The SEEKING Drive and Its Fixation: A Neuro-Psycho-Evolutionary Approach to the Pathology of Addiction.

Neuro-ethological studies conducted by Panksepp and his colleagues have provided an understanding of how the activity of the mesolimbic dopaminergic (ML DA) system leads to the emotional disposition to SEEK/Explore, which is involved in all appetitive motivated behavior and mental activity. In pathological addiction phenomena, this emotional disposition "fixes" itself on certain obsessive-compulsive habits, losing its versatility and its natural predisposition to spontaneous and unconditioned activation. Overall, the result is a consistent disinterest in everything that is not the object of addiction. From a neuro-psycho-evolutionary point of view, the predisposition to develop addictive behavior can be attributed to a loss of "functional autonomy" of the SEEKING/Explorative disposition. Indeed, as shown by animal and human studies, the tendency to be conditioned by situations and contexts that provide an immediate reward can be closely related to a deficit in the tonic endogenous activity of the ML DA-SEEKING system.

Panic disorder: attack of fear or acute attack of solitude? Convergences between affective neuroscience and phenomenological-Gestalt perspective.

There is consensus among scientists in considering Panic Attack (PA) as an exaggerated fear response triggered by intense activation of the amygdala and related Fear brain network. Current guidelines for treatment (e.g. National Institute for Clinical Excellence, NICE, 2011), that are based on this view, do not achieve satisfactory results: one-third of all treated patients report persistent PAs and other Panic Disorder (PD) symptoms, and several meta-analyses report the high likelihood of relapse. Here we review findings from Affective Neuroscience and clinical insights from a phenomenological-Gestalt perspective, putting into question the link between PD and activation of the Fear brain network. We propose an alternative hypothesis about PD etiology: PD is mainly connected to the Panic system, that is activated in situations of separation from affective support and overexposure to the environment. In our view, PA can be understood as an acute attack of solitude which is not adequately recognized by the patient due to the intervention of a dissociative component that makes it impossible to integrate all neuro-physiological responses activated by the Panic/Separation brain system within a coherent emotional feeling. This perspective can explain many evidences that otherwise remain isolated elements without a comprehensive frame: i.e., the association with agoraphobia, the onset of PD during adolescence and young adult life, the need to be accompanied, the connection with air hunger and other respiratory anomalies, the efficacy of antidepressants and the lack of activation of the Hypothalamic-Pituitary-Adrenal (HPA) axe. We discuss future steps to test this hypothesis and the consequences for psychotherapeutic treatment.

The Brain Emotional Systems in Addictions: From Attachment to Dominance/Submission Systems.

Human development has become particularly complex during the evolution. In this complexity, adolescence is an extremely important developmental stage. Adolescence is characterized by biological and social changes that create the prerequisites to psychopathological problems, including both substance and non-substance addictive behaviors. Central to the dynamics of the biological changes during adolescence are the synergy between sexual and neurophysiological development, which activates the motivational/emotional systems of Dominance/Submission. The latter are characterized by the interaction between the sexual hormones, the dopaminergic system and the stress axis (HPA). The maturation of these motivational/emotional systems requires the integration with the phylogenetically more recent Attachment/CARE Systems, which primarily have governed the subject's relationships until puberty. The integration of these systems is particularly complex in the human species, due to the evolution of the process of competition related to sexual selection: from a simple fight between two individuals (of the same genus and species) to a struggle for the acquisition of a position in rank and the competition between groups. The latter is an important evolutionary acquisition and believed to be the variable that has most contributed to enhancing the capacity for cooperation in the human species. The interaction between competition and cooperation, and between competition and attachment, characterizes the entire human relational and emotional structure and the unending work of integration to which the BrainMind is involved. The beginning of the integration of the aforementioned motivational/emotional systems is currently identified in the prepubertal period, during the juvenile stage, with the development of the Adrenarche-the so-called Adrenal Puberty. This latter stage is characterized by a low rate of release of androgens, the hormones released by the adrenal cortex, which activate the same behaviors as those observed in the PLAY system. The Adrenarche and the PLAY system are biological and functional prerequisites of adolescence, a period devoted to learning the difficult task of integrating the phylogenetically ancient Dominance/Submission Systems with the newer Attachment/CARE Systems. These systems accompany very different adaptive goals which can easily give rise to mutual conflict and can in turn make the balance of the BrainMind precarious and vulnerable to mental suffering.

