Modeling nicotine addiction in rats.

Among the human population, 15% of drug users develop a pathological drug addiction. This figure increases substantially with nicotine, whereby more than 30% of those who try smoking develop a nicotine addiction. Drug addiction is characterized by compulsive drug-seeking and drug-taking behaviors (craving), and loss of control over intake despite impairment in health, social, and occupational functions.

Repeated episodes of heroin cause enduring alterations of circadian activity in protracted abstinence.

Opiate withdrawal is followed by a protracted abstinence syndrome consisting of craving and physiological changes. However, few studies have been dedicated to both the characterization and understanding of these long-term alterations in post-dependent subjects. The aim of the present study was to develop an opiate dependence model, which induces long-lasting behavioral changes in abstinent rats.

Cerebral blood flow modulation by transcutaneous cranial electrical stimulation with Limoge's current.

Objectives: Transcutaneous cranial electrical stimulation (TCES) delivers a high-frequency (166 kHz) pulsed biphasic balanced current with a pulse repetition frequency of 100 Hz with 40% duty cycle through a negative electrode and two positive electrodes over the skull. TCES has a proven ability to potentiate anesthesia and analgesia, although the physiological mechanisms of this effect remain unclear. We hypothesized that the mechanism is a modulation of CBF in the central endogenous opioid system.

The addition of five minor tobacco alkaloids increases nicotine-induced hyperactivity, sensitization and intravenous self-administration in rats.

Several minor tobacco alkaloids have been found to exhibit properties pharmacologically relevant to the addictive profile of tobacco; however, little is known of their effects on a behavioural model of drug addiction. In this study we compared the locomotor and reinforcing effects of intravenous nicotine (30 microg/kg per infusion) vs. a cocktail of nicotine plus five minor alkaloids found in tobacco smoke (anabasine, nornicotine, anatabine, cotinine and myosmine).

Reactivity and plasticity in the amygdala nuclei during opiate withdrawal conditioning: differential expression of c-fos and arc immediate early genes.

Opiate withdrawal leads to the emergence of an aversive state that can be conditioned to a specific environment. Reactivation of these withdrawal memories has been suggested to be involved in relapse to drug-seeking of abstinent opiate addicts. Among the limbic areas that are likely to mediate these features of opiate dependence, amygdala nuclei represent critical neural substrates.

Monoamine oxidase inhibition dramatically prolongs the duration of nicotine withdrawal-induced place aversion.

Background: Long-lasting effects of withdrawal from nicotine are hypothesized to contribute to relapse and persistence of tobacco habits, and significant evidence supports a role of monoamine oxidase inhibitors (MAOI) contained in cigarette smoke as potent modulators of the rewarding effects of tobacco.

Methods: With quantification of somatic signs of withdrawal and the place aversion conditioning paradigm, we assessed the effects of MAOI pretreatment on both somatic and aversive motivational components of mecamylamine-induced nicotine withdrawal in rats rendered dependent on nicotine by the subcutaneous implantation of osmotic minipumps (vehicle or nicotine tartrate 9 mg/kg/day).

Results: In nicotine-infused rats, mecamylamine induced a place aversion that lasted 6 weeks.

Monoamine oxidase A rather than monoamine oxidase B inhibition increases nicotine reinforcement in rats.

Although nicotine is considered to be responsible for the addictive properties of tobacco, growing evidence underlines the importance of non-nicotine components in smoking reinforcement. It has been shown that tobacco smoke contains monoamine oxidase (MAO) A and B inhibitors and decreases MAO-A and MAO-B activity in smokers. Here, we investigated the effects of clorgyline hydrochloride (irreversible MAO-A inhibitor; 2 mg/kg/day), selegiline (irreversible MAO-B inhibitor; 4 mg/kg) and the beta-carboline norharmane hydrochloride (reversible MAO-B inhibitor; 5 mg/kg/day) treatments on nicotine self-administration (30 microg/kg/infusion, free base) in rats.

High-efficacy 5-hydroxytryptamine 1A receptor activation counteracts opioid hyperallodynia and affective conditioning.

Pain may become intractable as tolerance develops to opioids and the opioids, paradoxically, induce pain. We examined the hypothesis that the analgesia produced by the novel analgesic and high-efficacy 5-hydroxytryptamine (5-HT)(1A) receptor agonist (3-chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]methyl]piperidin-1-yl]methanone, fumaric acid salt (F 13640) may counteract opioid-induced pain. In studies of the somatosensory quality of pain in infraorbital nerve-injured rats, morphine infusion (5 mg/day) by means of osmotic pumps initially caused analgesia (i.

