Non-pharmacological factors that determine drug use and addiction

Based on their pharmacological properties, psychoactive drugs are supposed to take control of the natural reward system to finally drive compulsory drug seeking and consumption. However, psychoactive drugs are not used in an arbitrary way as pure pharmacological reinforcement would suggest, but rather in a highly specific manner depending on non-pharmacological factors. While pharmacological effects of psychoactive drugs are well studied, neurobiological mechanisms of non-pharmacological factors are less well understood. Here we review the emerging neurobiological mechanisms beyond pharmacological reinforcement which determine drug effects and use frequency. Important progress was made on the understanding of how the character of an environment and social stress determine drug self-administration. This is expanded by new evidence on how behavioral alternatives and opportunities for drug instrumentalization generate different patterns of drug choice. Emerging evidence suggests that the neurobiology of non-pharmacological factors strongly determines pharmacological and behavioral drug action and may, thus, give rise for an expanded system’s approach of psychoactive drug use and addiction

Effect of social instigation and aggressive behavior on hormone levels of lactating dams and adult male Wistar rats

Among rodents, maternal aggression in the postpartum period represents a species-typical adaptation, but when aggressive behavior increases beyond this adaptive level, it can represent a model of excessive aggression. This study assessed the neuroendocrine response of lactating rats and socially instigated male rats. The aim of the present study was to assess neuroendocrine responses and the behavioral pattern of lactating rats and males that were subjected to an emotional stressor using the social instigation protocol. We measured plasma corticosterone levels as the key hormonal parameter of the hypothalamic-pituitary-adrenal (HPA) axis and oxytocin, prolactin, and progesterone, which are released in response to several types of stressors. Our results showed that lactating rats that were subjected to only social instigation or aggressive confrontation in the presence of their pups had lower plasma corticosterone levels, and this response was similar to oxytocin, prolactin, and progesterone levels. By contrast, male rats showed increased corticosterone levels after being subjected only to social instigation. Male rats also engaged in aggressive behavior compared with the control group. In conclusion, this study demonstrated that lactating rats subjected to social instigation exhibited an attenuation of the HPA axis response, which is considered to be crucial to the dam's welfare so that it can care for its offspring. Thus, we can infer that lactation is a relevant factor in neuroendocrine responses to stress because of the increased levels of corticosterone in males.Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES

Effect of social instigation and aggressive behavior on hormone levels of lactating dams and adult male Wistar rats

Among rodents, maternal aggression in the postpartum period represents a species-typical adaptation, but when aggressive behavior increases beyond this adaptive level, it can represent a model of excessive aggression. This study assessed the neuroendocrine response of lactating rats and socially instigated male rats. The aim of the present study was to assess neuroendocrine responses and the behavioral pattern of lactating rats and males that were subjected to an emotional stressor using the social instigation protocol. We measured plasma corticosterone levels as the key hormonal parameter of the hypothalamic-pituitary-adrenal (HPA) axis and oxytocin, prolactin, and progesterone, which are released in response to several types of stressors. Our results showed that lactating rats that were subjected to only social instigation or aggressive confrontation in the presence of their pups had lower plasma corticosterone levels, and this response was similar to oxytocin, prolactin, and progesterone levels. By contrast, male rats showed increased corticosterone levels after being subjected only to social instigation. Male rats also engaged in aggressive behavior compared with the control group. In conclusion, this study demonstrated that lactating rats subjected to social instigation exhibited an attenuation of the HPA axis response, which is considered to be crucial to the dam's welfare so that it can care for its offspring. Thus, we can infer that lactation is a relevant factor in neuroendocrine responses to stress because of the increased levels of corticosterone in males.Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES

Identification of Serotonergic Neuronal Modules that Affect Aggressive Behavior

SummaryEscalated aggression can have devastating societal consequences, yet underlying neurobiological mechanisms are poorly understood. Here, we show significantly increased inter-male mouse aggression when neurotransmission is constitutively blocked from either of two subsets of serotonergic, Pet1+ neurons: one identified by dopamine receptor D1(Drd1a)::cre-driven activity perinatally, and the other by Drd2::cre from pre-adolescence onward. Blocking neurotransmission from other Pet1+ neuron subsets of similar size and/or overlapping anatomical domains had no effect on aggression compared with controls, suggesting subtype-specific serotonergic neuron influences on aggression. Using established and novel intersectional genetic tools, we further characterized these subtypes across multiple parameters, showing both overlapping and distinct features in axonal projection targets, gene expression, electrophysiological properties, and effects on non-aggressive behaviors. Notably, Drd2::cre marked 5-HT neurons exhibited D2-dependent inhibitory responses to dopamine in slices, suggesting direct and specific interplay between inhibitory dopaminergic signaling and a serotonergic subpopulation. Thus, we identify specific serotonergic modules that shape aggression

