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The prefrontal cortex regulates emotions and is influenced by serotonin. Rodents lacking the serotonin transporter (5-HTT) show increased anxiety and changes in excitatory and inhibitory cell markers in the prefrontal cortex. However, these observations are constrained by limitations in brain representation and cell segmentation, as standard immunohistochemistry is inadequate to consider volume variations in regions of interest. We utilized the deep learning network of the StarDist method in combination with novel open-source methods for automated cell counts in a wide range of prefrontal cortex subregions. We found that 5-HTT knockout rats displayed increased anxiety and diminished relative numbers of subclass excitatory VGluT2+ and activated ΔFosB+ cells in the infralimbic and prelimbic cortices and of inhibitory GAD67+ cells in the prelimbic cortex. Anxiety levels and ΔFosB cell counts were positively correlated in wild-type, but not in knockout, rats. In conclusion, we present a novel method to quantify whole brain subregions of multilabeled cells in animal models and demonstrate reduced excitatory and inhibitory neuronal marker expression in prefrontal cortex subregions of 5-HTT knockout rats., (© The Author(s) 2025. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Human neuroimaging studies indicate that the amygdala plays a key role in cocaine addiction. One key plasticity factor that modulates effects of cocaine on the brain is Brain-Derived Neurotrophic Factor (BDNF). A wealth of evidence shows that cocaine exposure alters BDNF signaling in corticolimbic structures, but, surprisingly, such evidence is very limited for the amygdala. Additionally, while BDNF is strongly regulated by serotonin levels and inherited serotonin transporter down-regulation is associated with increased vulnerability to cocaine addiction, the effects of serotonin transporter genotype on BDNF signaling in the amygdala under naïve and cocaine exposure conditions are unknown., Methods: We measured BDNF signaling in the central amygdala of wild-type and serotonin transporter knockout rats 24 h into withdrawal from long-access cocaine self-administration., Results: In wild-type rats mature BDNF (mBDNF) protein levels were decreased, whereas the phosphorylation of its receptor TrkB as well as of its intracellular signaling molecules Akt and ERK1 were increased. mBDNF protein expression and its signaling in cocaine-naïve serotonin transporter knockout rats resembled that of wild-type rats with a history of long-access cocaine self-administration. Interestingly, cocaine-exposed serotonin transporter knockout rats showed increased BDNF levels, with no signs of phospho-TrkB receptor coupling to phospho-Akt and phospho-ERK1., Conclusions: Long-access cocaine self-administration dysregulates BDNF signaling in the central amygdala. Vulnerability to cocaine addiction is associated with dysregulation of this signaling., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Evidence based treatment for Substance use disorders (SUD) includes psychotherapy and pharmacotherapy. However, these are only partially effective. Hallucinogens, such as psilocybin, may represent potential new treatment options for SUD. This review provides a summary of (human) studies on the putative therapeutic effects of psilocybin, and discusses the receptor systems, brain regions and cognitive and emotional processes mediating psilocybin's effects. Psilocybin's chemical structure is similar to that of serotonin. Dysregulations in the serotonin system are associated with alterations in stress hormones, such as cortisol, and mood disorders. After psilocybin administration cortisol levels spike and activate the executive control network, with subsequent increased control over emotional processes, and relief of negative thinking and persistent negative emotions. Preliminary data of ongoing alcohol and smoking addiction studies in humans shows promising effects of psilocybin administration on substance use. Importantly, psilocybin has a low risk of toxicity and dependence and can be used safely under controlled clinical conditions. Areas covered: This paper is a narrative review based on the search terms: psilocybin, substance use disorder, addiction, depression, serotonin. Literature on potential efficacy and mechanisms of action of psilocybin in SUD is discussed. Expert commentary: Recent positive findings with psilocybin need confirmation in well-designed placebo controlled randomized trials employing a large sample size.

