Alpha1b-adrenergic receptors control locomotor and rewarding effects of psychostimulants and opiates - PubMed (original) (raw)
Alpha1b-adrenergic receptors control locomotor and rewarding effects of psychostimulants and opiates
Candice Drouin et al. J Neurosci. 2002.
Abstract
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.
Figures
Fig. 1.
Catecholamine transmission markers in WT and α1b-AR KO mice. A, Autoradiograms show the localization of α1-adrenergic receptors revealed by3H-prazosin (1 n
m
). Binding densities were quantified in the cortex (layer III) and the thalamus (N = 4 animals per group). _B,_Autoradiograms show the localization of D1 and D2 dopamine receptors (D1R and D2R), dopamine transporter (DAT), and vesicular monoamine transporter (VMAT) revealed, respectively, by3H-SCH23390, 125I-iodosulpride,3H-WIN35,428, and 3H-tetrabenazine.C, Binding densities were quantified in the striatum (N = 4 animals per group). _D,_Histograms show the formation of cAMP in striatal membranes under basal conditions or in response to DA (100 μ
m
) (N = 4 animals per group).
Fig. 2.
Locomotor responses to novelty, saline, scopolamine, and chloro-APB in WT and α1b-AR KO mice.A, Locomotor response to novelty was measured every 5 min during the first 50 min mice spent in the experimental apparatus.B, C, Animals were placed in the experimental apparatus for 90 min, received a saline injection, and were replaced in the apparatus for 60 min. On the next day, animals were placed in the experimental apparatus for 90 min, they received an intraperitoneal injection of either saline or scopolamine (1 mg/kg), and their locomotor response was measured every 5 min for 60 min.D, Animals were placed in the experimental apparatus for 90 min, received a saline injection, and were replaced in the apparatus for 60 min. On the following days, animals were placed in the experimental apparatus for 90 min, they received an intraperitoneal injection of chloro-APB, and their locomotor response was measured every 5 min for 60 min. Several doses of chloro-APB were tested on consecutive days in a random order. Groups of 8–14 animals were used in all of these experiments (A–D).
Fig. 3.
Locomotor responses to
d
-amphetamine, cocaine, and morphine in WT and α1b-AR KO mice. Locomotor responses to different doses of
d
-amphetamine, cocaine, and morphine were measured every 5 min under conditions similar to Figure 2_B_except that locomotor response to morphine was measured for 120 min. Independent groups of animals were used for each treatment to avoid eventual behavioral sensitization (N = 6–16 per group). A, Total locomotor responses measured during the first hour after the drug administration are presented in function of the dose. *p < 0.05 and **p < 0.01 when WT and α1b-AR KO mice locomotor responses were significantly different from basal locomotor responses. °p < 0.05 and °°p < 0.01 when WT and α1b-AR KO mice locomotor responses were significantly different (Student's t test).B, Time courses of locomotor responses measured every 5 min are illustrated for
d
-amphetamine (2 mg/kg), cocaine (15 mg/kg), and morphine (7.5 mg/kg).
Fig. 4.
Prazosin effect on the locomotor responses of WT and α1b-AR KO mice to
d
-amphetamine, cocaine, and morphine. Animals were placed in the experimental apparatus for 150 min, and they received two saline injections after 60 and 90 min spent in the corridor. On the next day, animals were placed in the experimental apparatus for 60 min, they received an intraperitoneal injection of either saline or prazosin (1 mg/kg), and they were replaced in the corridor for 30 min. Then, they received an intraperitoneal injection of
d
-amphetamine, cocaine, or morphine, and their locomotor response was measured every 5 min for 60 or 120 min. Independent groups of animals were used for each treatment to avoid eventual behavioral sensitization (N = 6–12 per group). Locomotor responses measured during the first hour after the injection are presented in histograms in A,and time courses are illustrated in B. *p < 0.05 and **p < 0.01 when locomotor responses after prazosin pretreatment were significantly different from locomotor responses after saline pretreatment (Student's t test). °_p < 0.05 significantly different from WT mice locomotor responses (Student's_t test).
Fig. 5.
Induction of locomotor sensitizations by repeated administration of
d
-amphetamine, cocaine, and morphine in WT and α1b-AR KO mice. Animals spent 90 min in the experimental apparatus, received a saline injection, and were replaced in the apparatus for 60 min. On the next day, they spent 90 min in the experimental apparatus, they received an intraperitoneal injection of saline, morphine, cocaine, or
d
-amphetamine, and their locomotor response was measured for 60 or 120 min. Four similar sessions took place every other day. The sixth session took place after a 10 d withdrawal. Locomotor responses measured during the first hour after each injection are presented in function of the number of injections, and slope values are given in Results.N = 6–15 animals per group.
Fig. 6.
Expression of locomotor sensitizations induced by repeated administration of
d
-amphetamine, cocaine, and morphine in WT and α1b-AR KO mice. Locomotor responses to
d
-amphetamine, cocaine, and morphine were measured in naive mice and in mice having previously received five drug injections, as described in Figure 5. N = 6–12 animals per group.A, Total locomotor responses measured during the first hour after the drug injection. *p < 0.05, **p < 0.01, and ***p < 0.001 significantly different between WT and α1b-AR KO mice. °p < 0.05, °°p < 0.01, and °°°p < 0.001 significantly different from respective naive mice. B, Time course of the locomotor responses measured every 5 min.
Fig. 7.
Oral consumption of cocaine, morphine, sucrose, and quinine in a two-bottle choice paradigm in WT and α1b-AR KO mice. Consumption of water, cocaine (0.2 mg/ml), morphine (0.15 mg/ml), and different concentrations of sucrose and quinine were measured in a two-bottle choice paradigm, as described in Materials and Methods, and were expressed in percentage of total fluid intake.N = 7–9 animals per group. *p< 0.05, **p < 0.01 when cocaine or morphine consumption significantly differed from water consumption (paired Student's t test). °p < 0.05, °°°p < 0.001 when consumption of α1b-AR KO mice significantly differed from consumption of WT mice (unpaired Student's t test).
Fig. 8.
Conditioned place preference induced by morphine in WT and α1b-AR KO mice. WT and α1b-AR KO mice were conditioned to receive morphine (5 mg/kg, s.c.) in a compartment and a saline injection in the other compartment. The saline group received saline injections in both compartments. N = 6–11 animals per group. Top, Left graph shows the time spent in the morphine-associated compartment before conditioning (pre-test), after four morphine injections and four saline injections (post-test 1), and after two supplementary morphine and two supplementary saline injections (post-test 2). *p < 0.05 and **p < 0.01 when time spent in the drug compartment was different between pre-test and post-test 1 or 2 (paired Student's_t_ test). On the right graph, scores correspond to the time spent in the morphine compartment during the post-test (1 and 2) minus time spent in the morphine compartment during the pre-test. °p< 0.05 when scores were higher for morphine-treated mice than for saline-treated mice (unpaired Student's t test).Bottom, Graphs show the locomotor activity measured during the 30 min of each of the 12 conditioning sessions corresponding either to morphine or to saline injection. ***p < 0.001 locomotor activity measured during the morphine session was higher than during the corresponding saline session (paired Student's_t_ test).
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