Projection neurons of nucleus accumbens (NAC) of the rat were identified by either antidromic activation from stimulation of midbrain ventral tegmental area-substantia nigra (VTA-SN) regions, or by tracing axons of intracellularly labeled NAC neurons into the ventral pallidum. The morphology of these NAC projection neurons were determined to be medium spiny neurons similar to those identified in the caudate-putamen.

Indiana University-Purdue University Indianapolis (IUPUI) / Communication is a vital tool used by humans to share information, coordinate behavior, and survive. However, the ability to communicate can become disrupted or remain absent in individuals with neurodevelopmental disorders: two prominent examples include autism spectrum disorders and developmental language disorders, found in nearly 2% and 10% of the population, respectively. Communication disorders are devastating to the autonomy and quality of life of affected individuals, but clinical solutions are limited due to the complex and often unknown neural etiology underlying these conditions. One known disorder with high incidence of disrupted communication is Neurofibromatosis type 1, the genetic disease caused by heterozygosity of the Ras GTPase-activating protein-coding gene NF1. Mice heterozygous for their ortholog of this gene (Nf1+/-) have been shown to recapitulate neuropsychiatric conditions seen in patients. Using a courtship trial paradigm as a model for testing communication, I have demonstrated that Nf1+/- male mice showed deficits in both courtship and non-courtship social behavior as well as a decrease in the number and duration of ultrasonic vocalizations (USVs). Immediate early gene (IEG) immunohistochemistry (IHC) in neurons of courtship-relevant brain regions revealed the Shell of the Nucleus Accumbens (NAcS) as a dysfunctional brain region in Nf1+/- mice compared to WT male mice following courtship trial. Optogenetic targeting of the Nucleus Accumbens (NAc) restored courtship social behaviors and USV number, but not USV duration or non-courtship gestural social behaviors, in Nf1+/- males. This study contributes to a preclinical foundation for understanding etiology of communication disorders in patients.

The purpose of this project was to investigate the mechanism of action of acupuncture on a critical neural substrate involved in alcoholism. Specifically, this study evaluated the effects of stimulation of the acupuncture Shenmen (HT7) point on inhibitory GABA neurons in the ventral tegmental area (VTA), a midbrain structure implicated in drug and alcohol abuse, and ethanol self-administration. In addition, the role of opioid receptors (ORs) in ethanol and acupuncture effects was explored. Using electrophysiological methods in mature rats, we evaluated the effects of HT7 stimulation and opioid antagonists on the VTA GABA neuron firing rate. With behavioral paradigms, we also assessed those effects on ethanol self-administration, using a modification of the sucrose fading procedure. We found that HT7 stimulation produced a biphasic modulation of VTA GABA neuron firing rate characterized by transient enhancement at the onset of stimulation followed by a prolonged inhibition and subsequent recovery in 5 min. HT7 stimulation blocked the typical suppression of VTA GABA neuron firing rate produced by a moderately intoxicating dose of ethanol. The late inhibition produced by HT7 stimulation as well as HT7 reversal of ethanol's effects on GABA neuron firing rate was blocked by the non-selective opioid receptor antagonist, naloxoneIn addition, HT7 acupuncture reduced ethanol self-administration without affecting sucrose consumption. More important, systemic administration of the δ-opioid receptor (DOR) antagonist, naltrindole blocked ethanol suppression of VTA GABA neuron firing rate and significantly reduced ethanol self-administration without affecting sucrose consumption. These findings suggest that DOR-mediated opioid modulation of VTA GABA neurons may be related to the role of acupuncture in modulating mesolimbic DA release and suppressing the reinforcing effects of ethanol. We confirmed that acupuncture stimulation may have a significant impact on the inhibitory neuron activity in the VTA and that acupuncture may serve as an effective adjunct to OR antagonist therapy for alcoholism.

