Auclair A, Drouin C, Cotecchia S, Glowinski J, Tassin JP. 5-HT2A and alpha1b-adrenergic receptors entirely mediate dopamine release, locomotor response and behavioural sensitization to opiates and psychostimulants. Eur J Neurosci 20: 3073-3084
ABSTRACT Addictive properties of drugs of misuse are generally considered to be mediated by an increased release of dopamine (DA) in the ventral striatum. However, recent experiments indicated an implication of alpha1b-adrenergic receptors in behavioural responses to psychostimulants and opiates. We show now that DA release induced in the ventral striatum by morphine (20 mg/kg) is completely blocked by prazosin (1 mg/kg), an alpha1-adrenergic antagonist. However, morphine-induced increases in DA release in the ventral striatum were found to be similar in mice deleted for the alpha1b-adrenergic receptor (alpha1b-AR KO) and in wild-type (WT) mice, suggesting the presence of a compensatory mechanism. This acute morphine-evoked DA release was completely blocked in alpha1b-AR KO mice by SR46349B (1 mg/kg), a 5-HT2A antagonist. SR46349B also completely blocked, in alpha1b-AR KO mice, the locomotor response and the development of behavioural sensitization to morphine (20 mg/kg) and D-amphetamine (2 mg/kg). Accordingly, the concomitant blockade of 5-HT2A and alpha1b-adrenergic receptors in WT mice entirely blocked acute locomotor responses but also the development of behavioural sensitization to morphine, D-amphetamine or cocaine (10 mg/kg). We observed, nevertheless, that inhibitory effects of each antagonist on locomotor responses to morphine or D-amphetamine were more than additive (160%) in naïve WT mice but not in those sensitized to either drug. Because of these latter data and the possible compensation by 5-HT2A receptors for the genetic deletion of alpha1b-adrenergic receptors, we postulate the existence of a functional link between these receptors, which vanishes during the development of behavioural sensitization.
- SourceAvailable from: Filippo S Giorgi
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- "In fact, the alpha1 AR antagonist prazosin reduces amphetamine-induced hyperlocomotion and sensitization [120-128], possibly through the involvement of the alpha1b AR subtype [124, 127, 128]. The reduced behavioural response to METH found in alpha1b AR knock out (KO) mice is accompanied by a reduced DA release [122, 123, 129] and absence of DA neurotoxicity . "
ABSTRACT: The activity of locus coeruleus (LC) neurons has been extensively investigated in a variety of behavioural states. In fact this norepinephrine (NE)-containing nucleus modulates many physiological and pathological conditions including the sleep-waking cycle, movement disorders, mood alterations, convulsive seizures, and the effects of drugs such as psychostimulants and opioids. This review focuses on the modulation exerted by central NE pathways on the behavioural and neurotoxic effects produced by the psychostimulant methamphetamine, essentially the modulation of the activity of mesencephalic dopamine (DA) neurons. In fact, although NE in itself mediates some behavioural effects induced by methamphetamine, NE modulation of DA release is pivotal for methamphetamine-induced behavioural states and neurotoxicity. These interactions are discussed on the basis of the state of the art of the functional neuroanatomy of central NE- and DA systems. Emphasis is given to those brain sites possessing a remarkable overlapping of both neurotransmitters.Current Neuropharmacology 01/2013; 11(1):80-94. DOI:10.2174/157015913804999522 · 2.35 Impact Factor
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- "α1R antagonism within the NAc also attenuates COC-induced increases in DA levels and behavioral activation . Taken together, the present study is congruent with numerous studies demonstrating the critical importance of NE, acting through α1Rs, in augmenting and controlling central DA neurotransmission as well as affecting neural circuits that alter the behavioral effects of stimulants in animals [19,20,21,65,66,67,68,69,70]. "
ABSTRACT: Medications that target norepinephrine (NE) neurotransmission alter the behavioral effects of cocaine and may be beneficial for stimulant-use disorders. We showed previously that the short-acting, α1-adrenergic antagonist, prazosin, blocked drug-induced reinstatement of cocaine-seeking in rats and doxazosin (DOX), a longer-acting α1 antagonist blocked cocaine's subjective effects in cocaine-dependent volunteers. To further characterize DOX as a possible pharmacotherapy for cocaine dependence, we assessed its impact on the development and expression of cocaine-induced locomotor sensitization in rats. Rats (n = 6–8) were administered saline, cocaine (COC, 10 mg/kg) or DOX (0.3 or 1.0 mg/kg) alone or in combination for 5 consecutive days (development). Following 10-days of drug withdrawal, all rats were administered COC and locomotor activity was again assessed (expression). COC increased locomotor activity across days indicative of sensitization. The high dose (1.0 mg/kg), but not the low dose (0.3 mg/kg) of DOX significantly decreased the development and expression of COC sensitization. DOX alone did not differ from saline. These results are consistent with studies showing that α1 receptors are essential for the development and expression of cocaine's behavioral effects. Results also suggest that blockade of both the development and expression of locomotor sensitization may be important characteristics of possible pharmacotherapies for cocaine dependence in humans.11/2012; 2(2):619-633. DOI:10.3390/brainsci2040619
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- "NE receptor mediated effects 'shifting' to being transduced through 5-HT 2 receptors when the α1 receptor gene is deleted (Auclair et al. 2004). In disorders with severe PPI disruptions, perhaps there is an abnormal function in multiple PPI-regulating systems. "
ABSTRACT: Prepulse inhibition (PPI), a preattentional information-filtering mechanism, is disrupted by serotonin (5-HT) or norepinephrine (NE) agonists to model deficits seen in schizophrenia, but whether this effect occurs through interactions between these systems is not known. These studies investigated whether PPI/activity changes induced by agonists of one system were dependent on neurotransmission within the other. Male Sprague-Dawley rats received the 5-HT(2) receptor agonist DOI (1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane) (0, 0.3 mg/kg), with or without antagonists for α1 (prazosin:0, 0.3, or 1 mg/kg) or β (timolol:0, 3, or 10 mg/kg) receptors or their combination (0 or 0.3 mg/kg prazosin + 3 mg/kg timolol), or the 5-HT(2) antagonist ritanserin (0, 2 mg/kg). Separately, the α1-adrenergic receptor agonist cirazoline (0, 0.68 mg/kg) was given with and without ritanserin (0, 0.5, or 2 mg/kg) or the NE antagonists (0 or 0.3 mg/kg prazosin + 3 mg/kg timolol). Finally, combinations of subthreshold doses of DOI (0, 0.01, 0.025 mg/kg) and cirazoline (0, 0.1, 0.25 mg/kg) were tested for their ability to disrupt PPI, and concomitant administration of all three antagonists (0 vs. 0.3 mg/kg prazosin + 3 mg/kg timolol + 2 mg/kg ritanserin) was assessed for its ability to modify PPI. Locomotion was assessed in an additional set of experiments. Doses/combinations of prazosin and timolol that reversed cirazoline-induced effects did not alter DOI-induced effects, and ritanserin did not affect cirazoline at doses that blocked DOI-mediated effects. Concomitant antagonism of α1 + β + 5-HT(2) receptors did not modify PPI, nor did combinations of subthreshold doses of cirazoline and DOI. 5-HT(2) receptors and α1 and β NE receptors may act through independent mechanisms to modulate sensorimotor gating and locomotor activity.Psychopharmacology 09/2011; 220(3):465-79. DOI:10.1007/s00213-011-2490-2 · 3.99 Impact Factor