RESUMEN
Adolescence is characterized by changes in reward-related behaviors, social behaviors, and decision-making. These behavioral changes are necessary for the transition into adulthood, but they also increase vulnerability to the development of a range of psychiatric disorders. Major reorganization of the dopamine system during adolescence is thought to underlie, in part, the associated behavioral changes and increased vulnerability. Here, we utilized fast scan cyclic voltammetry and microdialysis to examine differences in dopamine release as well as mechanisms that underlie differential dopamine signaling in the nucleus accumbens (NAc) core of adolescent (P28-35) and adult (P70-90) male rats. We show baseline differences between adult and adolescent-stimulated dopamine release in male rats, as well as opposite effects of the α6 nicotinic acetylcholine receptor (nAChR) on modulating dopamine release. The α6-selective blocker, α-conotoxin, increased dopamine release in early adolescent rats, but decreased dopamine release in rats beginning in middle adolescence and extending through adulthood. Strikingly, blockade of GABAA and GABAB receptors revealed that this α6-mediated increase in adolescent dopamine release requires NAc GABA signaling to occur. We confirm the role of α6 nAChRs and GABA in mediating this effect in vivo using microdialysis. Results herein suggest a multisynaptic mechanism potentially unique to the period of development that includes early adolescence, involving acetylcholine acting at α6-containing nAChRs to drive inhibitory GABA tone on dopamine release.
During adolescence, chemicals and cells in the brain undergo significant reorganization. These changes are thought to be why teenagers are often more vulnerable to developing drug addictions and psychiatric disorders. However, it is not fully understood how the brain transforms during this transitional period. Most of this reorganization takes place in the dopamine system which is responsible for triggering pleasurable sensations, including the feeling of reward after taking drugs. In 2020, a group of researchers found that adolescent male rats released less of the chemical dopamine in a part of the brain involved in the reward pathway than adult rats. But it was unclear what was causing this age-related effect. To investigate, Iacino et al. including some of the researchers involved in the 2020 study blocked a family of receptors called nAChRs (short for nicotinic acetylcholine receptors) in the brain cells of male rats. These receptors bind to a neurotransmitter called acetylcholine which stimulates cells to release dopamine. Iacino et al. found that inhibiting a specific type of nAChR led to a decrease in dopamine in adult rats, but an increase in early adolescent rats. However, this effect was not observed when other types of nAChRs were inhibited. Iacino et al. found that the adolescent male rats also had higher levels of another neurotransmitter called GABA which blocks the release of dopamine. This led them to hypothesize that the reduced levels of dopamine in early adolescence may be due to increased levels of GABA, which is secreted by specialized cells which also have nAChRs on their surface. To investigate, Iacino et al. blocked two receptors for GABA that are found on dopamine-releasing neurons before exposing the rats to the nAChR inhibitor. This caused the adolescent rats to release less dopamine following nAChR inhibition, similar to the levels observed in adult rats. These findings suggest that the nAChR inhibitor leads to a rise in dopamine by stopping cells from releasing GABA but only in adolescent rats. The work of Iacino et al. demonstrates how the dopamine system differs in adolescence, which may provide new insights in to why teenagers are often more susceptible to addiction. For instance, nicotine, the addictive substance in cigarettes, can also bind to nAChRs and make them less sensitive to acetylcholine. This may reduce the release of GABA, resulting in more dopamine being released which is then sensed as a reward by the teenage brain. However, more research is needed to fully understand how this brain circuit is modulated by nicotine intake.