The "Instinct" of Imagination. A Neuro-Ethological Approach to the Evolution of the Reflective Mind and Its Application to Psychotherapy.

Recent neuro-psychoanalytic literature has emphasized the view that our subjective identity rests on ancient subcortical neuro-psychic processes expressing unthinking forms of experience, which are "affectively intense without being known" (Solms and Panksepp, 2012). Devoid of internal representations, the emotional states of our "core-Self" (Panksepp, 1998b) are entirely "projected" towards the external world and tend to be discharged through instinctual action-patterns. However, due to the close connections between the subcortical and the cortical midline brain, the emotional drives may also find a way to be reflected within an intrinsic self-referential processing, evident when the organism is not actively engaged with the external world. Thanks to such endogenous functioning, the core-Self emotional dispositions are not overtly executed, but they are organized within coherent dynamic mental structures, called "feeling-toned complexes" by C. G. Jung and "unconscious phantasies" by Melanie Klein. The intrinsic self-referential dynamism of the "brainmind" originated from REM sleep arousal and then evolved in the resting-state activity of a complex of cortico-limbic midline brain structures (CMS), also called Default Mode Network (DMN). From our neuro-ethological perspective, it is sustained by an "introverted" SEEKING activity leading to the subjective exploration of internally constructed virtual scenarios. This "mind wandering" function, implicated in dreaming, fantasy processing, remembering and thinking, is the essence of the imaginative function and constitutes the first form of reflection, where intentions and drives gain a primordial form of conscious (but not self-conscious) representation. During postnatal development, this original ("archetypal") imaginative function is slowly attuned in a relational "transitional" space and may be expressed first in non-verbal and eventually in abstract-verbal social communicative patterns. Our view has noticeable implications for psychotherapy. Instead of trying to directly modify interpersonal, extrinsic relationships (a top-down approach), dysfunctional emotional-relational patterns may be modified by a process in which the patient is helped to let-go of the perceived feeling-objects in favor of an immersion, via the actual feeling, from the superficial level of perception towards a void feeling-state, empty of images. Only starting from this "anoetic" feeling-state, the deep imaginal creative and re-structuring self-referential activity may be reactivated by a process of spontaneous imagination.

The Affective Core of the Self: A Neuro-Archetypical Perspective on the Foundations of Human (and Animal) Subjectivity.

Psychologists usually considered the "Self" as an object of experience appearing when the individual perceives its existence within the conscious field. In accordance with such a view, the self-representing capacity of the human mind has been related to corticolimbic learning processes taking place within individual development. On the other hand, Carl Gustav Jung considered the Self as the core of our personality, in its conscious and unconscious aspects, as well as in its actual and potential forms. According to Jung, the Self originates from an inborn dynamic structure integrating the essential drives of our "brain-mind," and leading both to instinctual behavioral actions and to archetypal psychological experiences. Interestingly, recent neuroethological studies indicate that our subjective identity rests on ancient neuropsychic processes that humans share with other animals as part of their inborn constitutional repertoire. Indeed, brain activity within subcortical midline structures (SCMSs) is intrinsically related to the emergence of prototypical affective states, that not only influence our behavior in a flexible way, but alter our conscious field, giving rise to specific feelings or moods, which constitute the first form of self-orientation in the world. Moreover, such affective dynamics play a central role in the organization of individual personality and in the evolution of all other (more sophisticated) psychological functions. Therefore, on the base of the convergence between contemporary cutting-edge scientific research and some psychological intuitions of Jung, we intend here to explore the first neuroevolutional layer of human mind, that we call the affective core of the Self.

d-Amphetamine stimulates unconditioned exploration/approach behaviors in crayfish: towards a conserved evolutionary function of ancestral drug reward.