Unlabelled: Cocaine exposure alters brain-derived neurotrophic factor (BDNF) expression in the brain. BDNF signaling through TrkB receptors differentially modulates cocaine self-administration, depending on the brain regions involved. In the present study, we determined how brain-wide inhibition of TrkB signaling affects cocaine intake, the motivation for the drug, and reinstatement of drug taking after extinction. To overcome the inability of TrkB ligands to cross the blood-brain barrier, the TrkB antagonist cyclotraxin-B was fused to the nontoxic transduction domain of the tat protein from human immunodeficiency virus type 1 (tat-cyclotraxin-B). Intravenous injection of tat-cyclotraxin-B dose-dependently reduced cocaine intake, motivation for cocaine (as measured under a progressive ratio schedule of reinforcement), and reinstatement of cocaine taking in rats allowed either short or long access to cocaine self-administration. In contrast, the treatment did not affect operant responding for a highly palatable sweet solution, demonstrating that the effects of tat-cyclotraxin-B are specific for cocaine reinforcement. Cocaine self-administration increased TrkB signaling and activated the downstream Akt pathway in the nucleus accumbens, and had opposite effects in the prefrontal cortex. Pretreatment with tat-cyclotraxin-B normalized protein levels in these two dopamine-innervated brain regions. Cocaine self-administration also increased TrkB signaling in the ventral tegmental area, where the dopaminergic projections originate, but pretreatment with tat-cyclotraxin-B did not alter this effect. Altogether, our data show that systemic administration of a brain-penetrant TrkB antagonist leads to brain region-specific effects and may be a potential pharmacological strategy for the treatment of cocaine addiction., Significance Statement: Brain-derived neurotrophic factor (BDNF) signaling through TrkB receptors plays a well established role in cocaine reinforcement. However, local manipulation of BDNF signaling yields divergent effects, depending on the brain region, thereby questioning the viability of systemic TrkB targeting for the treatment of cocaine use disorders. Our study provides first-time evidence that systemic administration of a brain-penetrant TrkB antagonist (tat-cyclotraxin-B) reduces several behavioral measures of cocaine dependence, without altering motor performance or reinforcement by a sweet palatable solution. In addition, although cocaine self-administration produced opposite effects on TrkB signaling in the nucleus accumbens and prefrontal cortex, tat-cyclotraxin-B administration normalized these cocaine-induced changes in both brain regions., (Copyright © 2016 the authors 0270-6474/16/368150-11$15.00/0.)

It has previously been demonstrated that mesolimbic α-adrenoceptors, but not β-adrenoceptors, control the release of dopamine that is derived from reserpine-sensitive storage vesicles. The aim of the present study was to investigate whether these storage vesicles also regulate α-adrenoceptor-mediated or β-adrenoceptor-mediated changes in behaviour. Accordingly, rats were pretreated with reserpine before the α-adrenoceptor antagonist phentolamine or the β-adrenoceptor agonist isoproterenol was locally applied to the nucleus accumbens. Both phentolamine and isoproterenol increased the duration of walking, rearing and grooming and decreased the duration of sitting. Reserpine counteracted the behavioural response elicited by phentolamine but not by isoproterenol. The results of the present study demonstrate that mesolimbic α-adrenoceptors, but not β-adrenoceptors, regulate behaviour that is mediated by reserpine-sensitive storage pools. It is hypothesized that the observed α-adrenoceptor-mediated increase in locomotor activity is due to the α-adrenoceptor-mediated increase in the release of accumbal intravesicular dopamine. Our finding that α-adrenoceptors inhibit, whereas β-adrenoceptors stimulate, locomotor activity may help explain why noradrenaline or environmental stressors have previously been found to have opposing effects on the regulation of behaviour.

Although several lines of evidence have shown that chronic cocaine use is associated with stress system dysregulation, the underlying neurochemical mechanisms are still elusive. To investigate whether the rapid stress-induced response of the glutamatergic synapse was influenced by a previous history of cocaine, rats were exposed to repeated cocaine injections during adolescence [from postnatal day (PND) 28-42], subjected to a single swim stress (5 minutes) three days later (PND 45) and sacrificed 15 minutes after the end of this stressor. Critical determinants of glutamatergic homeostasis were measured in the medial prefrontal cortex (mPFC) whereas circulating corticosterone levels were measured in the plasma. Exposure to stress in saline-treated animals did not show changes in the crucial determinants of the glutamatergic synapse. Conversely, in cocaine-treated animals, stress dynamically altered the glutamatergic synapse by: (1) enhancing the presynaptic vesicular mediators of glutamate release; (2) reducing the transporters responsible for glutamate clearance; (3) increasing the postsynaptic responsiveness of the N-methyl-D-aspartate subunit GluN1; and (4) causing hyperresponsive spines as evidenced by increased activation of the postsynaptic cdc42-Pak pathway. These findings indicate that exposure to cocaine during adolescence sensitizes mPFC glutamatergic synapses to stress. It is suggested that changes in glutamatergic signaling may contribute to the increased sensitivity to stress observed in cocaine users. Moreover, glutamatergic processes may play an important role in stress-induced reinstatement of cocaine seeking., (© 2013 Society for the Study of Addiction.)

