Daina Economidou

Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction

We hypothesize that drug addiction can be viewed as the endpoint of a series of transitions from initial voluntary drug use through the loss of control over this behaviour, such that it becomes habitual and ultimately compulsive. We describe evidence that the switch from controlled to compulsive drug seeking represents a transition at the neural level from prefrontal cortical to striatal control over drug-seeking and drug-taking behaviours as well as a progression from ventral to more dorsal domains of the striatum, mediated by its serially interconnecting dopaminergic circuitry. These neural transitions depend upon the neuroplasticity induced by chronic self-administration of drugs in both cortical and striatal structures, including long-lasting changes that are the consequence of toxic drug effects. We further summarize evidence showing that impulsivity, a spontaneously occurring behavioural tendency in outbred rats that is associated with low dopamine D2/3 receptors in the nucleus accumbens, predicts both the propensity to escalate cocaine intake and the switch to compulsive drug seeking and addiction.

Neurobehavioral mechanisms of impulsivity: Fronto-striatal systems and functional neurochemistry

Impulsive acts and decisions are a part of everyday normal behavior. However, in its pathological forms, impulsivity can be a debilitating disorder often associated with a number of neuropsychiatric disorders, including attention-deficit hyperactivity disorder (ADHD). This article reviews recent progress in our understanding of the neurobiology of impulsivity using examples from recent investigations in experimental animals. Evidence is reviewed from several well-established paradigms with putative utility in assessing distinct forms of impulsive behavior in rodents, including the 5-choice serial reaction time (5CSRT) task and the delay discounting paradigm. We discuss, in particular, recent psychopharmacological and in-vivo neurochemical data in task-performing rats showing functional heterogeneity of the forebrain dopamine (DA), noradrenaline (NA), serotonin (5-HT) and acetylcholine (ACh) systems and identify how these systems normally function to facilitate flexible goal-directed behavior in situations that tax basic attentional functions and inhibitory response control mechanisms. We also discuss future research needs in terms of understanding the functional diversity of different sub-regions of prefrontal cortex (PFC) and how these systems normally interact with the striatum and main nuclei of origin of DA and NA neurons. Finally, we argue in line with others that animal paradigms are unlikely to model all aspects of complex psychiatric conditions such as ADHD but components of such syndromes may be amenable to investigation using sophisticated animal models based on highly-defined psychiatric endophenotypes.

High impulsivity predicts relapse to cocaine-seeking after punishment-induced abstinence.

BACKGROUND Relapse is a hallmark feature of cocaine addiction and a main challenge for treatment strategies. Human studies indicate a link between impulsivity and increased susceptibility to relapse. METHODS Rats were screened for high (HI) and low impulsivity (LI) on the 5-choice serial reaction time task. The HI and LI rats were trained to self-administer cocaine under a seeking-taking chained schedule: responses on the seeking lever resulted in presentation of the taking lever, responding upon which resulted in cocaine reinforcement. After the establishment of stable responding, an intermittent punishment schedule was introduced: completion of the seeking link resulted in the random presentation of either the taking lever or a mild footshock. This resulted in a progressive decrease in cocaine-seeking approaching abstinence. Relapse was assessed 7 days after punishment, during which responding on the seeking lever resulted in the presentation of the cocaine-associated stimuli (i.e., in the absence of cocaine or footshock). RESULTS The HI and LI animals significantly reinstated the cocaine-seeking response after a single phase of seeking punishment. However, after a second punishment phase only the HI rats reinitiated suppressed seeking responses and relapsed, an effect that was facilitated by prior extended cocaine access. In a preliminary study we found that the selective noradrenaline reuptake inhibitor, atomoxetine, a drug known to reduce impulsivity, prevented the reinstatement of cocaine-seeking. CONCLUSIONS Impulsivity pre-dating drug abuse increases the susceptibility to relapse after abstinence. Medications targeting impulsivity might have utility as treatment interventions for relapse prevention and the promotion of abstinence.

Genetically selected Marchigian Sardinian alcohol-preferring (msP) rats: an animal model to study the neurobiology of alcoholism.

The present article provides an up‐to‐date review summarizing almost 18 years of research in genetically selected Marchigian Sardinian alcohol‐preferring (msP) rats. The results of this work demonstrate that msP rats have natural preference for ethanol characterized by a spontaneous binge‐type of drinking that leads to pharmacologically significant blood ethanol levels. This rat line is highly vulnerable to relapse and presentation of stimuli predictive of alcohol availability or foot‐shock stress can reinstate extinguished drug‐seeking up to 8 months from the last alcohol experience. The msP rat is highly sensitive to stress, shows an anxious phenotype and has depressive‐like symptoms that recover following ethanol drinking. Interestingly, these animals have an up‐regulated corticotrophin releasing factor (CRF) receptor 1 system. Clinical studies have shown that alcoholic patients often drink ethanol in the attempt to self‐medicate from negative affective states and to search for anxiety relief. We propose that msP rats represent an animal model that largely mimics the human alcoholic population that due to poor ability to engage in stress‐coping strategies drink ethanol as a tension relief strategy and for self‐medication purposes.