In mammals, rewarding properties of drugs depend on their capacity to activate a dopamine-mediated appetitive motivational seeking state--a system that allows animals to pursue and find all kinds of objects and events needed for survival. With such states strongly conserved in evolution, invertebrates have recently been developed into a powerful model in addiction research, where a shared ancestral brain system for the acquisition of reward can mediate drug addiction in many species. A conditioned place preference paradigm has illustrated that crayfish seek out environments that had previously been paired with psychostimulant and opioid administration. The present work demonstrates that the administration of D-amphetamine stimulates active explorative behaviors in crayfish through the action of the drug within their head ganglion. Crayfish, with a modularly organized and experimentally accessible, ganglionic nervous system offers a unique model to investigate (1) the fundamental, biological mechanisms of addictive drug reward; (2) how an appetitive/seeking disposition is implemented in a simple neural system, and (3) how it mediates the rewarding actions of major drugs of abuse.

The SEEKING mind: primal neuro-affective substrates for appetitive incentive states and their pathological dynamics in addictions and depression.

Appetitive motivation and incentive states are essential functions sustained by a common emotional brain process, the SEEKING disposition, which drives explorative and approach behaviors, sustains goal-directed activity, promotes anticipatory cognitions, and evokes feelings of positive excitement which control reward-learning. All such functions are orchestrated by the same "archetypical" neural processes, activated in ancient subcortical areas and transported to the forebrain by the mesolimbic dopamine (ML-DA) system. In mammals, the neurophysiology of the SEEKING urge is expressed by DA-promoted high-frequency oscillations, in the form of transient and synchronized gamma waves (>30Hz) emerging in limbic forebrain and diffusing throughout basal ganglia-thalamocortical (BG-T-C) circuits. These patterns may be considered basic "SEEKING neurodynamic impulses" which represent the primary-process exploratory disposition getting integrated with information relative to the external and the internal environment. Abnormal manifestation of SEEKING and its neural substrates are evident in clinical depression and addiction. Specifically, depression is characterized by reduced recruitment of SEEKING, while addictions reflect re-organizations of the SEEKING disposition around ultra-specific appetitive memories and compulsive activities.

Drug-sensitive reward in crayfish: an invertebrate model system for the study of SEEKING, reward, addiction, and withdrawal.

In mammals, rewarding properties of drugs depend on their capacity to activate appetitive motivational states. With the underlying mechanisms strongly conserved in evolution, invertebrates have recently emerged as a powerful new model in addiction research. In crayfish natural reward has proven surprisingly sensitive to human drugs of abuse, opening an unlikely avenue of research into the basic biological mechanisms of drug addiction. In a series of studies we first examined the presence of natural reward systems in crayfish, then characterized its sensitivity to a wide range of human drugs of abuse. A conditioned place preference (CPP) paradigm was used to demonstrate that crayfish seek out those environments that had previously been paired with the psychostimulants cocaine and amphetamine, and the opioid morphine. The administration of amphetamine exerted its effects at a number of sites, including the stimulation of circuits for active exploratory behaviors (i.e., SEEKING). A further study examined morphine-induced reward, extinction and reinstatement in crayfish. Repeated intra-circulatory infusions of morphine served as a reward when paired with distinct visual or tactile cues. Morphine-induced CPP was extinguished after repeated saline injections. Following this extinction phase, morphine-experienced crayfish were once again challenged with the drug. The priming injections of morphine reinstated CPP at all tested doses, suggesting that morphine-induced CPP is unrelenting. In an exploration of drug-associated behavioral sensitization in crayfish we concurrently mapped measures of locomotion and rewarding properties of morphine. Single and repeated intra-circulatory infusions of morphine resulted in persistent locomotory sensitization, even 5 days following the infusion. Moreover, a single dose of morphine was sufficient to induce long-term behavioral sensitization. CPP for morphine and context-dependent cues could not be disrupted over a drug free period of 5 days. This work demonstrates that crayfish offer a comparative and complementary approach in addiction research. Serving as an invertebrate animal model for the exposure to mammalian drugs of abuse, modularly organized and experimentally accessible nervous systems render crayfish uniquely suited for studying (1) the basic biological mechanisms of drug effects, (2) to explore how the appetitive/seeking disposition is implemented in a simple neural system, and (3) how such a disposition is related to the rewarding action of drugs of abuse. This work aimed to contribute an evolutionary, comparative context to our understanding of a key component in learning, and of natural reward as an important life-sustaining process.