Introduction: There are currently no treatments approved by the FDA to effectively treat cocaine dependence. Research of recent years has gradually revealed the importance of 5-hydroxytryptamine (5-HT) in the reinforcing and rewarding effects of cocaine and the potential for relapse. Brain-derived neurotropic factor (BDNF) is an important modulator of the serotonergic system and 5-HT modulates BDNF expression. Their reciprocal interaction is of crucial importance for synaptic plasticity during long-term cocaine intake. Thus, agents modifying BDNF-5-HT interactions might have therapeutic potential for cocaine dependence by reversing the altered brain structure that underlies relapse after cocaine withdrawal., Areas Covered: On the basis of the available literature, the authors propose an interaction between BDNF and the serotonergic system in the response to cocaine and during cocaine intake. Furthermore, they discuss putative therapies that are based on 5-HT and BDNF., Expert Opinion: Recent studies are beginning to elucidate the role of 5-HT and BDNF in cocaine addiction. Additionally, animal studies modeling addiction-like drug intake will only further help to gain a better understanding of how to treat cocaine addiction. Based on the current evidence, the authors believe that BDNF, as a modulator of the serotonergic pathway, or 5-HT, as a modulator of the BDNF system, represent a valuable target to treat drug addiction, which may yield novel therapeutics in the future.

It has recently been proposed that the increased reinforcing properties of cocaine and ecstasy observed in rats with a genetic deletion of serotonin transporters are the result of a reduction in the psychostimulant-induced release of serotonin. Here we provide the neurochemical evidence in favor of this hypothesis and show that changes in synaptic levels of dopamine or noradrenaline are not very likely to play an important role in the previously reported enhanced psychostimulant intake of these serotonin transporter knockout rats. The results may very well explain why human subjects displaying a reduced expression of serotonin transporters have an increased risk to develop addiction., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

Previous studies have shown that intra-accumbens infusion of isoproterenol (ISO), a beta-adrenoceptor-agonist, and phenylephrine (PE), an alpha-adrenoceptor-agonist, increase the release of accumbal dopamine (DA). In the present study we analyzed whether the ISO-induced release of DA is sensitive to pretreatment with the DA synthesis inhibitor alpha-methyl-para-tyrosine (AMPT). Earlier studies have shown that the PE-induced release of DA is derived from DA pools that are resistant to AMPT. In addition to PE, the alpha-adrenoceptor-antagonist phentolamine (PA) was also found to increase accumbal DA release. Therefore, we investigated whether similar to the DA-increasing effect of PE, the DA increase induced by PA is resistant to AMPT. Pretreatment with AMPT prevented the ISO-induced increase of accumbal DA. The accumbal DA increase after PA was not reduced by the DA synthesis inhibitor, independently of the amount of DA released. These results show that mesolimbic beta-, but not alpha-adrenoceptors, control the release of accumbal newly-synthesized DA pools. The DA-increasing effects of PE have previously been ascribed to stimulation of presynaptic receptors located on noradrenergic terminals, whereas the DA-increasing effects of PA and ISO have been ascribed to an action of these drugs at postsynaptic receptors on dopaminergic terminals. The fact that AMPT did not affect the accumbal DA response to PE and PA, whereas it did prevent the accumbal DA increase to ISO, supports our previously reported hypothesis that the noradrenergic neurons of the nucleus accumbens containing presynaptic alpha-adrenoceptors impinge upon the dopaminergic terminals in the nucleus accumbens containing postsynaptic adrenoceptors of the alpha but not of the beta type. The putative therapeutic effects of noradrenergic agents in the treatment of DA-related disorders are shortly discussed.

Schizophrenia is a complex mental disorder caused by an interplay between genetic and environmental factors, including early postnatal stressors. To explore this issue, we use two rat lines, apomorphine-susceptible (APO-SUS) rats that display schizophrenia-relevant features and their phenotypic counterpart, apomorphine-unsusceptible (APO-UNSUS) rats. These rat lines differ not only in their gnawing response to apomorphine, but also in their behavioral response to novelty (APO-SUS: high, APO-UNSUS: low). In this study, we examined the effects of early postnatal cross-fostering on maternal care and on the phenotypes of the cross-fostered APO-SUS and APO-UNSUS animals later in life. Cross-fostered APO-UNSUS animals showed decreased body weights as pups and decreased novelty-induced locomotor activity as adults (i.e., more extreme behavior), in accordance with the less appropriate maternal care provided by APO-SUS vs. their own APO-UNSUS mothers (i.e., the APO-SUS mother displayed less non-arched-back nursing and more self-grooming, and was more away from its nest). In contrast, cross-fostered APO-SUS animals showed increased body weights as pups and reduced apomorphine-induced gnawing later in life (i.e., normalization of their extreme behavior), in line with the more appropriate maternal care provided by APO-UNSUS relative to their own APO-SUS mothers (i.e., the APO-UNSUS mother displayed more non-arched-back nursing and similar self-grooming, and was not more away). Furthermore, we found that, in addition to arched-back nursing, non-arched-back nursing was an important feature of maternal care, and that cross-fostering APO-SUS mothers, but not cross-fostering APO-UNSUS mothers, displayed increased apomorphine-induced gnawing. Thus, cross-fostering not only causes early postnatal stress shaping the phenotypes of the cross-fostered animals later in life, but also affects the phenotypes of the cross-fostering mothers.