Asunto(s)
Acetilcolina , Dopamina , Núcleo Accumbens , Ácido gamma-Aminobutírico , Masculino , Ratas , Acetilcolina/metabolismo , Dopamina/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Núcleo Accumbens/metabolismo , Ratas Sprague-Dawley , Receptores Nicotínicos/metabolismo , AnimalesRESUMEN
Cocaine self-administration can disrupt the capacity of humans and rodents to flexibly modify familiar behavioral routines, even when they become maladaptive or unbeneficial. However, mechanistic factors, particularly those driving long-term behavioral changes, are still being determined. Here, we capitalized on individual differences in oral cocaine self-administration patterns in adolescent mice and revealed that the post-synaptic protein PSD-95 was reduced in the orbitofrontal cortex (OFC) of escalating, but not stable, responders, which corresponded with later deficits in flexible decision-making behavior. Meanwhile, NMDA receptor GluN2B subunit content was lower in the OFC of mice that were resilient to escalatory oral cocaine seeking. This discovery led us to next co-administer the GluN2B-selective antagonist ifenprodil with cocaine, blocking the later emergence of cocaine-induced decision-making abnormalities. GluN2B inhibition also prevented cocaine-induced dysregulation of neuronal structure and function in the OFC, preserving mature, mushroom-shaped dendritic spine densities on deep-layer pyramidal neurons, which were otherwise lower with cocaine, and safeguarding functional BLAâOFC connections necessary for action flexibility. We posit that cocaine potentiates GluN2B-dependent signaling, which triggers a series of durable adaptations that result in the dysregulation of post-synaptic neuronal structure in the OFC and disruption of BLAâOFC connections, ultimately weakening the capacity for flexible choice. And thus, inhibiting GluN2B-NMDARs promotes resilience to long-term cocaine-related sequelae.
Asunto(s)
Cocaína , Humanos , Ratones , Animales , Receptores de N-Metil-D-Aspartato/metabolismo , Corteza Prefrontal/metabolismo , Neuronas/metabolismo , Transducción de SeñalRESUMEN
Behavioral flexibility-that is, the ability to deviate from established behavioral sequences-is critical for navigating dynamic environments and requires the durable encoding and retrieval of new memories to guide future choice. The orbitofrontal cortex (OFC) supports outcome-guided behaviors. However, the coordinated neural circuitry and cellular mechanisms by which OFC connections sustain flexible learning and memory remain elusive. Here we demonstrate in mice that basolateral amygdala (BLA)âOFC projections bidirectionally control memory formation when familiar behaviors are unexpectedly not rewarded, whereas OFCâdorsomedial striatum (DMS) projections facilitate memory retrieval. OFC neuronal ensembles store a memory trace for newly learned information, which appears to be facilitated by circuit-specific dendritic spine plasticity and neurotrophin signaling within defined BLA-OFC-DMS connections and obstructed by cocaine. Thus, we describe the directional transmission of information within an integrated amygdalo-fronto-striatal circuit across time, whereby novel memories are encoded by BLAâOFC inputs, represented within OFC ensembles and retrieved via OFCâDMS outputs during future choice.
Asunto(s)
Complejo Nuclear Basolateral , Aprendizaje , Animales , Complejo Nuclear Basolateral/fisiología , Cuerpo Estriado , Aprendizaje/fisiología , Ratones , Corteza Prefrontal/fisiología , RecompensaRESUMEN
Dysregulation of biological rhythms plays a role in a wide range of psychiatric disorders. We report mechanistic insights into the rhythms of rapid dopamine signals and cholinergic interneurons (CINs) working in concert in the rodent striatum. These rhythms mediate diurnal variation in conditioned responses to reward-associated cues. We report that the dopamine signal-to-noise ratio varies according to the time of day and that phasic signals are magnified during the middle of the dark cycle in rats. We show that CINs provide the mechanism for diurnal variation in rapid dopamine signals by serving as a gain of function to the dopamine signal-to-noise ratio that adjusts across time of day. We also show that conditioned responses to reward-associated cues exhibit diurnal rhythms, with cue-directed behaviors observed exclusively midway through the dark cycle. We conclude that the rapid dopamine signaling rhythm is mediated by a diurnal rhythm in CIN activity, which influences learning and motivated behaviors across the time of day.