Is subcortical-cortical midline activity in depression mediated by glutamate and GABA? A cross-species translational approach.

Major depressive disorder has recently been characterized by abnormal resting state hyperactivity in anterior midline regions. The neurochemical mechanisms underlying resting state hyperactivity remain unclear. Since animal studies provide an opportunity to investigate subcortical regions and neurochemical mechanisms in more detail, we used a cross-species translational approach comparing a meta-analysis of human data to animal data on the functional anatomy and neurochemical modulation of resting state activity in depression. Animal and human data converged in showing resting state hyperactivity in various ventral midline regions. These were also characterized by abnormal concentrations of glutamate and gamma-aminobutyric acid (GABA) as well as by NMDA receptor up-regulation and AMPA and GABA receptor down-regulation. This cross-species translational investigation suggests that resting state hyperactivity in depression occurs in subcortical and cortical midline regions and is mediated by glutamate and GABA metabolism. This provides insight into the biochemical underpinnings of resting state activity in both depressed and healthy subjects.

Behavioral functions of the mesolimbic dopaminergic system: an affective neuroethological perspective.

The mesolimbic dopaminergic (ML-DA) system has been recognized for its central role in motivated behaviors, various types of reward, and, more recently, in cognitive processes. Functional theories have emphasized DA's involvement in the orchestration of goal-directed behaviors and in the promotion and reinforcement of learning. The affective neuroethological perspective presented here views the ML-DA system in terms of its ability to activate an instinctual emotional appetitive state (SEEKING) evolved to induce organisms to search for all varieties of life-supporting stimuli and to avoid harms. A description of the anatomical framework in which the ML system is embedded is followed by the argument that the SEEKING disposition emerges through functional integration of ventral basal ganglia (BG) into thalamocortical activities. Filtering cortical and limbic input that spreads into BG, DA transmission promotes the "release" of neural activity patterns that induce active SEEKING behaviors when expressed at the motor level. Reverberation of these patterns constitutes a neurodynamic process for the inclusion of cognitive and perceptual representations within the extended networks of the SEEKING urge. In this way, the SEEKING disposition influences attention, incentive salience, associative learning, and anticipatory predictions. In our view, the rewarding properties of drugs of abuse are, in part, caused by the activation of the SEEKING disposition, ranging from appetitive drive to persistent craving depending on the intensity of the affect. The implications of such a view for understanding addiction are considered, with particular emphasis on factors predisposing individuals to develop compulsive drug seeking behaviors.

Ethanol consumption and reward depend on norepinephrine in the prefrontal cortex.

We studied the involvement of norepinephrine in the medial prefrontal cortex in the rewarding/reinforcing effects of ethanol. We evaluated the effects of norepinephrine selective depletion in the medial prefrontal cortex of C57/BL6J inbred mice that are commonly used in molecular studies and are highly susceptible to the behavioral effects of ethanol. In mice with prefrontal norepinephrine depletion, ethanol did not induce conditioned place preference, and a clear-cut reduction of ethanol consumption and preference was evident. These results indicate that prefrontal norepinephrine transmission is a critical factor in the rewarding/reinforcing effects of ethanol.

Dopamine beta-hydroxylase knockout mice have alterations in dopamine signaling and are hypersensitive to cocaine.