Cocaine use leads to addiction in only a subset of individuals. Understanding the mechanisms underlying these individual differences in the transition from cocaine use to cocaine abuse is important to develop treatment strategies. There is agreement that specific behavioural traits increase the risk for addiction. As such, both high impulsivity and high anxiety have been reported to predict (compulsive) cocaine self-administration behaviour. Here, we set out a new view explaining how these two behavioural traits may affect addictive behaviour. According to psychological and psychiatric evolutionary views, organisms flourish well when they fit (match) their environment by trait and genotype. However, under non-fit conditions, the need to compensate the failure to deal with this environment increases, and, as a consequence, the functional use of rewarding drugs like cocaine may also increase. It suggests that neither impulsivity nor anxiety are bad per se, but that the increased risk to develop cocaine addiction is dependent on whether behavioural traits are adaptive or maladaptive in the environment to which the animals are exposed. This 'behavioural (mal)adaptation view' on individual differences in vulnerability to cocaine addiction may help to improve therapies for addiction., (© 2013 The Authors, Addiction Biology © 2013 Society for the Study of Addiction.)

In vivo microdialysis was used to analyse the role of the α(1)- and α(2)-adrenoceptor subtypes in the regulation of noradrenaline and dopamine efflux in the nucleus accumbens of freely moving rats. Intra-accumbal infusion of α(1)-adrenoceptor agonist methoxamine (24pmol) failed to alter the noradrenaline efflux, but decreased the dopamine efflux. The intra-accumbal infusion of α(1)-adrenoceptor antagonist prazosin (6, 600 and 6000pmol) produced a dose-related increase and decrease of the noradrenaline and dopamine efflux, respectively. An ineffective dose of prazosin (6pmol) counteracted the methoxamine (24pmol)-induced decrease of dopamine efflux. The prazosin (6000pmol)-induced increase of noradrenaline efflux, but not the decrease of dopamine efflux, was suppressed by the co-administration of an ineffective dose of methoxamine (0.024pmol). Neither the α(2)-adrenoceptor agonist clonidine (300pmol) and UK 14,304 (300pmol) nor the α(2)-adrenoceptor antagonist RX 821002 (0.6, 3, 600 and 6000pmol) significantly affected the accumbal noradrenaline and dopamine efflux. The doses mentioned are the total amount of drug over the 60-min infusion period. The present results show that (1) accumbal α(1)-adrenoceptors which are presynaptically located on noradrenergic nerve terminals inhibit the accumbal noradrenaline efflux, increasing thereby the accumbal dopamine efflux, (2) accumbal α(1)-adrenoceptors which are postsynaptically located on dopaminergic nerve terminals inhibit the accumbal dopamine efflux, and (3) accumbal α(2)-adrenoceptors play no major role in the regulation of accumbal efflux of noradrenaline and dopamine., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Cocaine addiction is a major health problem that affects millions of people. Cocaine acts by inhibiting dopamine, noradrenaline and serotonin [5-hydroxytryptamine(5-HT)] reuptake. The dopaminergic system is generally assumed to be involved in the reinforcing aspects of the drug, but the role of 5-HT in the addictive potential of cocaine is unclear. In light of pharmacological manipulations and cocaine use-related disease states affecting brain 5-HT levels, we review studies on the effect of cocaine on central 5-HT function. In addition, the contribution of 5-HT to the rewarding, aversive, discriminative and subjective, as well as the motivational and reinforcing effects of cocaine is discussed. We specifically focus on net changes in the extracellular 5-HT levels that occur as a consequence of acute and chronic cocaine exposure and how these influence cocaine abuse-related behaviour. Overall, the data indicate that 5-HT plays a major role in the psychomotor stimulant, rewarding and discriminative stimulant effects of cocaine, but also affects the motivational and reinforcing effects of the drug. In addition, 5-HT mediates, to some extent, the aversive effects of cocaine. Difficulties with data interpretation are discussed.