Asunto(s)
Ritmo Circadiano , Dopamina , Animales , Colinérgicos , Condicionamiento Clásico , Humanos , Núcleo Accumbens/fisiología , Ratas , RecompensaRESUMEN
Heightened novelty-seeking phenotypes are associated with a range of behavioural traits including susceptibility to drug use. These relationships are recapitulated in preclinical models, where rats that exhibit increased exploratory activity in novel environments (high responders-HR) acquire self-administration of psychostimulants more rapidly compared to rats that display low novelty exploration (low responders-LR). Dopamine release dynamics in the nucleus accumbens (NAc) covaries with response to novelty, and differences in dopaminergic signalling are thought to be a major underlying driver of the link between novelty seeking and drug use vulnerability. Accumbal dopamine release is controlled by local microcircuits including modulation through glutamatergic and nicotinic acetylcholine receptor (nAChR) systems, but whether these mechanisms contribute to disparate dopamine signalling across novelty phenotypes is unclear. Here, we used ex vivo voltammetry in the NAc of rats to determine if α7 nAChRs contribute to differential dopamine dynamics associated with individual differences in novelty exploration. We found that blockade of α7 nAChRs attenuates tonic dopamine release evoked by low-frequency stimulations across phenotypes but that phasic release is decreased in LRs while HRs are unaffected. These stimulation frequency- and phenotype-dependent effects result in a decreased dynamic range of release exclusively in LRs. Furthermore, we found that differential α7 modulation of dopamine release in LRs is dependent on AMPA but not NMDA receptors. These results help to form an understanding of the local NAc microcircuitry and provide a potential mechanism for covariance of dopamine dynamics and sensitivity to the reinforcing effects of drugs of abuse.
Asunto(s)
Dopamina , Receptores Nicotínicos , Animales , Dopamina/farmacología , Conducta Exploratoria , Núcleo Accumbens , Ratas , Receptores Nicotínicos/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
Calcium-dependent activator protein for secretion 2 (CAPS2; also referred to as CADPS2) is a dense core vesicle-associated protein that promotes the activity-dependent release of neuropeptides including neurotrophins. Addictive drugs appear to prime neurotrophin release in multiple brain regions, but mechanistic factors are still being elucidated. Here, experimenters administered cocaine to adolescent mice at doses that potentiated later cocaine self-administration. Experimenter-administered cocaine elevated the CAPS2 protein content in the orbitofrontal cortex (OFC; but not striatum) multiple weeks after drug exposure. Meanwhile, proteins that are sensitive to brain-derived neurotrophic factor (BDNF) release and binding (phosphorylated protein kinase B and phosphoinositide 3-kinase, and GABAAα1 levels) did not differ between cocaine-exposed and naive mice in the OFC. This pattern is consistent with evidence that CAPS2 primes stimulated release of neurotrophins like BDNF, rather than basal levels. Thus, cocaine administered at behaviorally relevant doses elevates CAPS2 protein content in the OFC, and the effects are detected long after cocaine exposure.
Asunto(s)
Cocaína , Proteínas del Tejido Nervioso , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteínas de Unión al Calcio/metabolismo , Calmodulina , Cocaína/farmacología , Vesículas de Núcleo Denso , Ratones , Proteínas del Tejido Nervioso/metabolismo , Fosfatidilinositol 3-Quinasas , Corteza Prefrontal/metabolismoRESUMEN
BACKGROUND: The PI3-kinase (PI3K) complex is a well-validated target for mitigating cocaine-elicited sequelae, but pan-PI3K inhibitors are not viable long-term treatment options. The PI3K complex is composed of p110 catalytic and regulatory subunits, which can be individually manipulated for therapeutic purposes. However, this possibility has largely not been explored in behavioral contexts. METHODS: Here, we inhibited PI3K p110ß in the medial prefrontal cortex (mPFC) of cocaine-exposed mice. Behavioral models for studying relapse, sensitization, and decision-making biases were paired with protein quantification, RNA sequencing, and cell type-specific chemogenetic manipulation and RNA quantification to determine whether and how inhibiting PI3K p110ß confers resilience to cocaine. RESULTS: Viral-mediated PI3K p110ß silencing reduced cue-induced reinstatement of cocaine seeking by half, blocked locomotor sensitization, and restored mPFC synaptic marker content after exposure to cocaine. Cocaine blocked the ability of mice to select actions based on their consequences, and p110ß inhibition restored this ability. Silencing dopamine D2 receptor-expressing excitatory mPFC neurons mimicked cocaine, impairing goal-seeking behavior, and again, p110ß inhibition restored goal-oriented action. We verified the presence of p110ß in mPFC neurons projecting to the dorsal striatum and orbitofrontal cortex and found that inhibiting p110ß in the mPFC altered the expression of functionally defined gene clusters within the dorsal striatum and not orbitofrontal cortex. CONCLUSIONS: Subunit-selective PI3K silencing potently mitigates drug seeking, sensitization, and decision-making biases after exposure to cocaine. We suggest that inhibiting PI3K p110ß provides neuroprotection against cocaine by triggering coordinated corticostriatal adaptations.