Role of imidazoline receptors in the anti-aversive properties of clonidine during opiate withdrawal in rats.

Clonidine is used as a treatment for heroin addiction. Previous studies have reported that clonidine attenuated conditioned place aversion (CPA) to naloxone-precipitated opiate withdrawal by acting on alpha2 adrenoceptors (alpha2R). However, clonidine acts as a partial agonist both at alpha2R and at imidazoline-1 receptors (I1Rs).

Monoamine oxidase inhibition dramatically increases the motivation to self-administer nicotine in rats.

Nicotine is the major neuroactive compound of tobacco, which has, by itself, weak reinforcing properties. It is known that levels of the enzymes monoamine oxidase A (MAO-A) and MAO-B are reduced in the platelets and brains of smokers and that substances, other than nicotine, present in tobacco smoke have MAO-inhibitory activities. Here, we report that inhibition of MAO dramatically and specifically increases the motivation to self-administer nicotine in rats.

Mesolimbic dopamine drives the diurnal variation in opiate-induced feeding.

Brain opioid peptides modulate feeding behavior and opiate drugs have powerful orexigenic effects in mammals. Recent studies have shown that opiate-induced eating depends, though not exclusively, on mu-opioid receptors located in the ventral striatum. Here we report that morphine orexigenic effects vary with the time of day according to a biphasic pattern.

A specific limbic circuit underlies opiate withdrawal memories.

Compulsive drug-seeking behavior and its renewal in former drug addicts is promoted by several situations, among which reactivation of drug withdrawal memories plays a crucial role. A neural hypothesis is that such memories reactivate the circuits involved in withdrawal itself and promote a motivational state leading to drug seeking or taking. To test this hypothesis, we have analyzed the neural circuits and cell populations recruited when opiate-dependent rats are reexposed to stimuli previously paired with withdrawal (memory retrieval) and compared them with those underlying acute withdrawal during conditioning (memory formation).

Buprenorphine and a CRF1 antagonist block the acquisition of opiate withdrawal-induced conditioned place aversion in rats.

Conditioned place aversion in rats has face validity as a measure of the aversive stimulus effects of opiate withdrawal that reflects an important motivational component of opiate dependence. The purpose of the present study was to validate conditioned place aversion as sensitive to medications that will alleviate the aversive stimulus effects of opiate withdrawal in humans, and to extend this model to the exploration of the neuropharmacological basis of the motivational effects of opiate withdrawal. Male Sprague-Dawley rats were implanted with two subcutaneous morphine pellets and 5 days later began place conditioning training following subcutaneous administration of a low dose of naloxone.

A non-invasive gating device for continuous drug delivery that allows control over the timing and duration of spontaneous opiate withdrawal.

Opiate dependence in laboratory animals is commonly induced by two methods: (1) subcutaneous (s.c.) insertion of morphine pellets, and (2) daily injections of increasing doses of opiates.

Changes in dopaminergic neurotransmission do not alter somatic or motivational opiate withdrawal-induced symptoms in rats.

Opiate withdrawal has been correlated with decreased extracellular dopamine (DA) levels in the nucleus accumbens (NAC) of morphine-dependent rats. The authors tested the hypothesis that DA transmission plays a critical role in the induction of motivational and somatic withdrawal symptoms. First, the authors used a 6-hydroxydopamine-induced lesion of the NAC to chronically disrupt mesolimbic DA transmission.

Chronic interferon-alpha potentiates latent inhibition in rats.

Several recent reports based on microdialysis have shown that repeated injections of IFN-alpha induce reduced dopamine (DA) activity in the rodent brain, and specifically within the striatum. This mesolimbic DA system is thought to play a central role in controlling latent inhibition (LI), which refers to the phenomenon in which conditioning proceeds more slowly to an irrelevant pre-exposed (PE) stimulus. The purpose of the present experiment was to evaluate whether chronic treatment with IFN-alpha may induce similar effects on LI as other DA-depleting manipulations.

Inhibition of 5-HT neurotransmission increases clonidine protective effects on naloxone-induced conditioned place aversion in morphine-dependent rats.

Previous pharmacological studies have implicated serotonergic brain systems in opiate-withdrawal-precipitated conditioned place aversion. To assess this hypothesis, we tested the effects of either (i). a near-total 5,7-dihydroxytryptamine-induced lesion (90% depletion) or (ii).