Alcohol use disorder (AUD) is a chronic, relapsing condition with a complex etiology and heritable susceptibility factors interact with environmental factors to produce and maintain the disease. One goal of current neuroscience research is to identify the neuroadaptations mediating the propensity to consume high amounts of alcohol, of either innate or environmental origin. Dysfunctional neuronal communication between prefrontal cortical regions and the nucleus accumbens (NAcc) have been implicated in excessive alcohol drinking and proposed to play a critical role in AUD. However, the exact mechanism by which altered prefrontostriatal transmission may perpetuate excessive drinking is poorly understood. In addition, the exact role of dopamine receptor 1 (D1R) or dopamine receptor 2 (D2R)-expressing medium spiny neurons in the NAcc is unclear and adds another layer of complexity to this framework. This thesis concerns pituitary adenylate cyclase-activating polypeptide (PACAP), a highly conserved 38 amino acid neuropeptide, and its receptor PAC1R. Studies in rodents and humans have implicated PACAP and PAC1R in the actions of drugs of abuse, including more recently, alcohol. Notably, the PACAP/PAC1R system has also been shown to increase glutamatergic neurotransmission in several circuits. The overall hypothesis of this project was that the PACAP/PAC1 system in the prefrontal cortex-NAcc pathway regulates excessive drinking and the long-lasting neuroplastic changes observed in alcohol addiction, via the modulation of the glutamatergic system. Using alcohol-preferring rats, a hereditary model of AUD, we found that intracerebroventricular administration of a PAC1R antagonist blocked excessive alcohol drinking, motivation to drink, and alcohol seeking behavior selectively in this line and not in outbred rats. Alcohol-preferring rats displayed a higher number of PAC1R positive cells in the NAcc Core. Blockade of PAC1R in the NAcc Core, via pharmacology or gene knockdown, resulted in reduced alcohol drinking. Conversely, we found that knockdown of the PAC1R in the NAcc Shell led to increased alcohol drinking and motivation to drink in alcohol-preferring rats, suggesting that the PACAP/PAC1R system may play an opposite role in these two NAcc subregions. Using a mouse exposure model of excessive drinking, a glutamatergic projection from PACAP-expressing cells in the prelimbic portion of the prefrontal cortex (PrL) to the NAcc Core circuit was found to be recruited by alcohol exposure. Inhibition of these neurons, as well as PACAP neuron ablation or PACAP deletion, led to decreased alcohol intake that was specific to male mice. Systemic PAC1R antagonism, and specific knockdown of PAC1R in the NAcc Core, also decreased alcohol intake in male mice. Using slice electrophysiology and channelrhodopsin assisted circuit mapping, we found that this pathway is biased to D1R-expressing neurons in the NAcc Core following alcohol exposure in males, and that PACAP application increases post-synaptic measures of glutamatergic transmission in this circuit. Overall, these data describe a key role for the corticostriatal PACAP/PAC1R system in aberrant alcohol drinking in both hereditary- and exposure-based models of AUD and give novel insights into the underlying mechanisms of alcohol addiction. / 2025-01-23T00:00:00Z

Die These fasst die ersten Untersuchungen zum Pawlowsch`-Instrumentellen Transfer in alkoholabhängigen (AA) Patienten zusammen. Es ist bekannt, dass kontextuelle Umgebungsreize Verhalten beeinflussen. Tier- und Humanstudien haben gezeigt, dass positive Pawlowsche Reize instrumentelles Antwortverhalten verstärken und negative Pawlowsche Reize dieses reduzieren (PIT-Effekt). Bei Abhängigkeit wird angenommen, dass dieser Mechanismus relevant für Rückfall ist, da z.B. drogenassoziierte Reize bei Patienten im Vergleich zu Kontrollen erhöhtes Verlagen und funktionelle Aktivität in Belohnungsarealen auslösen. In Tier- und Humanstudien wurden stärkere PIT-Effekte vor allem mit funktioneller Aktivierung im Nucleus Accumbens (NAcc) beobachtet. Weiterhin zeigten sich bei Probanden mit stärkerem PIT-Effekt und bei AA Patienten erhöhte Impulsivitätswerte. Die PIT-Aufgabe besteht aus 3 Hauptteilen: i) Instrumentelle Konditionierung, ii) Pawlowsche Konditionierung, iii) Transfer mit Pawlowschen oder alkoholassoziierten Kontextstimuli. Impulsives Auswahlverhalten wurde durch die delay discounting Aufgabe erhoben. Es zeigten sich signifikant stärkere PIT-Effekte mit Pawlowschen Kontextreizen in AA Patienten im Vergleich zu Kontrollen mit funktioneller Aktivierung im NAcc, die zur Rückfallvorhersage beitrug. Der Transfer mit alkoholassoziierten Kontextreizen bewirkte eine signifikante Reduktion des instrumentellen Antwortverhaltens mit neuronalem Korrelat im NAcc nur bei abstinenten Patienten. Impulsives Auswahlverhalten und PIT hingen nur bei Patienten positiv zusammen. Die Studien lassen darauf schließen, dass PIT ein für Rückfall wichtiger Mechanismus ist mit funktionellem Korrelat im NAcc, der sich für motivationale Prozesse als auch als Salienzsignal relevant gezeigt hat. Die Subgruppe von hoch impulsiven Patienten ist im Besonderen durch Kontextreize im instrumentellen Antwortverhalten beeinflussbar, daher sollte ihr besondere Aufmerksamkeit bei Interventionen zukommen. / This thesis summarizes the first Pavlovian-to-instrumental transfer (PIT) studies in alcohol-dependent (AD) patients. Contextual stimuli are known to influence our behavior. Animal and human studies showed that positive Pavlovian stimuli enhance and negative Pavlovian stimuli reduce instrumental behavior (PIT effect). This mechanism might be relevant for relapse risk, as drug-associated stimuli have shown to enhance e.g. craving and functional activation in reward-related brain areas in patients compared to controls. In animal and human studies enhanced PIT effects were associated with activation particularly in the nucleus accumbens (NAcc). Moreover, control subjects with stronger PIT effects and AD patients were more impulsive on different facets of impulsivity. The PIT task consists of three main parts: i) instrumental conditioning, ii) Pavlovian conditioning, iii) transfer with Pavlovian background stimuli and instrumental task in the foreground (nondrug-related PIT: Pavlovian contextual cues; drug-related PIT: alcohol-related contextual cues). Choice impulsivity was measured by delay discounting task. We observed significantly enhanced nondrug-related PIT effects in AD patients compared to controls with a functional activation in the NAcc being predictive for relapse. Regarding drug-related PIT effects, we observed significantly reduced instrumental behavior during alcohol-related backgrounds with neural correlates in the NAcc in abstainers only. Choice impulsivity was positively related to PIT in AD patients only. Our data suggest that PIT is a mechanism contributing to relapse in AD patients with functional correlations within the NAcc, which based on our data is involved in motivation and attribution of salience. The subgroup of high impulsive patients is particularly susceptible for PIT effects, thus should be main target for intervention programs.