Current epidemic obesity levels apply great medical and financial pressure to the strenuous economy of obesity-prone cultures, and neuropeptides involved in body weight regulation are regarded as attractive targets for a possible treatment of obesity in humans. The lateral hypothalamus and the nucleus accumbens shell (AcbSh) form a hypothalamic-limbic neuropeptide feeding circuit mediated by Melanin-Concentrating Hormone (MCH). MCH promotes feeding behavior via MCH receptor-1 (MCH1R) in the AcbSh, although this relationship has not been fully characterized. Given the AcbSh mediates reinforcing properties of food, we hypothesized that MCH modulates motivational aspects of feeding.Here we show that chronic loss of the rat MCH-precursor Pmch decreased food intake predominantly via a reduction in meal size during rat development and reduced high-fat food-reinforced operant responding in adult rats. Moreover, acute AcbSh administration of Neuropeptide-GE and Neuropeptide-EI (NEI), both additional neuropeptides derived from Pmch, or chronic intracerebroventricular infusion of NEI, did not affect feeding behavior in adult pmch(+/+) or pmch(-/-) rats. However, acute administration of MCH to the AcbSh of adult pmch(-/-) rats elevated feeding behavior towards wild type levels. Finally, adult pmch(-/-) rats showed increased ex vivo electrically evoked dopamine release and increased limbic dopamine transporter levels, indicating that chronic loss of Pmch in the rat affects the limbic dopamine system.Our findings support the MCH-MCH1R system as an amplifier of consummatory behavior, confirming this system as a possible target for the treatment of obesity. We propose that MCH-mediated signaling in the AcbSh positively mediates motivational aspects of feeding behavior. Thereby it provides a crucial signal by which hypothalamic neural circuits control energy balance and guide limbic brain areas to enhance motivational or incentive-related aspects of food consumption.

Individuals are known to differ in their sensitivity to cocaine. Cocaine is known to inhibit the re-uptake of monoamines. The response to cocaine has also been found to depend on monoamines inside reserpine-sensitive storage vesicles. The present study examined the effects of reserpine (1-2 mg/kg) on cocaine-induced behavior (10-15 mg/kg) in Low Responders (LR) and High Responders (HR) to novelty rats. LR displayed less cocaine-induced walking, wall rearing, free rearing and stereotyped behavior than HR did. The dose of 1 mg/kg of reserpine decreased cocaine-induced walking, wall rearing, free rearing and stereotyped behavior in LR, but not in HR. A dose of 2 mg/kg of reserpine was required to inhibit cocaine-induced behavior in HR. Combining these behavioral findings with our previously reported neurochemical finding that a higher dose of reserpine was required to inhibit the accumbal dopamine response to cocaine in HR than in LR (Verheij et al., 2008), suggests that HR are more sensitive to the behavioral effects of cocaine than LR because cocaine can release more monoamines from storage vesicles in HR than in LR. Our behavioral data also demonstrate that the individual differences in sensitivity to reserpine are not only limited to the dopaminergic system of the nucleus accumbens., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Deficits in sensorimotor gating measured by prepulse inhibition (PPI) of the startle have been known as characteristics of patients with schizophrenia and related neuropsychiatric disorders. PPI disruption is thought to rely on the activity of the mesocorticolimbic dopaminergic system and is inhibited by most antipsychotic drugs. These drugs however act also at the nigrostriatal dopaminergic pathway and exert adverse locomotor responses. Finding a way to inhibit the mesocorticolimbic- without affecting the nigrostriatal-dopaminergic pathway may thus be beneficial to antipsychotic therapies. The melanin-concentrating hormone (MCH) system has been shown to modulate dopamine-related responses. Its receptor (MCH1R) is expressed at high levels in the mesocorticolimbic and not in the nigrostriatal dopaminergic pathways. Interestingly a genomic linkage study revealed significant associations between schizophrenia and markers located in the MCH1R gene locus. We hypothesize that the MCH system can selectively modulate the behavior associated with the mesocorticolimbic dopamine pathway. Using mice, we found that central administration of MCH potentiates apomorphine-induced PPI deficits. Using congenic rat lines that differ in their responses to PPI, we found that the rats that are susceptible to apomorphine (APO-SUS rats) and exhibit PPI deficits display higher MCH mRNA expression in the lateral hypothalamic region and that blocking the MCH system reverses their PPI deficits. On the other hand, in mice and rats, activation or inactivation of the MCH system does not affect stereotyped behaviors, dopamine-related responses that depend on the activity of the nigrostriatal pathway. Furthermore MCH does not affect dizocilpine-induced PPI deficit, a glutamate related response. Thus, our data present the MCH system as a regulator of sensorimotor gating, and provide a new rationale to understand the etiologies of schizophrenia and related psychiatric disorders.