Social instigation and aggressive behavior in mice: role of 5-HT 1A and 5-HT 1B receptors in the prefrontal cortex

Abstract Rationale Social instigation is used in rodents to induce high levels of aggression, a pattern of behavior with certain parallels to that of violent individuals. This procedure consists of a brief exposure to a provocative stimulus male, before direct confrontation with an intruder. Studies using 5-HT 1A and 5-HT 1B receptor agonists show an effective reduction in aggressive behavior. An important site of action for these drugs is the ventral orbitofrontal cortex (VO PFC), an area of the brain which is particularly relevant in the inhibitory control of aggressive and impulsive behavior. Objectives The objectives of the study are to assess the anti-aggressive effects of 5-HT 1A and 5-HT 1B agonist receptors [8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT) and 129] in the VO PFC of socially provoked male mice. To confirm the specificity of the receptor, 5-HT 1A and 5-HT 1B antagonist receptors (WAY-100,635 and SB-224,289) were microinjected into the same area, in order to reverse the agonist effects. Results 8-OH-DPAT (0.56 and 1.0 μg) reduced the frequency of attack bites. The lowest dose of CP-93,129 (0.1 μg) also decreased the number of attack bites and lateral threats. 5-HT1A and 5-HT1B receptor agonists differed in their effects on non-aggressive activities, the former decreasing rearing and grooming, and the latter, increasing these acts. Specific participation of the 1A and 1B receptors was verified by reversal of anti-aggressive effects using selective antagonists WAY-100,635 (10.0 μg) and SB-224,289 (1.0 μg). Conclusions The decrease in aggressiveness observed with microinjections of 5-HT 1A and 5-HT 1B receptor agonists into the VO PFC of socially provoked mice, supports the hypothesis that activation of these receptors modulates high levels of aggression in a behaviorally specific manner

Social Stimulus Causes Aberrant Activation of the Medial Prefrontal Cortex in a Mouse Model With Autism-Like Behaviors

Autism spectrum disorder (ASD) is a highly prevalent and genetically heterogeneous brain disorder. Developing effective therapeutic interventions requires knowledge of the brain regions that malfunction and how they malfunction during ASD-relevant behaviors. Our study provides insights into brain regions activated by a novel social stimulus and how the activation pattern differs between mice that display autism-like disabilities and control littermates. Adenomatous polyposis coli (APC) conditional knockout (cKO) mice display reduced social interest, increased repetitive behaviors and dysfunction of the β-catenin pathway, a convergent target of numerous ASD-linked human genes. Here, we exposed the mice to a novel social vs. non-social stimulus and measured neuronal activation by immunostaining for the protein c-Fos. We analyzed three brain regions known to play a role in social behavior. Compared with control littermates, APC cKOs display excessive activation, as evidenced by an increased number of excitatory pyramidal neurons stained for c-Fos in the medial prefrontal cortex (mPFC), selectively in the infralimbic sub-region. In contrast, two other social brain regions, the medial amygdala and piriform cortex show normal levels of neuron activation. Additionally, APC cKOs exhibit increased frequency of miniature excitatory postsynaptic currents (mEPSCs) in layer 5 pyramidal neurons of the infralimbic sub-region. Further, immunostaining is reduced for the inhibitory interneuron markers parvalbumin (PV) and somatostatin (SST) in the APC cKO mPFC. Our findings suggest aberrant excitatory-inhibitory balance and activation patterns. As β-catenin is a core pathway in ASD, we identify the infralimbic sub-region of the mPFC as a critical brain region for autism-relevant social behavior

Ventral tegmental area dopamine revisited: effects of acute and repeated stress

Aversive events rapidly and potently excite certain dopamine neurons in the ventral tegmental area (VTA), promoting phasic increases in the medial prefrontal cortex and nucleus accumbens. This is in apparent contradiction to a wealth of literature demonstrating that most VTA dopamine neurons are strongly activated by reward and reward-predictive cues while inhibited by aversive stimuli. How can these divergent processes both be mediated by VTA dopamine neurons? The answer may lie within the functional and anatomical heterogeneity of the VTA. We focus on VTA heterogeneity in anatomy, neurochemistry, electrophysiology, and afferent/efferent connectivity. Second, recent evidence for a critical role of VTA dopamine neurons in response to both acute and repeated stress will be discussed. Understanding which dopamine neurons are activated by stress, the neural mechanisms driving the activation, and where these neurons project will provide valuable insight into how stress can promote psychiatric disorders associated with the dopamine system, such as addiction and depression