Importance of the Noradrenaline–Dopamine Coupling in the Locomotor Activating Effects of d-Amphetamine

Abstract

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.

α1-Adrenergic receptors mediate the locomotor response to systemic administration of (±)-3,4-methylenedioxymethamphetamine (MDMA) in rats

“…The effect of prazosin observed here is similar to the effects reported in other studies examining the role of the α 1 -adrenergic receptor in the locomotor response to amphetamine or cocaine (Arnt 1995;Blanc et al 1994;Darracq et al 1998;Dickinson et al 1988;Drouin et al 2002a;Drouin et al 2002b;Snoddy et al 1985;Wellman et al 2002). In fact, our data indicate that MDMA-induced motor behavior is more sensitive to α 1 -adrenoceptor blockade than that produced by (+)-amphetamine.…”

“…The results of this experiment are consistent with the findings of Darracq et al (1998), who had previously reported that prazosin blocked the locomotor stimulant effect of amphetamine. A one-way ANOVA indicated an overall significant effect of prazosin administration on the locomotor response to 2 mg/kg amphetamine (p < 0.01).…”

“…The 1 mg/ kg (2.4 μmol/kg) dose of prazosin was administered IP in a volume of 2 mL/kg. The doses of prazosin were selected based on the results of Darracq et al (1998).…”

“…In studies of drug-induced increases in locomotor activity, local administration of prazosin into the prefrontal cortex (PFC) decreased the locomotor response to amphetamine and morphine (Blanc et al 1994;Darracq et al 1998;Drouin et al 2001), indicating that NE may modulate stimulant-induced locomotor activity through activation of α 1 -adrenoceptors in this region. α 1 -Adrenoceptors in the VTA also facilitate the ability of stimulant drugs to regulate the mesolimbic system.…”

The Effects of Locus Coeruleus and Norepinephrine in Methamphetamine Toxicity

“…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 [130]. Conversely, transgenic mice overexpressing either wild-type or constitutively active alpha1b ARs show nigrostriatal damage associated with serious locomotor dysfunction, tremor at rest, epileptic seizures, and autonomic dysfunctions [131].…”