The Effects of Acamprosate and Neramexane on Cue-Induced Reinstatement of Ethanol-Seeking Behavior in Rat

This study examines, for the first time, the effects of acamprosate and the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist neramexane on ethanol-seeking induced by alcohol-related environmental stimuli in an animal model of relapse. Wistar rats were trained to operantly self-administer ethanol (10% w/v) or water on a fixed-ratio 1 schedule in a 30-min daily session. Ethanol availability was signaled by an olfactory discriminative stimulus of orange extract (S+). In addition, each lever press was accompanied by a 5-s illumination of the operant chambers house light (CS+). Water availability was signaled by anise odor (S−) and 5-s white noise stimulus (CS−). After completion of the conditioning phase, indicated by stable levels of responding, operant behaviors were extinguished. Prior to reinstatement tests, animals were divided into groups according to either treatment with acamprosate (100, 200 mg/kg given twice), neramexane (1.0, 2.0, 4.0 mg/kg), or vehicle. In vehicle-treated rats, re-exposure to the S+/CS+ in the absence of further ethanol availability elicited strong recovery of responding. No effect was observed following presentation of water-paired cues (S−/CS−). Acamprosate dose-dependently attenuated recovery of responding elicited by ethanol-paired cues (S+/CS+), whereas responding under S−/CS− was not modified by drug administration. Treatment with 1.0 and 2.0 mg/kg of neramexane did not significantly modify responding under both S+/CS+ and S−/CS− conditions. However, a slight reduction of cue-induced reinstatement of alcohol seeking was observed. At the dose of 4.0 mg/kg, neramexane elicited a marked inhibition of responding following presentation of both ethanol- and water-paired cues. In conclusion, acamprosate significantly and selectively reduced alcohol-seeking elicited by environmental stimuli predictive of alcohol availability. Treatment with neramexane that shares part of the pharmacological effects of acamprosate on NMDA receptors, however, resulted in a nonselective reduction of lever responding.

Modulation of high impulsivity and attentional performance in rats by selective direct and indirect dopaminergic and noradrenergic receptor agonists

RationaleImpulsivity is associated with a number of psychiatric disorders, most notably attention deficit/hyperactivity disorder (ADHD). Drugs that augment catecholamine function (e.g. methylphenidate and the selective noradrenaline reuptake inhibitor atomoxetine) have clinical efficacy in ADHD, but their precise mechanism of action is unclear.ObjectiveThe objective of this study is to investigate the relative contribution of dopamine (DA) and noradrenaline (NA) to the therapeutic effects of clinically effective drugs in ADHD using rats selected for high impulsivity on the five-choice serial reaction time task (5CSRTT).MethodsWe examined the effects of direct and indirect DA and NA receptor agonists and selective DA and NA reuptake inhibitors in rats showing high and low levels of impulsivity on the 5CSRTT (designated high impulsive ‘HI’ and low impulsive ‘LI’, respectively). Drugs were administered by systemic injection in a randomized, counterbalanced manner.ResultsLow doses of quinpirole (a D2/D3 agonist) and sumanirole (a D2 agonist) selectively reduced impulsivity on the 5CSRTT, whilst higher doses resulted in increased omissions and slower response latencies. The NA reuptake inhibitor, atomoxetine, and the alpha-2 adrenoreceptor agonist, guanfacine, dose dependently decreased premature responding. The dopaminergic reuptake inhibitor GBR-12909 increased impulsivity, whereas the nonselective DA and NA reuptake inhibitor methylphenidate had no significant effect on impulsive responses in HI and LI rats.ConclusionsThese findings indicate that high impulsivity can be ameliorated in rats by drugs that mimic the effects of DA and NA, just as in ADHD, and that activation of D2/3 receptors selectively decreases high impulsivity on the 5CSRTT.

Dysregulation of Nociceptin/Orphanin FQ Activity in the Amygdala Is Linked to Excessive Alcohol Drinking in the Rat

BACKGROUND Alcoholism is a complex behavioral disorder in which interactions between stressful life events and heritable susceptibility factors contribute to the initiation and progression of disease. Neural substrates of these interactions remain largely unknown. Here, we examined the role of the nociceptin/orphanin FQ (N/OFQ) system, with an animal model in which genetic selection for high alcohol preference has led to co-segregation of elevated behavioral sensitivity to stress (Marchigian Sardinian alcohol-preferring [msP]). METHODS The msP and Wistar rats trained to self-administer alcohol received central injections of N/OFQ. In situ hybridization and receptor binding assays were also performed to evaluate N/OFQ receptor (NOP) function in naïve msP and Wistar rats. RESULTS Intracerebroventricular (ICV) injection of N/OFQ significantly inhibited alcohol self-administration in msP but not in nonselected Wistar rats. The NOP receptor messenger RNA expression and binding was upregulated across most brain regions in msP compared with Wistar rats. However, in msP rats [(35)S]GTPgammaS binding revealed a selective impairment of NOP receptor signaling in the central amygdala (CeA). Ethanol self-administration in msP rats was suppressed after N/OFQ microinjection into the CeA but not into the bed nucleus of the stria terminalis or the basolateral amygdala. CONCLUSIONS These findings indicate that dysregulation of N/OFQ-NOP receptor signaling in the CeA contributes to excessive alcohol intake in msP rats and that this phenotype can be rescued by local administration of pharmacological doses of exogenous N/OFQ. Data are interpreted on the basis of the anti-corticotropin releasing factor (CRF) actions of N/OFQ and the significance of the CRF system in promoting excessive alcohol drinking in msP rats.