Asunto(s)
Cocaína , Animales , Ratones , Fosfatidilinositol 3-Quinasas , Corteza Prefrontal , Isoformas de Proteínas , Ratas , Ratas Sprague-Dawley , TranscriptomaRESUMEN
Adolescence is characterized by changes in behavior, such as increases in sensation seeking and risk taking, and increased vulnerability to developing a range of psychiatric disorders, including substance abuse disorders (SUD) and mood disorders. The mesolimbic dopamine system plays an essential role in mediating these behaviors and disorders. Therefore, it is imperative to understand how the dopamine system and its regulation are changing during this period of development. Here, we used ex vivo fast scan cyclic voltammetry to compare stimulated dopamine release and its local circuitry regulation between early adolescent and adult male and female Sprague-Dawley rats. We found that, compared to adults, adolescent males have decreased stimulated dopamine release in the NAc core, while adolescent females have increased dopamine release in the NAc shell, NAc core, and DMS. We also found sex- and region-specific differences in other dopamine dynamics, including maximal dopamine uptake (Vmax), release across a range of stimulation frequencies, and autoreceptor regulation of dopamine release. Better understanding how the dopamine system develops during adolescence will be imperative for understanding what mediates adolescent vulnerability to developing psychiatric disorders and how disruptions during this period of reorganization could alter behaviors and vulnerability into adulthood.
Asunto(s)
Cuerpo Estriado/fisiología , Dopamina/fisiología , Receptores de Dopamina D2/fisiología , Factores de Edad , Animales , Femenino , Masculino , Neuronas/fisiología , Núcleo Accumbens/fisiología , Ratas Sprague-DawleyRESUMEN
Smoking remains the primary cause of preventable death in the United States and smoking related illness costs more than $300 billion annually. Nicotine (the primary reinforcer in cigarettes) causes changes in behavior and neurochemistry that lead to increased probability of relapse. Given the role of mesolimbic dopamine projections in motivation, substance use disorder, and drug relapse, we examined the effect of repeated nicotine on rapid dopamine signals in the nucleus accumbens (NAc) of rats. Adult, male Sprague-Dawley rats were exposed to nicotine (0.2 or 0.4 mg/kg, subcutaneous) once daily for 7 days. On day 8, dopamine release and uptake dynamics, and their modulation by nicotinic receptor agonists and antagonists, were assessed using fast scan cyclic voltammetry in the NAc core. Nicotine exposure decreased electrically-stimulated dopamine release across a range of stimulation frequencies and decreased α6ß2-containing nicotinic receptor control over dopamine release. Additionally, nicotine locomotor sensitization correlated with accumbal dopamine modulation by nicotine and mecamylamine. Taken together, our study suggests that repeated exposure to nicotine blunts dopamine release in the NAc core through changes in α6ß2 modulation of dopamine release and individual differences in the sensitivity to this outcome may predict variation in behavioral models of vulnerability to substance use disorder.
Asunto(s)
Dopamina/metabolismo , Locomoción/fisiología , Actividad Motora/fisiología , Nicotina/farmacología , Agonistas Nicotínicos/farmacocinética , Núcleo Accumbens/metabolismo , Receptores Nicotínicos/metabolismo , Animales , Locomoción/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Cocaine use during adolescence decreases the likelihood that individuals will seek treatment for recurrent drug use. In rodents, developmental cocaine exposure weakens action-consequence decision-making, causing a deferral to familiar, habit-like behavioral response strategies. Here, we aimed to improve action-outcome decision-making. We found that acute pharmacological stimulation of the tyrosine/tropomyosin receptor kinase B (trkB) via 7,8-dihydroxyflavone (7,8-DHF) or 3,4-methylenedioxymethamphetamine (MDMA) blocked cocaine-induced habit biases by strengthening memory for action-outcome associations. We believe that MDMA acts by stimulating neurotrophin/trkB systems in the orbitofrontal cortex (OFC), a region involved in prospectively evaluating the consequences of one's action, because 1) MDMA also increased brain-derived neurotrophic factor (BDNF) in the OFC, 2) MDMA corrected habit biases due to Bdnf loss in the OFC, and 3) overexpression of a truncated isoform of trkB occluded the memory-enhancing effects of MDMA. Thus, selecting actions based on their consequences requires BDNF-trkB in the OFC, the stimulation of which may improve goal attainment in both drug-naïve and cocaine-exposed individuals. SIGNIFICANCE STATEMENT: Cocaine use during adolescence decreases the likelihood that individuals will seek treatment for recurrent drug use, even as adults. Understanding how early-life cocaine exposure impacts goal-oriented action and prospective decision-making in adulthood is thus important. One key aspect of goal-directed decision-making is anticipating the consequences of one's actions, a process that likely involves the orbitofrontal cortex (OFC). In rodents, developmental cocaine exposure weakens action-consequence decision-making, causing a deferral to familiar, habit-like behavioral response strategies. Here, we report that we can improve memory for action-consequence relationships by stimulating neurotrophic factors, which support cell survival, development, and plasticity in the brain. With strengthened action-consequence associations, cocaine-exposed mice regain the ability to optimally select actions based on their likely outcomes. Brain region-selective manipulations reveal that neurotrophin systems in the OFC are necessary for stable memory of action-consequence relationships.