No description available.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 5 uppsatser.

Le sommeil a un effet sur la mémoire mais également sur l'oubli. Nous avons soumis des rats à des tâches impliquant différents degrés d'oubli. Ces tâches, impliquant mémoire de référence (MR), ou mémoire de travail (MT) avec différents niveaux d'interférences, ont été réalisées dans un même dispositif comportemental. Alors que nous avons observés une augmentation du sommeil paradoxal (SP) lors de la tâche de MR, les performances en MT nécessitant l'oubli sont dépendantes du sommeil lent (SL). Seuls les rats entrainés en MR montrent une augmentation du thêta phasique durant le SP, ainsi que des fuseaux durant le SL. Ces résultats indiquent donc un rôle du SP dans les apprentissages spatiaux à long terme alors que la flexibilité comportementale requise en MT semble dépendante du SL. Il existe de nombreuses évidences suggérant que l'apprentissage résulte de modifications synaptiques, et différentes théories suggèrent des rôles différents du SL et du SP dans ces changements. Nous avons donc ensuite examiné l'évolution de la transmission synaptique dans l'hippocampe (HPC), mais aussi entre l'HPC et le cortex préfrontal médian (CPFm) ainsi que le noyau accumbens (NAc). Alors que le SL accroit la transmission synaptique dans l'HPC, le SP la diminue. Au niveau des efférences de l'HPC, le SL diminue la transmission vers le CPFm alors que les épisodes de SP favorisent la communication vers le NAc. Plutôt que de favoriser globalement des processus communs à l'ensemble du cerveau, nos résultats suggèrent que le SL et le SP permettent de rediriger les flux d'informations entre différents réseaux, et que cet aiguillage de l'information est modulé par les oscillations du sommeil / Numerous studies have now demonstrated that sleep has a beneficial influence on memory but also impact forgetting. We have submitted rats to behavioral tasks involving different levels of forgetting. These tasks, implying reference memory (RM) or working memory (WM) with different level of interferences, were executed in the same behavioral apparatus. Whereas we observed an increase of paradoxical sleep (PS) during the RM training, the WM tasks requiring forgetting are dependent on slow-wave sleep (SWS). Only the RM trained rats exhibited an increase in theta bursts during PS, as well as spindles during SWS. These results thus indicate the role of PS in long-term spatial learning, whereas behavioral flexibility required by WM tasks is dependent on SWS. Numerous pieces of evidence suggest that learning is caused by modifications of synaptic connections, and different theories suggest different roles of the SWS and PS to optimize these changes. We sought to understand the evolution of synaptic transmission in the hippocampal network but also between the hippocampus (HPC) and the medial prefrontal cortex (mPFC), as well as between the HPC and the nucleus accumbens (NAc). While SWS increases synaptic transmission in the HPC, PS decreases it rapidly. In contrast and regarding hippocampal efferents, SWS reduces transmission to the mPFC while PS enhances transmission to the NAc. In contrast to the hypotheses posing that sleep promotes a global process common to the entire brain; our results suggest that SWS and PS redirect data flows between different networks, and that this switch between different information pathways could be modulated by the various sleep oscillations