Mesolimbic beta-, but not alpha-adrenoceptors control the accumbal release of dopamine that is derived from alpha-methyl-para-tyrosine-sensitive pools of newly synthesized neurotransmitter. The aim of this study was to investigate which of these adrenoceptors control the accumbal release of dopamine that is derived from reserpine-sensitive pools of previously stored neurotransmitter. Rats, that were divided in low-responders and high-responders to novelty, were pretreated with 1 mg/kg of reserpine before the alpha-adrenergic-agent phentolamine or the beta-adrenergic-agent isoproterenol was locally applied into the nucleus accumbens. The original finding that phentolamine and isoproterenol increased accumbal dopamine levels in low-responders and high-responders was replicated. Reserpine reduced the phentolamine-induced increase of accumbal dopamine in both types of rat. However, phentolamine could still increase accumbal dopamine levels in reserpine-treated high-responders, but not anymore in reserpine-treated low-responders. Reserpine did not reduce the isoproterenol-induced increase of accumbal dopamine in any type of rat. This study demonstrates that mesolimbic alpha-, but not beta-adrenoceptors control the accumbal release of dopamine that is derived from reserpine-sensitive storage vesicles. In addition, these data confirm our previous finding that dopamine can still be released from storage vesicles of reserpinized high-responders, but not of reserpinized low-responders. The collected data underline our notion that alpha- and beta-adrenergic drugs may have therapeutic effects in patients suffering from diseases in which accumbal dopamine is involved.

Rationale: The mechanisms underlying individual differences in the response to serotonergic drugs are poorly understood. Rat studies may contribute to our knowledge of the neuronal substrates that underlie these individual differences., Objectives: A pharmacobehavioural study was performed to assess individual differences in the sensitivity to serotonergic drugs in rats that were selected based on their response to a novel environment., Methods: Low responders (LR) and high responders (HR) to novelty rats were tested on the elevated T-maze following systemic injections of increasing doses of various serotonergic agents. The duration of avoidance of the open arms was scored for five trials., Results: The duration of avoidance behaviour was larger in saline-treated LR rats compared to saline-treated HR rats. The 5-HT1A agonist 8-OH-DPAT and the 5-HT2 agonists mCPP and DOI decreased the duration of avoidance behaviour in LR rats, but increased it in HR rats. The 5-HT3 agonist SR57227A and the 5-HT releaser/reuptake inhibitor d-fenfluramine increased the duration of avoidance behaviour in both types of rat. However, higher doses of SR57227A were required to alter avoidance behaviour in HR than in LR rats. The onset of the effects of SR57227A, d-fenfluramine and WAY100635 was faster in LR than in HR rats. The described effects were receptor specific. A model explaining the data is presented., Conclusions: These data demonstrate that LR and HR rats differ in their sensitivity to serotonergic drugs that act at 5-HT3, 5-HT2 and 5-HT1A receptors. The implications of these individual differences for individual-specific treatment of substance abuse are briefly discussed.

Alpha-adrenoceptors in the nucleus accumbens are known to inhibit accumbal dopamine release from reserpine-sensitive pools. The aim of this study was to test our previously reported hypothesis that accumbal noradrenaline that controls the dopamine release from these storage vesicles is derived from alpha-methyl-para-tyrosine-sensitive pools. The sensitivity of accumbal alpha-adrenoceptors to noradrenergic agents depends on the amount of noradrenaline that is available in the synapse. In case the synaptic noradrenaline levels decrease, the conformation of alpha-adrenoceptors changes into a state that makes these receptors more sensitive to its agonists. The effects of alpha-methyl-para-tyrosine, respectively reserpine, on the alpha-adrenoceptor-agonist-induced changes of accumbal dopamine release were investigated. Alpha-methyl-para-tyrosine, but not reserpine, made accumbal postsynaptic alpha-adrenoceptors more sensitive to phenylephrine. These results indicate that noradrenaline that inhibits the release of dopamine from reserpine-sensitive storage vesicles, via stimulation of accumbal postsynaptic alpha-adrenoceptors, is derived from alpha-methyl-para-tyrosine-sensitive pools. The clinical impact of these data is discussed.

