehyde (ACD), EtOHs first metabolite, has been classically considered aversive and useful in the pharmacologic therapy of alcoholics. Here we show that EtOH‐derived ACD is necessary for EtOH‐induced place preference, a preclinical test with high predictive validity for reward liability. We also found that ACD is essential for EtOH‐increased microdialysate dopamine (DA) levels in the nucleus accumbens (NAcc), and that this effect is mimicked by ACD administration to the intraventral tegmental area (VTA). Furthermore, in vitro, ACD enhances VTA DA neuronal firing. Coherently, EtOH‐stimulating properties on DA neurons are prevented by pharmacologic blockade of local catalase: the main metabolic step for biotransformation of EtOH into ACD in the central nervous system. These results provide in vivo and in vitro evidence for a key role of ACD in EtOH motivational properties and its activation of the mesolimbic DA system. Additionally, these observations suggest that ACD, by increasing VTA DA neuronal activity, would oppose its well‐known peripherally originating aversive properties. These findings could help in devising new effective pharmacologic therapies in alcoholism.

Simultaneous Golgi-Cox and immunofluorescence using confocal microscopy.

Visualization of neuronal elements is of fundamental importance in modern neuroscience. Golgi-Cox impregnation is a widely employed method that provides detailed information about morphological characteristics of neurons, but none regarding their neurochemical features. Immunocytochemical procedures, on the other hand, can provide a high degree of biochemical specificity but poorer morphological details, in particular if compared to Golgi-Cox impregnation. Hence, the combined use of these two approaches is highly desirable, especially for confocal microscopy that can exploit the advantages of both methods simultaneously. Here we show an innovative procedure of perfusion and fixation of brain tissue, that allows, by applying Golgi-Cox impregnation and immunofluorescence in the same histological section, to obtain high-quality histological material, with a very simple and inexpensive method. This procedure is based on three simple fixation steps: (1) a paraformaldehyde perfusion followed by a standard post-fixation to stabilize the subsequent immunofluorescence reaction; (2) the classical Golgi-Cox impregnation and (3) an immunofluorescence reaction in previously impregnated material. This combination allows simultaneous visualization of (a) the structural details (Golgi-Cox impregnated neurons), (b) the antigens’ characterization, (c) the anatomical interactions between discrete neuronal elements and (d) the 3D reconstruction and modeling. The method is easy to perform and can be reproducibly applied by small laboratories and expanded through the use of different antibodies. Overall, the method presented in this study offers an innovative and powerful approach to study the nervous system, especially by using confocal microscopy.

Addiction and Cognitive Functions

Drug addiction is a compulsive behavioral abnormality. In spite of pharmacologic and psychosocial treatments to reduce or eliminate drug taking, addiction tends to persist over time. Preclinical and human observations have converged on the hypothesis that addiction represents the pathologic deterioration of neural processes that normally serve affective and cognitive functioning. The major elements of persistent compulsive drug use are hypothesized to be molecular and cellular mechanisms that underlie enduring changes in a number of forebrain circuits (involving the ventral striatum and prefrontal cortex) that receive input from midbrain dopamine neurons and are involved in affective and cognitive mechanisms, respectively. Here we review progress in identifying crucial elements useful in understanding the pathophysiology of the disease and its pharmacologic treatment. Pharmacologic targeting of K‐opiate receptors, with their discrete distribution within the dopaminergic system(s), and thus different actions on dopaminoceptive areas, may provide beneficial effects at the affective and cognitive level.

Effect of Emotion and Personality on Deviation from Purely Rational Decision-Making

Human decision-making has consistently demonstrated deviation from ”pure” rationality. Emotions are a primary driver of human actions and the current study investigates how perceived emotions and personality traits may affect decision-making during the Ultimatum Game (UG). We manipulated emotions by showing images with emotional connotation while participants decided how to split money with a second player. Event-related potentials (ERPs) from scalp electrodes were recorded during the whole decision-making process. We observed significant differences in the activity of central and frontal areas when participants offered money with respect to when they accepted or rejected an offer. We found that participants were more likely to offer a higher amount of money when making their decision in association with negative emotions. Furthermore, participants were more likely to accept offers when making their decision in association with positive emotions. Honest, conscientious, and introverted participants were more likely to accept offers. Our results suggest that factors others than a rational strategy may predict economic decision-making in the UG.