Asunto(s)
Cocaína/administración & dosificación , Toma de Decisiones/efectos de los fármacos , Toma de Decisiones/fisiología , Factores de Crecimiento Nervioso/fisiología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiología , Animales , Conducta Animal/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Condicionamiento Operante/fisiología , Femenino , Flavonas/administración & dosificación , Hábitos , Masculino , Glicoproteínas de Membrana/agonistas , Glicoproteínas de Membrana/fisiología , Memoria/efectos de los fármacos , Memoria/fisiología , Ratones Endogámicos C57BL , N-Metil-3,4-metilenodioxianfetamina/administración & dosificación , Proteínas Tirosina Quinasas/fisiologíaRESUMEN
Specific corticostriatal structures and circuits are important for flexibly shifting between goal-oriented versus habitual behaviors. For example, the orbitofrontal cortex and dorsomedial striatum are critical for goal-directed action, while the dorsolateral striatum supports habits. To determine the role of neurotrophin signaling, we overexpressed a truncated, inactive form of tropomyosin receptor kinase B [also called tyrosine receptor kinase B (TrkB)], the high-affinity receptor for Brain-derived Neurotrophic Factor, in the orbitofrontal cortex, dorsomedial striatum and dorsolateral striatum. Overexpression of truncated TrkB interfered with phosphorylation of full-length TrkB and ERK42/44, as expected. In the orbitofrontal cortex and dorsomedial striatum, truncated trkB overexpression also occluded the ability of mice to select actions based on the likelihood that they would be reinforced. Meanwhile, in the dorsolateral striatum, truncated trkB blocked the development of habits. Thus, corticostriatal TrkB-mediated plasticity appears necessary for balancing actions and habits.
Asunto(s)
Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Animales , Conducta Animal , Corteza Cerebral/metabolismo , Cuerpo Estriado/metabolismo , Regulación de la Expresión Génica , Masculino , Ratones , Factores de Crecimiento Nervioso/metabolismo , Transducción de SeñalRESUMEN
The use of (±)-3,4-methylenedioxymethamphetamine ((±)-MDMA) as an adjunct to psychotherapy in the treatment of psychiatric and behavioral disorders dates back over 50 years. Only in recent years have controlled and peer-reviewed preclinical and clinical studies lent support to (±)-MDMA's hypothesized clinical utility. However, the clinical utility of (±)-MDMA is potentially mitigated by a range of demonstrated adverse effects. One potential solution could lie in the individual S(+) and R(-) enantiomers that comprise (±)-MDMA. Individual enantiomers of racemic compounds have been employed in psychiatry to improve a drug's therapeutic index. Although no research has explored the individual effects of either S(+)-MDMA or R(-)-MDMA in humans in a controlled manner, preclinical research has examined similarities and differences between the two molecules and the racemic compound. This review addresses information related to the pharmacodynamics, neurotoxicity, physiological effects, and behavioral effects of S(+)-MDMA and R(-)-MDMA that might guide preclinical and clinical research. The current preclinical evidence suggests that R(-)-MDMA may provide an improved therapeutic index, maintaining the therapeutic effects of (±)-MDMA with a reduced side effect profile, and that future investigations should investigate the therapeutic potential of R(-)-MDMA.