Cocaine (COC) inhibits the re-uptake of dopamine. However, the dopamine response to COC also depends on dopamine inside storage vesicles. The aim of this study was to investigate whether rats that differentially respond to COC differ in their dopaminergic storage capacity of the nucleus accumbens. Total and vesicular levels of accumbal dopamine as well as accumbal vesicular monoamine transporter-2 levels were established in high (HR) and low responders (LR) to novelty rats. Moreover, the effects of reserpine (RES) on the COC-induced increase of extracellular accumbal dopamine were investigated. HR displayed higher accumbal levels of total and vesicular dopamine than LR. Moreover, HR displayed more accumbal vesicular monoamine transporters-2 than LR. COC increased extracellular accumbal dopamine more strongly in HR than in LR. A low dose of RES prevented the COC-induced increase of accumbal dopamine in LR, but not in HR. A higher dose of RES was required to inhibit the COC-induced increase of accumbal dopamine in HR. These data demonstrate that HR were marked by a larger accumbal dopaminergic storage pool than LR. It is hypothesized that HR are more sensitive to COC than LR, because COC can release more dopamine from accumbal storage vesicles in HR than in LR.

Individual differences in the dopaminergic system of the nucleus accumbens of rats have extensively been reported. These individual differences have frequently been used to explain individual differences in response to environmental and pharmacological challenges. Remarkably, only little attention is paid to the factors that underlie these individual differences. This review gives an overview of the studies that have been performed in our institute during the last 20 years to investigate individual differences in accumbal dopamine release. Data are summarised demonstrating that individual differences in accumbal dopamine release are due to individual differences in: the functional reactivity of the noradrenergic system, the accumbal concentration of vesicular monoamine transporters and tyrosine hydroxylase as well as in the quantal size of the presynaptic pools of dopamine. Our data are embedded in the available literature to create a model that illustrates the putative hardware giving rise to the individual-specific release of accumbal dopamine. An important role is contributed to individual differences in the reactivity of the: hypothalamic-pituitary-adrenal axes, the reactivity of second messenger systems as well in the aminergic reactivity of the accumbens shell and core. The consequences of the individual-specific make-up and reactivity of the nucleus accumbens on the regulation of behaviour and the response to drugs of abuse will also be discussed. Apart from agents that interact with dopaminergic receptors, re-uptake or breakdown, noradrenergic agents as well as agents that interact with vesicular monoamine transporters or tyrosine hydroxylase are suggested to have therapeutic effects in subjects that are suffering from diseases in which the dopaminergic system is disturbed.

The present study examined the effects of reserpine on the extracellular concentration of accumbal dopamine in high responders (HR) and low responders (LR) to novelty rats. Reserpine reduced the baseline concentration of extracellular accumbal dopamine more in HR than in LR, indicating that the dopamine release is more dependent on reserpine-sensitive storage vesicles in non-challenged HR than in non-challenged LR. In addition, reserpine reduced the novelty-induced increase of the extracellular concentration of accumbal dopamine in LR, but not in HR, indicating that the dopamine release in response to novelty depends on reserpine-sensitive storage vesicles only in LR, not in HR. Our data clearly demonstrate that HR and LR differ in the characteristics of those monoaminergic storage vesicles that mediate accumbal dopamine release.

Behaviourally relevant novel stimuli are known to activate the mesocorticolimbic dopaminergic (DAergic) system. In this study we tested the reactivity of this system in response to distinct kinds of novelty processing. Using the in vivo microdialysis technique, we measured extracellular amounts of dopamine (DA) in different DAergic terminal regions during a social learning task in rats. In the first session (40 min) rats were exposed to two never previously encountered juveniles (i.e. unconditional novelty). Afterwards, the animals were divided into three groups: Control group was not exposed to any other stimulus; Discrimination group was exposed to one familiar and one new juvenile (i.e. novel stimulus discrimination); and Recognition group was re-exposed to the two familiar juveniles (i.e. familiarity recognition). In both the medial prefrontal cortex and the nucleus accumbens shell DA increased in response to the first presentation of the juveniles, showing that both structures are involved in processing unconditional social novelty. During the novel stimulus discrimination, we found no change in the prefrontal cortex, although DA increased in the accumbal shell in comparison with the group exposed to two familiar juveniles, showing that the shell is also involved in processing novel social stimulus discrimination. None of the stimuli presented affected DA in the accumbal core. This study provided the original evidence that DA in the various terminal regions is differentially coupled to distinct aspects of novelty processing.