Multiple lines of evidence demonstrate that the noradrenergic system provides both direct and indirect excitatory drive onto midbrain dopamine (DA) neurons. We used DA beta-hydroxylase (DBH) knockout (Dbh-/-) mice that lack norepinephrine (NE) to determine the consequences of chronic NE deficiency on midbrain DA neuron function in vivo. Basal extracellular DA levels were significantly attenuated in the nucleus accumbens (NAc) and caudate putamen (CP), but not prefrontal cortex (PFC), of Dbh-/- mice, while amphetamine-induced DA release was absent in the NAc and attenuated in the CP and PFC. The decrease in dopaminergic tone was associated with a profound increase in the density of high-affinity state D1 and D2 DA receptors in the NAc and CP, while DA receptors in the PFC were relatively unaffected. As a behavioral consequence of these neurochemical changes, Dbh-/- mice were hypersensitive to the psychomotor, rewarding, and aversive effects of cocaine, as measured by locomotor activity and conditioned place preference. Antagonists of DA, but not 5-HT, receptors attenuated the locomotor hypersensitivity to cocaine in Dbh-/- mice. As DBH activity in humans is genetically controlled and the DBH inhibitor disulfiram has shown promise as a pharmacotherapy for cocaine dependence, these results have implications for the influence of genetic and pharmacological DBH inhibition on DA system function and drug addiction.

Prefrontal cortical norepinephrine release is critical for morphine-induced reward, reinstatement and dopamine release in the nucleus accumbens.

Increasing evidence suggests that in addition to the mesoaccumbens dopamine (DA) system other neurotransmitter and brain systems are also involved in opiate addiction. Recent evidence points to a major involvement of brain norepinephrine (NE) in the behavioral and central effects of opiates and, more specifically, indicates that NE in the prefrontal cortex may have a critical role in rewarding effects of opiates. Moreover, a body of data points to regions within the medial prefrontal cortex (mpFC) acting as final common pathway of drug relapse behavior. The present experiments were aimed at investigating the possibility of a selective involvement of the prefrontal cortical NE in the rewarding and reinstating effects of morphine. In a first set of experiments, we found that morphine enhances NE and DA release in the mpFC and DA release in the nucleus accumbens, as measured by intra-cerebral microdialysis. Selective depletion of medial prefrontal cortical noradrenergic afferents abolished the morphine-induced increase in DA release in the nucleus accumbens. In a second series of experiments, we demonstrated that the same lesion impaired both conditioned place preference (CPP) induced by morphine and reinstatement of an extinguished CPP. The present results indicate that an intact prefrontal cortical NE transmission is necessary for morphine-induced rewarding effects, reinstatement, and mesoaccumbens dopamine release.

In vivo evidence that genetic background controls impulse-dependent dopamine release induced by amphetamine in the nucleus accumbens.

Amphetamine is known to increase dopamine (DA) release by acting directly on dopamine transporters (DAT), primarily through a mechanism that is independent of impulse flow. We present evidence to show that impulse-dependent increase in DA outflow in the nucleus accumbens (NAc) is produced by amphetamine depending on genetic background. Systemic amphetamine produced higher accumbal DA release in the widely exploited C57BL/6J background than in the DBA/2J. By contrast, intra-accumbens perfusion using increasing doses of amphetamine dramatically increased DA outflow in the DBA/2J background, whereas very low DA outflow was evident in C57BL/6J mice. The fast sodium channel blocker tetrodotoxin infused through the microdialysis probe abolished accumbal DA release induced by systemic amphetamine only in the C57BL/6J background. Finally, medial prefrontal excitotoxic lesion abolished amphetamine-induced mesoaccumbens DA release in C57BL/6J mice, without significantly affecting it in the DBA/2J background. These results represent the first functional evidence in an in vivo study that amphetamine can increase DA release in the NAc mainly through an impulse-dependent mechanism regulated by prefronto-cortical glutamatergic transmission. Moreover, they point to a genetic control of impulse-dependent DA release in the accumbens, providing an exploitable tool to investigate aetiological factors involved in psychopathology and drug addiction.

Dopamine in the medial prefrontal cortex controls genotype-dependent effects of amphetamine on mesoaccumbens dopamine release and locomotion.