Asunto(s)
Alucinógenos/química , Alucinógenos/uso terapéutico , Trastornos Mentales/tratamiento farmacológico , N-Metil-3,4-metilenodioxianfetamina/química , N-Metil-3,4-metilenodioxianfetamina/uso terapéutico , Animales , Humanos , Trastornos Mentales/psicología , Estereoisomerismo , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/psicologíaRESUMEN
3,4-Methylenedioxymethamphetamine (MDMA) increases sociality in humans and animals. Release of serotonin (5-HT) is thought to have an important role in the increase in social behaviors, but the mechanisms underlying these effects are poorly understood. Despite the advantages of nonhuman primate models, no studies have examined the mechanisms of the social effects of MDMA in nonhuman primates. The behavior and vocalizations of four group-housed squirrel monkeys were examined following administration of MDMA, its enantiomers, and methamphetamine. 5-HT receptor antagonists and agonists were given as drug pretreatments. Data were analyzed using linear mixed-effects models. MDMA and its enantiomers increased affiliative social behaviors and vocalizations, whereas methamphetamine had only modest effects on affiliative behaviors. Pretreatment with a 5-HT2A receptor antagonist and a 5-HT2C receptor agonist attenuated the MDMA-induced increase in social behaviors, while a 5-HT1A receptor antagonist did not alter affiliative vocalizations and increased MDMA-induced social contact. Nonhuman primates show MDMA-specific increases in affiliative social behaviors following MDMA administration, in concordance with human and rodent studies. MDMA-induced increases in social behaviors are 5-HT2A, but not 5-HT1A, receptor dependent. Understanding the neurochemical mechanisms mediating the prosocial effects of MDMA could help in the development of novel therapeutics with the unique social effects of MDMA but fewer of its limitations.
Asunto(s)
N-Metil-3,4-metilenodioxianfetamina/farmacología , Psicotrópicos/farmacología , Receptor de Serotonina 5-HT2A/metabolismo , Conducta Social , Animales , Relación Dosis-Respuesta a Droga , Modelos Lineales , Masculino , Metanfetamina/farmacología , Receptor de Serotonina 5-HT1A/metabolismo , Saimiri , Serotoninérgicos/farmacología , Vocalización Animal/efectos de los fármacos , Vocalización Animal/fisiologíaRESUMEN
Drug-primed reinstatement of cocaine seeking in rats is thought to reflect relapse-like behavior and is mediated by the integration of signals from mesocorticolimbic dopaminergic projections and corticostriatal glutamatergic innervation. Cocaine-primed reinstatement can also be attenuated by systemic administration of dopamine ß-hydroxylase (DBH) inhibitors, which prevent norepinephrine (NE) synthesis, or by α1-adrenergic receptor (α1AR) antagonists, indicating functional modulation by the noradrenergic system. In the present study, we sought to further discern the role of NE in cocaine-seeking behavior by determining whether α1AR activation can induce reinstatement on its own or is sufficient to permit cocaine-primed reinstatement in the absence of all other AR signaling, and identifying the neuroanatomical substrate within the mesocorticolimbic reward system harboring the critical α1ARs. We found that while intracerebroventricular infusion of the α1AR agonist phenylephrine did not induce reinstatement on its own, it did overcome the blockade of cocaine-primed reinstatement by the DBH inhibitor nepicastat. Furthermore, administration of the α1AR antagonist terazosin in the medial prefrontal cortex (mPFC), but not the ventral tegmental area (VTA) or nucleus accumbens (NAc) shell, attenuated cocaine-primed reinstatement. Combined, these data indicate that α1AR activation in the mPFC is required for cocaine-primed reinstatement, and suggest that α1AR antagonists merit further investigation as pharmacotherapies for cocaine dependence.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Norepinefrina/farmacología , Corteza Prefrontal/efectos de los fármacos , Receptores Adrenérgicos alfa 1/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Animales , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Condicionamiento Operante/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Extinción Psicológica/efectos de los fármacos , Alimentos , Masculino , Núcleo Accumbens/efectos de los fármacos , Prazosina/análogos & derivados , Prazosina/farmacología , Corteza Prefrontal/metabolismo , Ratas , Ratas Sprague-Dawley , Esquema de Refuerzo , Autoadministración , Área Tegmental Ventral/efectos de los fármacosRESUMEN