Individual differences in responses to mild, acute stressors in laboratory animals have commonly been observed in behavioural tests and at the level of hypothalamic-pituitary-adrenal axis responses. These differences are associated with dopamine transmission in the nucleus accumbens. Although the effect of mild stressors on dopamine transmission has been studied with microdialysis, it has not been studied at the level of the catecholaminergic network in the nucleus accumbens. In this study we have used microdialysis to measure extracellular concentrations of dopamine in vivo and immunocytochemistry for the enzyme tyrosine hydroxylase to assess the effect of a single exposure to novelty on the neurochemistry of the nucleus acc umbens in apomorphine-susceptible and apomorphine-unsusceptible rats. These rats are a valid animal model for studying individual differences in responses to environmental stressors and drugs of abuse. We demonstrated that a mild stressor like novelty increased the extracellular concentration of dopamine in the nucleus accumbens in apomorphine-susceptible rats to a larger and longer-lasting degree than in apomorphine-unsusceptible rats. Furthermore we demonstrated that novelty increased the tyrosine hydroxylase-immunoreactive fibre network in the nucleus accumbens shell of apomorphine-susceptible rats, which are rats that are particularly reactive to stressors, but not in the shell of apomorphine-unsusceptible rats, which are rats that are relatively stress-resistant. In conclusion, we have shown that the accumbal dopaminergic system of apomorphine-susceptible rats is more sensitive to an environmental stressor than that of apomorphine-unsusceptible rats. Combined with the fact that these animals also differ in their sensitivity to drugs of abuse, which are known to affect the dopaminergic system, these data provide a solid basis for further studying the differences in the dopaminergic responsiveness to drugs of abuse between apomorphine-susceptible and apomorphine-unsusceptible rats.

The goal of the present study was to provide neurochemical evidence for a shift in the functional balance between the nigrostriatal and mesolimbic pathway in favour of the mesolimbic pathway by investigating the effects of a partial, nigral, bilateral 6-hydroxydopamine lesion on basal and novelty-induced extracellular dopamine release in the accumbens of Low responder rats to novelty (LR). Low responders were chosen because the above-mentioned shift was seen in LR rats, but not in rats that have a high response to novelty (HR). About 1 microg/microl of 6-hydroxydopamine was injected bilaterally into the substantia nigra pars compacta and a guide cannula was placed into the right accumbens. Changes in extracellular dopamine in response to novelty, a new cage, were measured using a microdialysis probe inserted into the accumbens. The lesion size was determined by quantification of tyrosine hydroxylase immunoreactivity of the substantia nigra and the ventral tegmental area. This revealed that the lesion partly destroyed the dopaminergic cells of the nigrostriatal pathway, thereby relatively sparing the dopaminergic cells of the mesolimbic pathway. The lesion significantly increased the amount of extracellular dopamine in the accumbens during both basal and novelty conditions. We suggest that the experimentally induced neuronal death in the substantia nigra pars compacta with subsequent removal of lateral inhibition of adjacent neurons underlies the observed changes in the amount of extracellular dopamine in the accumbens.

The aim of this study was to investigate the differential long-term after-effects on the apomorphine-susceptibility in the apomorphine-susceptible (APO-SUS) and apomorphine-unsusceptible (APO-UNSUS) rats of either a saline injection (a mild stressor) or a clonidine-injection (a moderate stressor) applied around the onset of the stress-hypo-responsive-period (SHRP) on postnatal day (PND) 2, 4, 6 or 9. The present study shows that an injection of saline on PND 2 decreases the apomorphine-induced gnawing score in adult APO-SUS rats, but increases this score in adult APO-UNSUS rats; clonidine given on this day has no effect. An injection of saline on PND 4 decreases the apomorphine score in adult APO-SUS rats, but has no effect in adult APO-UNSUS rats. An injection of clonidine on PND 4 counteracts the long-term after-effects of a saline injection on this PND in adult APO-SUS rats, but has no effect in adult APO-UNSUS rats. Finally, an injection of clonidine on PND 9 has no effect on the apomorphine score in adult APO-SUS rats, but increases this score in adult APO-UNSUS rats; saline given on this day has no effect. It is concluded that the long-term after-effects of early postnatal stressors depend on the interrelationship between, rather than the separate impact of, the genetic background of the rat, the nature of the event, and time of exposure to the event, thereby implying that these factors direct the phenotypic expression of a particular genotype at adult age.