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The locomotor hyperactivity induced by systemic or local (nucleus accumbens) D-amphetamine injections can be blocked by systemic or local (prefrontal cortex) injections of prazosin, an alpha1-adrenergic antagonist (Blance et al., 1994). Microdialysis studies performed on freely moving animals indicated that prazosin (0.5 mg/kg, i.p.) does not modify the increase in the extracellular dopamine (DA) levels in the nucleus accumbens that are induced by D-amphetamine (2.0 mg/kg, i.p.), but it inhibits the D-amphetamine-induced locomotor hyperactivity (-63%, p < 0.0001). No behavioral activation occurred after the bilateral local perfusion of 3 microM D-amphetamine in the nucleus accumbens, although it led to a fivefold increase in extracellular DA levels. This increase in extracellular DA levels was not affected by prazosin (0.5 mg/kg, i.p.). When an intraperitoneal injection of D-amphetamine (0.5 mg/kg) was superimposed to the continuous local perfusion of 3 microM D-amphetamine, it induced a 64% increase in the extracellular DA levels in the nucleus accumbens, and this response was associated with simultaneous behavioral activation. Both the increases in extracellular DA levels and in locomotor activity were completely blocked by a pretreatment with prazosin, injected either systemically (0.5 mg/kg, i.p.) or locally and bilaterally into the prefrontal cortex (500 pmol/side). Complementary experiments indicated that the focal application of D-amphetamine requires at least a 4.8-fold higher increase in DA output compared with systemic D-amphetamine for the behavioral effects to be elicited. Altogether, these results suggest that locomotor activating effects of D-amphetamine are caused by the stimulation of cortical alpha1-adrenergic receptors by noradrenaline, which increases the release of a functional part of subcortical DA.

Drugs of abuse, such as psychostimulants and opiates, are generally considered as exerting their locomotor and rewarding effects through an increased dopaminergic transmission in the nucleus accumbens. Noradrenergic transmission may also be implicated because most psychostimulants increase norepinephrine (NE) release, and numerous studies have indicated interactions between noradrenergic and dopaminergic neurons through alpha1-adrenergic receptors. However, analysis of the effects of psychostimulants after either destruction of noradrenergic neurons or pharmacological blockade of alpha1-adrenergic receptors led to conflicting results. Here we show that the locomotor hyperactivities induced by d-amphetamine (1-3 mg/kg), cocaine (5-20 mg/kg), or morphine (5-10 mg/kg) in mice lacking the alpha1b subtype of adrenergic receptors were dramatically decreased when compared with wild-type littermates. Moreover, behavioral sensitizations induced by d-amphetamine (1-2 mg/kg), cocaine (5-15 mg/kg), or morphine (7.5 mg/kg) were also decreased in knock-out mice when compared with wild-type. Ruling out a neurological deficit in knock-out mice, both strains reacted similarly to novelty, to intraperitoneal saline, or to the administration of scopolamine (1 mg/kg), an anti-muscarinic agent. Finally, rewarding properties could not be observed in knock-out mice in an oral preference test (cocaine and morphine) and conditioned place preference (morphine) paradigm. Because catecholamine tissue levels, autoradiography of D1 and D2 dopaminergic receptors, and of dopamine reuptake sites and locomotor response to a D1 agonist showed that basal dopaminergic transmission was similar in knock-out and wild-type mice, our data indicate a critical role of alpha1b-adrenergic receptors and noradrenergic transmission in the vulnerability to addiction.

Using specific antibodies and cDNA probes, we have investigated, in rat basal ganglia, the distribution and the regulation of the expression of the alpha subunits of Gs and G(olf), two GTP-binding proteins (G-proteins) that stimulate adenylyl cyclase. We confirmed that G(olf) alpha is highly expressed in caudate-putamen, nucleus accumbens, and olfactory tubercle, whereas Gs alpha is less abundant in these areas than in the other brain regions. Intrastriatal injections of quinolinic acid decreased dramatically the levels of G(olf) alpha protein in the striatum and the substantia nigra, and those of G(olf) alpha mRNA in the striatum. Retrograde lesions of striatonigral neurons with volkensin reduced markedly the levels of D1 dopamine (DA) binding sites, as well as those of G(olf) alpha protein and mRNA in the striatum, without altering D2 binding sites. In contrast, both types of lesions increased the levels of Gs alpha protein in the striatum and substantia nigra. Immunocytochemistry showed the presence of G(olf) alpha protein in striatal medium-sized neurons and in several other neuronal populations. These results demonstrate that striatonigral neurons contain high levels of G(olf) alpha and little, if any, Gs alpha, suggesting that the coupling of D1 receptor to adenylyl cyclase is provided by G(olf) alpha. The levels of G(olf) alpha were five- to sixfold higher in the striatum than in the substantia nigra, indicating a preferential localization of G(olf) alpha in the somatodendritic region of striatonigral neurons and providing a basis for the low efficiency of D1 receptor coupling in the substantia nigra. Six weeks after 6-hydroxydopamine lesions of DA neurons, an increase in G(olf) alpha (+53%) and Gs alpha (+64%) proteins was observed in the striatum. This increase in G(olf) alpha levels may account for the DA-activated adenylyl cyclase supersensitivity, without change in D1 receptors density, that follows destruction of DA neurons. Fine regulation of the levels of G(olf) alpha in physiological or pathological situations may be a critical parameter for the efficiency of DA neurotransmission.

Repeated traumatic events induce long-lasting behavioral changes that are key to organism adaptation and that affect cognitive, emotional, and social behaviors. Rodents subjected to repeated instances of aggression develop enduring social aversion and increased anxiety. Such repeated aggressions trigger a stress response, resulting in glucocorticoid release and activation of the ascending dopamine (DA) system. We bred mice with selective inactivation of the gene encoding the glucocorticoid receptor (GR) along the DA pathway, and exposed them to repeated aggressions. GR in dopaminoceptive but not DA-releasing neurons specifically promoted social aversion as well as dopaminergic neurochemical and electrophysiological neuroadaptations. Anxiety and fear memories remained unaffected. Acute inhibition of the activity of DA-releasing neurons fully restored social interaction in socially defeated wild-type mice. Our data suggest a GR-dependent neuronal dichotomy for the regulation of emotional and social behaviors, and clearly implicate GR as a link between stress resiliency and dopaminergic tone.

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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.