Norepinephrine and dopamine modulate impulsivity on the five-choice serial reaction time task through opponent actions in the shell and core sub-regions of the nucleus accumbens.

Impulsive behavior is a hallmark of several neuropsychiatric disorders (eg, attention-deficit/hyperactivity disorder, ADHD). Although dopamine (DA) and norepinephrine (NE) have a significant role in the modulation of impulsivity their neural loci of action is not well understood. Here, we investigated the effects of the selective NE re-uptake inhibitor atomoxetine (ATO) and the mixed DA/NE re-uptake inhibitor methylphenidate (MPH), both with proven clinical efficacy in ADHD, on the number of premature responses on a five-choice serial reaction time task, an operational measure of impulsivity. Microinfusions of ATO into the shell, but not the core, sub-region of the nucleus accumbens (NAcb) significantly decreased premature responding whereas infusions of MPH in the core, but not the shell, sub-region significantly increased premature responding. However, neither ATO nor MPH significantly altered impulsive behavior when infused into the prelimbic or infralimbic cortices. The opposing effects of ATO and MPH in the NAcb core and shell on impulsivity were unlikely mediated by ancillary effects on behavioral activation as locomotor activity was either unaffected, as in the case of ATO infusions in the core and shell, or increased when MPH was infused into either the core and shell sub-region. These findings indicate an apparently ‘opponent’ modulation of premature responses by NE and DA in the NAcb shell or core, respectively, and suggest that the symptom clusters of hyperactive-impulsive type ADHD may have distinct neural and neurochemical substrates.

Buprenorphine Reduces Alcohol Drinking Through Activation of the Nociceptin/Orphanin FQ-NOP Receptor System

BACKGROUND Activation of the NOP receptor by its endogenous ligand nociceptin/orphanin FQ reduces ethanol intake in genetically selected alcohol preferring Marchigian Sardinian alcohol preferring (msP) rats. Here we evaluated whether buprenorphine, a partial agonist at micro-opioid and NOP receptors, would reduce ethanol consumption in msP rats via activation of NOP receptors. METHODS Marchigian Sardinian alcohol preferring rats trained to drink 10% alcohol 2 hours/day were injected with buprenorphine (.03, .3, 3.0, or 6.0 mg/kg intraperitoneally [IP]) 90 min before access to ethanol. RESULTS Similar to prototypical micro-agonists, the two lowest doses of buprenorphine significantly increased ethanol consumption (p < .01); in contrast, the two highest doses reduced it (p < .05). Pretreatment with naltrexone (.25 mg/kg IP) prevented the increase of ethanol intake induced by .03 mg/kg of buprenorphine (p < .001) but did not affect the inhibition of ethanol drinking induced by 3.0 mg/kg of buprenorphine. Conversely, pretreatment with the selective NOP receptor antagonist UFP-101 (10.0 or 20.0 microg/rat) abolished the suppression of ethanol drinking by 3.0 mg/kg of buprenorphine. CONCLUSIONS Buprenorphine has dualistic effects on ethanol drinking; low doses increase alcohol intake via stimulation of classic opioid receptors, whereas higher doses reduce it via activation of NOP receptors. We suggest that NOP agonistic properties of buprenorphine might be useful in the treatment of alcoholism.

The nociceptin/orphanin FQ/NOP receptor system as a target for treatment of alcohol abuse: a review of recent work in alcohol-preferring rats

The intracerebroventricular administration of the 17 amino acid peptide nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the NOP receptor (previously referred to as ORL-1 or OP4 receptor), reduces voluntary 10% ethanol intake in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. Studies aimed at the pharmacological characterization of the receptor, which mediates the effect, have shown that the C-terminal 13 amino acid sequence is crucial for activity and that the selective NOP receptor antagonist [Nphe(1)]N/OFQ(1-13)NH(2) blocks the effect of N/OFQ on ethanol drinking. In place conditioning studies, N/OFQ abolishes the conditioned place preference (CPP) induced by ethanol in msP rats, or by morphine in nonselected Wistar rats; these findings suggest that N/OFQ is able to abolish the rewarding properties of ethanol and morphine. Moreover, N/OFQ inhibits reinstatement of alcohol-seeking behavior induced to electric footshock stress, as well as reinstatement of alcohol-seeking behavior induced by ethanol-paired cues. Together, these findings suggest that N/OFQ and its receptor may represent an interesting target for pharmacological treatment of alcohol abuse.