In the rat forced swimming test, chronic but not subacute administration of dual 5-HT/NA antidepressant treatments may produce greater effects than selective drugs.

Unlabelled: The rat forced swimming test (FST) distinguishes selective serotonin (5-HT) and selective noradrenaline (NA) reuptake-inhibitors, which respectively increase swimming and climbing behaviours. However, NA-system-mediated inhibition of 5-HT-induced swimming prevents dual 5-HT/NA reuptake-inhibition to produce concurrently climbing with swimming. Since adaptative neurochemical processes occur in the treatment of depression, we examined the influence of long-term antidepressant treatment on these interactions.

Neural correlates of the motivational and somatic components of naloxone-precipitated morphine withdrawal.

In morphine-dependent rats, low naloxone doses have been shown to induce conditioned place aversion, which reflects the negative motivational component of opiate withdrawal. In contrast, higher naloxone doses are able to induce a 'full' withdrawal syndrome, including overt somatic signs. The c-fos gene is commonly used as a marker of neuronal reactivity to map the neural substrates that are recruited by various stimuli.

Dorsal and median raphe serotonergic system lesion does not alter the opiate withdrawal syndrome.

Previous pharmacological studies have implicated serotonergic brain systems in opiate withdrawal. To test the hypothesis that serotonin (5-HT) has a critical role in the development of opiate withdrawal, we have employed a near-total brain 5-HT system lesion technique (90% depletion) using 5,7-dihydroxytryptamine combined with induction of opiate dependence by implantation of morphine pellets or by repeated injections of increasing doses of morphine. The effects of serotonergic neuron lesion were examined on spontaneous opiate withdrawal (changes in circadian locomotor activity) and naloxone-precipitated opiate withdrawal syndrome (the somatic aspect).

Interaction between neuropeptide FF and opioids in the ventral tegmental area in the behavioral response to novelty.

Considerable evidence has focused on the interaction between endogenous opioid peptides and the dopaminergic mesocorticolimbic system in behavioral responses to stress. Recently, it has been proposed that the CNS synthesizes and secretes neuropeptides that act as part of a homeostatic system to attenuate the effects of morphine or endogenous opioid peptides. Among these antiopioids, neuropeptide FF (NPFF) is particularly interesting since both NPFF immunoreactive-like terminals and NPFF binding sites are located in the vicinity of the dopaminergic cell bodies within the ventral tegmental area (VTA) suggesting an interaction at this level.

Central 5-HT(4) receptors and dopamine-dependent motor behaviors: searching for a functional role.

In this study, we evaluated the role of central 5-HT(4) receptors in the control of motor behaviors related to change of nigrostriatal dopamine (DA) transmission, namely, stereotyped behavior and catalepsy in rats. Indeed, given that 5-HT(4) receptors indirectly modulate nigrostriatal DA neuron activity, we hypothesized that these receptors would regulate nigrostriatal DA transmission in the basal ganglia, and consequently, associated motor responses. Stereotypy was induced either by an acute administration of apomorphine (0.

In the rat forced swimming test, NA-system mediated interactions may prevent the 5-HT properties of some subacute antidepressant treatments being expressed.

In the rat forced swimming test (FST), reuptake inhibitors selective of either serotonin (5-HT) or noradrenaline (NA) decrease immobility duration, and increase, respectively, swimming and climbing behaviour. In this study, an almost total 6-OHDA-induced NA-depletion prevented the behavioural effects of desipramine, but not fluoxetine. Interestingly, the serotonin/noradrenaline-reuptake-inhibitor milnacipran, as well as a (desipramine+fluoxetine) combination, could produce both swimming and climbing behaviour in NA-lesioned rats, but not in non-lesioned.

D-amphetamine-induced behavioral sensitization: effect of lesioning dopaminergic terminals in the medial prefrontal cortex, the amygdala and the entorhinal cortex.

The behavioral sensitization produced by the repeated administration of D-amphetamine is known to involve dopaminergic neurons in the mesoaccumbens pathway. Induction of this process is dependent on action of the drug in the ventral tegmental area while its expression involves action in the nucleus accumbens. We studied here the putative involvement of dopaminergic projections other than the mesoaccumbens in this phenomenon.

Ethological analysis of morphine withdrawal with different dependence programs in male mice.

This work was performed to clarify the differences between a long or short development of morphine dependence as well as between a recently installed or a long-term dependence. Morphine withdrawal in rats is a well-characterized phenomenon but this is not so in mice. A study of the principal withdrawal signs have been performed in mice, evaluating their specificity and particular profile of appearance in each type of dependence.