Mice of background DBA/2J are hyporesponsive to the behavioral effects of D-amphetamine in comparison with the widely exploited murine background C57BL/6J. In view of the important role of dopamine (DA) release in the nucleus accumbens (NAc) regarding the behavioral effects of psychostimulants, we tested the hypothesis of an inverse relationship between mesocortical and mesoaccumbens DA functioning in the two backgrounds. Systemic D-amphetamine induces a sustained increase in DA release in the medial prefrontal cortex (mpFC) accompanied by a poor increase in the NAc in mice of the low-responsive DBA/2J background, as shown by intracerebral microdialysis in freely moving animals. The opposite occurs in C57BL/6J mice, which show low prefrontal cortical DA outflow accompanied by high accumbal extracellular DA. Moreover, the DBA/2J background showed lower locomotor activity than C57BL/6J mice following D-amphetamine challenge. Selective DA depletion in the mpFC of DBA/2J mice produced a clear-cut increase in D-amphetamine-induced DA outflow in the NAc as well as locomotor activity that reached levels similar to those observed in C57BL/6J mice. Finally, local infusion of D-amphetamine by reverse microdialysis produced a similar increase in extracellular DA in both the mpFC and the NAc of DBA/2J mice. This finding points to similar transporter-related mechanisms in the two brain areas and supports the hypothesis that low accumbal DA release induced by systemic D-amphetamine in the DBA/2J background is determined by the inhibitory action of prefrontal cortical DA. The present results indicate that genotype-dependent susceptibility to addictive properties of D-amphetamine involves unbalanced DA transmission in the mesocorticolimbic system.

Norepinephrine in the prefrontal cortex is critical for amphetamine-induced reward and mesoaccumbens dopamine release.

Increasing evidence points to a major involvement of cortical areas in addictive mechanisms. Noradrenergic transmission in the medial prefrontal cortex (mpFC) has been shown to affect the motor effects of amphetamine, although there is no evidence of its involvement in the rewarding effects of this psychostimulant. The present experiments were aimed at investigating the possibility of a selective involvement of prefrontal cortical norepinephrine (NE) in the rewarding-reinforcing effects of amphetamine. To do so, we evaluated the effects of mpFC NE selective depletion in mice of C57BL/6J inbred strain, a background commonly used in molecular approaches that is known to be highly susceptible to the rewarding effects of the psychostimulant. In a first set of experiments, we demonstrated the absence of amphetamine-induced conditioned place preference in mice bearing prefrontal NE depletion. In a second series of experiments, we demonstrated that the same lesion dramatically reduced amphetamine-induced mesoaccumbens dopamine release as measured by intracerebral microdialysis. These results indicate that noradrenergic prefrontal transmission, by allowing increased dopamine release in the nucleus accumbens induced by amphetamine, is a critical factor for the rewarding-reinforcing effects of this drug.

Genotype- and experience-dependent susceptibility to depressive-like responses in the forced-swimming test.

RATIONALE: The forced-swimming test (FST) is utilized to reproduce passive coping responses to stress that may model a relevant aspect of human depression in rodent species. Animals showing high levels of passive responses to the FST are assumed to model pathologically depressed individuals. OBJECTIVES: We evaluated sensitivity of FST-induced behavioral responses to the interaction between genetic and environmental influences. METHODS: Behavioral responses to FST were evaluated in naive mice of the C57BL/6 and DBA/2 strains, in mice of both strains pre-exposed to FST 14 days before test, and in FST-experienced animals subsequently exposed to 12 days of stress experience (food restriction). RESULTS: C57BL/6 mice are characterized by high propensity to adopt passive coping responses in the FST. Moreover, stress enhances FST-induced immobility in mice of the C57BL/6 strain but reduces this response in DBA/2 mice. Finally, FST-induced immobility in C57BL/6 mice is reduced by chronic treatment with clinically effective antidepressants. CONCLUSIONS: These results support the view that behavioral and neural responses to FST exhibited by C57BL/6 mice can be usefully exploited by pre-clinical research on depression.