Brain-derived neurotrophic factor (BDNF) affects synaptic plasticity and neural structure and plays key roles in learning and memory processes. Recent evidence also points to important, yet complex, roles for BDNF in rodent models of cocaine abuse and addiction. Here we examine the role of prefrontal cortical (PFC) BDNF in reward-related decision making and behavioral sensitivity to, and responding for, cocaine. We focus on BDNF within the medial and orbital PFC, its regulation by cocaine during early postnatal development and in adulthood, and how BDNF in turn influences responding for drug reinforcement, including in reinstatement models. When relevant, we draw comparisons and contrasts with experiments using natural (food) reinforcers. We also summarize findings supporting, or refuting, the possibility that BDNF in the medial and orbital PFC regulate the development and maintenance of stimulus-response habits. Further investigation could assist in the development of novel treatment approaches for cocaine use disorders.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cocaína/farmacología , Toma de Decisiones/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Animales , Toma de Decisiones/fisiología , Humanos , Plasticidad Neuronal/fisiología , Corteza Prefrontal/metabolismo , RecompensaRESUMEN
There have been recent calls to examine the efficacy of drug-combination therapies in the treatment of substance use disorders. The purpose of the present study was to examine the ability of a novel stimulant-opioid combination to reduce cocaine self-administration, and to compare these effects to those of each drug administered alone. To this end, male Long-Evans rats were implanted with intravenous catheters and trained to self-administer cocaine under positive reinforcement contingencies. Once self-administration was acquired, rats were divided into four different groups and treated chronically for 20 days with (1) saline, (2) the psychomotor stimulant and monoamine releaser amphetamine, (3) the mu/kappa opioid agonist butorphanol, or (4) a combination of amphetamine and butorphanol. During chronic treatment, cocaine self-administration was examined on both fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. On the FR schedule, butorphanol significantly decreased cocaine self-administration, but this effect was not enhanced by amphetamine. On the PR schedule, amphetamine and butorphanol non-significantly decreased cocaine self-administration when administered alone but significantly decreased cocaine self-administration when administered in combination. These data suggest that under some conditions (e.g., when the response requirement of cocaine is high), a dual stimulant-opioid pharmacotherapy may be more effective than a single-drug monotherapy.
Asunto(s)
Anfetamina/farmacología , Butorfanol/farmacología , Cocaína/administración & dosificación , Condicionamiento Operante/efectos de los fármacos , Inhibidores de Captación de Dopamina/administración & dosificación , Narcóticos/farmacología , Animales , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ingestión de Líquidos/efectos de los fármacos , Combinación de Medicamentos , Masculino , Ratas , Ratas Long-Evans , AutoadministraciónRESUMEN
BACKGROUND: selection models of substance use propose that individuals choose or self-select into peer groups based on shared substance use histories. Few experimental studies have examined the role of selection in substance use, possibly because few preclinical models allow subjects to choose or select individuals based on a shared self-administration history. METHODS: In the present study, we used custom-built, three-compartment, operant conditioning chambers that permitted multiple rats to self-administer cocaine simultaneously in the same session. Rats assigned to the center compartment had access to two response levers, each in close physical proximity to one of its partners. In one group, a rat with access to cocaine was assigned to the center compartment and flanked by one rat with access to cocaine and one rat without access. In a second group, a rat without access to cocaine was assigned to the center compartment and flanked by one rat with access to cocaine and one rat without access. RESULTS: In the first group, rats with access to cocaine emitted more responses on the lever in close proximity to the other rat with access to cocaine; in the second group, rats without access to cocaine emitted more responses on the lever in close proximity to the other rat without access. These preferences were not apparent immediately but developed gradually over the course of several days of testing. CONCLUSION: These data suggest that rats prefer to be in close physical proximity to another rat with a shared behavioral history during periods of drug self-administration.