Altered Mesolimbic Dopamine System in THC Dependence

To explore the functional consequences of cannabinoid withdrawal in the rat mesolimbic dopamine system, we investigated the anatomical morphology of the mesencephalic, presumed dopaminergic, neurons and their main post-synaptic target in the Nucleus Accumbens. We found that TH-positive neurons shrink and Golgi-stained medium spiny neurons loose dendritic spines in withdrawal rats after chronic cannabinoids administration. Similar results were observed after administration of the cannabinoid antagonist rimonabant to drug-naïve rats supporting a role for endocannabinoids in neurogenesis, axonal growth and synaptogenesis. This evidence supports the tenet that withdrawal from addictive compounds alters functioning of the mesolimbic system. The data add to a growing body of work which indicates a hypodopaminergic state as a distinctive feature of the “addicted brain”.

Visual thalamocortical circuits in parvalbumin-deficient mice

The dorsal lateral geniculate nucleus (dLGN) is considered as the visual gateway to the visual cortex (VC) and sends collaterals to the thalamic reticular nucleus (RTN) that in turn receives collaterals of the corticofugal feedback projections. At all levels of this thalamocortical circuit there are GABAergic neurons expressing the calcium-buffer parvalbumin (PV). The present study reports for the first time the analysis of in vivo extracellular electrophysiological recordings performed simultaneously in dLGN, RTN and VC of anesthetized wild-type (WT) and parvalbumin-deficient (PVKO) mice. The firing rates of VC and RTN cells were increased in PVKO during spontaneous activity as well as in the presence of a photic stimulation (strobe flash at 2.5Hz). Interestingly, dLGN cells in PVKO did not show significant changes in the rate of firing in comparison to WT. dLGN responses to the light flashes were characterized by ripples of inhibition and phasic excitation/rebound. We have analyzed the pattern of functional interactions between pairs of neighboring cells in VC, dLGN and RTN and across these areas in simultaneously recorded thalamocortical triplets, with one neuron from each area. We found that in PVKO the strength of the interactions tended to decrease locally, between neighboring cells, but tended to increase across the areas. The combination of these analyses provides new evidence on the important role played by PV-expression in regulating information processing in the central visual pathway suggesting that the ability to process information along parallel channels is decreased in the thalamocortical pathway of PV-deficient mice. This article is part of a Special Issue entitled Neural Coding 2012.

Imperfect Decision Making and Risk Taking Are Affected by Personality

Classic game theory predicts that individuals should behave as rational agents in order to maximize their gain. In real life situations it is observed that human decision making does not follow this theory. Specific patterns of activity in several brain circuits identified in recent years have been associated with irrational and imperfect decision making. Brain activity modulated by dopamine and serotonin is assumed to be among the main drivers of the expression of personality traits and patients affected by Attention deficit hyperactivity disorder (ADHD) are characterized by altered activity in those neuromodulating circuits. We investigated the effect of fairness and personality traits on neuronal and psychological mechanisms of decision making and risk taking in two sets of experiments based on the Ultimatum Game (UG) and the Investment Game (IG). In the UG we found that Fairness and Conscientiousness were associated with responder’s gain and with event-related potentials (ERP) components Feedback-Related Negativity (FRN) and Late Positive component (LPP). In the IG the sum gained during the risky gambling task were presented immediately after half of the trials (condition “high frequency feedback”, HFFB), while the other half were presented at the end of each block (condition “low frequency feedback”, LFFB). Conscientiousness, Agreeableness and Sincerity influenced latencies of the negative deflection occurring at around 200 ms (N200) and the positive wave peaking at around 250 ms (P250) components. The contingent negative variation (CNV) component was affected in a different way in controls and participants with ADHD as a function of the feedback frequency (HFFB versus LFFB). These results clearly show that imperfect decision making and risk taking are affected by personality traits and cannot be accounted by models based on rational computations.