The goal of this dissertation was to investigate the role of μ-opioid receptors in the mechanism of ethanol-stimulated dopamine release in the nucleus accumbens shell (NAcS) of rats. The underlying hypothesis is that blockade of the μ-opioid receptors leads to an attenuation of ethanol-stimulated mesolimbic dopamine release. We prepared ethanol-naïve male Long Evans rats (n = 95) for intravenous (i.v.) drug administration and in vivo microdialysis (in awake, freely moving animals), and analyzed our samples using HPLC and GC for dopamine and ethanol detection, respectively. In one set of experiments, we looked at the effects of naltrexone, a non-selective opioid antagonist, on ethanol-stimulated mesolimbic dopamine release. First of all, we checked to see if naltrexone affected basal dopamine levels in the NAcS. Thereafter, we looked for a dose of naltrexone (i.v.) that was effective in suppressing the release of dopamine in the NAcS evoked by morphine (1 mg/kg, i.v.). Subsequently, we checked to see if doses of naltrexone that inhibited morphine-evoked dopamine were also effective in attenuating dopamine release due to ethanol (1g/kg, 10% w/v, i.v.). To do this, we pretreated rats with naltrexone doses, followed 20 min later by morphine, ethanol or saline (all drugs were administered i.v.). In another set of experiments, we looked at the effect of β-funaltrexamine, a selective μ-opioid antagonist, on ethanol-stimulated dopamine release in the NAcS. Similarly to the previous set of experiments, we looked for a dose of β-funaltrexamine (s.c.) that was effective in suppressing the release of dopamine the NAcS evoked by morphine (1 mg/kg, i.v.), and checked to see if this dose of β-funaltrexamine was also effective in attenuating ethanol-stimulated dopamine release in the NAcS. For the β- funaltrexamine experiments, rats were pretreated with β-funaltrexamine (s.c.) 20- 25 h before i.v. infusions of saline, morphine and ethanol. Morphine increased dopamine release in the NAcS. Naltrexone and β- funaltrexamine significantly attenuated morphine-evoked dopamine release. Also, ethanol increased dopamine release in the NAcS. Naltrexone and β- funaltrexamine, at doses effective in attenuating morphine-evoked dopamine release, suppressed the prolongation, but not the initiation of dopamine release in the NAcS due to ethanol. Naltrexone and β-funaltrexamine did not affect the peak concentration and clearance of ethanol in the brain. The conclusion of this study is that the μ-opioid receptors are involved in a delayed component of ethanol-stimulated dopamine release in the NAcS in ethanol-naïve rats. This is the first study to show that the ethanol-stimulated dopamine response consists of a delayed μ-opioid mechanism. / text

Stress is a major risk factor for substance abuse. Intermittent social defeat stress increases drug self-administration (SA) and elevates brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area (VTA) in rats. Intra-VTA BDNF overexpression enhances social defeat stress-induced cross-sensitization to psychostimulants and induces nucleus accumbens (NAc) ΔFosB expression. Therefore, increased VTA BDNF may mimic or augment the development of drug abuse-related behavior following social stress. To test this hypothesis, adeno-associated virus (AAV) was infused into the VTA to overexpress either GFP alone (control) or GFP + BDNF. Rats were then either handled or exposed to intermittent social defeat stress before beginning cocaine SA training. The SA acquisition and maintenance phases were followed by testing on a progressive ratio (PR) schedule of cocaine reinforcement, and then during a 12-h access "binge" cocaine SA session. BDNF and ΔFosB were quantified postmortem in regions of the mesocorticolimbic circuitry using immunohistochemistry. Social defeat stress increased cocaine intake on a PR schedule, regardless of virus treatment. While stress alone increased intake during the 12-h binge session, socially-defeated rats that received VTA BDNF overexpression exhibited even greater cocaine intake compared to the GFP-stressed group. However, VTA BDNF overexpression alone did not alter binge intake. BDNF expression in the VTA was also positively correlated with total cocaine intake during binge session. VTA BDNF overexpression increased ΔFosB expression in the NAc, but not in the dorsal striatum. Here we demonstrate that VTA BDNF overexpression increases long-access cocaine intake, but only under stressful conditions. Therefore, enhanced VTA-BDNF expression may be a facilitator for stress-induced increases in drug abuse-related behavior specifically under conditions that capture compulsive-like drug intake.