Asunto(s)
Conducta de Elección/efectos de los fármacos , Cocaína/administración & dosificación , Condicionamiento Operante/efectos de los fármacos , Modelos Animales , Grupo Paritario , Conducta Social , Animales , Masculino , Ratas , Ratas Long-Evans , AutoadministraciónRESUMEN
Social-learning theories of substance use propose that members of peer groups influence the drug use of other members by selectively modeling, reinforcing, and punishing either abstinence-related or drug-related behaviors. The objective of the present study was to examine the social influences on cocaine self-administration in isolated and socially housed rats, under conditions where the socially housed rats were tested simultaneously with their partner in the same chamber. To this end, male rats were obtained at weaning and housed in isolated or pair-housed conditions for 6 weeks. Rats were then implanted with intravenous catheters and cocaine self-administration was examined in custom-built operant conditioning chambers that allowed two rats to be tested simultaneously. For some socially housed subjects, both rats had simultaneous access to cocaine; for others, only one rat of the pair had access to cocaine. An econometric analysis was applied to the data, and the reinforcing strength of cocaine was measured by examining consumption (i.e. quantity demanded) and elasticity of demand as a function of price, which was manipulated by varying the dose and ratio requirements on a fixed ratio schedule of reinforcement. Cocaine consumption decreased as a function of price in all groups. Elasticity of demand did not vary across groups, but consumption was significantly lower in socially housed rats paired with a rat without access to cocaine. These data suggest that the presence of an abstaining peer decreases the reinforcing strength of cocaine, thus supporting the development of social interventions in drug abuse prevention and treatment programs.
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Estimulantes del Sistema Nervioso Central/administración & dosificación , Trastornos Relacionados con Cocaína/psicología , Cocaína/administración & dosificación , Modelos Econométricos , Modelos Psicológicos , Conducta Social , Animales , Conducta Animal/efectos de los fármacos , Trastornos Relacionados con Cocaína/prevención & control , Condicionamiento Operante , Masculino , Análisis por Apareamiento , Actividad Motora/efectos de los fármacos , Grupo Paritario , Distribución Aleatoria , Ratas , Ratas Long-Evans , Refuerzo en Psicología , Autoadministración , Aislamiento Social , DesteteRESUMEN
BACKGROUND: The purpose of this study was to examine the effects of voluntary wheel running on the positive reinforcing effects of heroin in rats with an established history of drug self-administration. METHODS: Rats were assigned to sedentary (no wheel) and exercise (wheel) conditions and trained to self-administer cocaine under positive reinforcement contingencies. Rats acquiring cocaine self-administration were then tested with various doses of heroin during daily test sessions. RESULTS: Sedentary rats self-administered more heroin than exercising rats, and this effect was greatest at low and moderate doses of heroin. CONCLUSION: These data suggest that voluntary wheel running decreases the positive reinforcing effects of heroin.
Asunto(s)
Heroína/administración & dosificación , Condicionamiento Físico Animal/fisiología , Carrera/fisiología , Animales , Cocaína/administración & dosificación , Masculino , Ratas , Ratas Long-Evans , Esquema de Refuerzo , Autoadministración/métodosRESUMEN
Physical activity decreases cocaine self-administration in laboratory animals and is associated with positive outcomes in substance abuse treatment programs; however, less is known about its efficacy in preventing the establishment of regular patterns of substance use in drug-naive individuals. The purpose of the present study was to examine the effects of access to a running wheel on the acquisition of cocaine self-administration in experimentally naive rats. Male, Long-Evans rats were obtained at weaning and assigned to sedentary (no wheel) or exercising (access to wheel) conditions immediately upon arrival. After six weeks, rats were surgically implanted with intravenous catheters and placed in operant conditioning chambers for 2 h/day for 15 consecutive days. Each session began with a noncontingent priming infusion of cocaine, followed by a free-operant period in which each response on the active lever produced an infusion of cocaine on a fixed ratio (FR1) schedule of reinforcement. For days 1-5, responding was reinforced with 0.25 mg/kg/infusion cocaine; for days 6-15, responding was reinforced with 0.75 mg/kg/infusion cocaine. In addition, all rats were calorically restricted during days 11-15 to 85% to 95% of their free-feeding body weight. Compared to sedentary rats, exercising rats acquired cocaine self-administration at a significantly slower rate and emitted significantly fewer active lever presses during the 15 days of behavioral testing. These data indicate that access to a running wheel inhibits the acquisition of cocaine self-administration, and that physical activity may be an effective intervention in substance abuse prevention programs.