Inhibition of Monoamine Oxidases Desensitizes 5-HT_1A Autoreceptors and Allows Nicotine to Induce a Neurochemical and Behavioral Sensitization

Repeated nicotine requires tranylcypromine to sensitize noradrenergic and serotonergic neurons and obtain behavioral sensitization. Nicotine (1 mg/kg), tranylcypromine (6 mg/kg), and nicotine plus tranylcypromine were used for repeated treatments. Four days after the last injection, d-amphetamine (2 mg/kg) or PCA (7 mg/kg) was administered and cortical extracellular NE (A) or 5-HT (C) levels, respectively or locomotor responses (B, D, respectively) were analyzed. Each group contained at least five animals for microdialysis experiments and eight animals for locomotor activity determination. A, Cortical extracellular NE levels are expressed as a percentage of the respective mean basal value. There was no significant difference in basal cortical extracellular NE levels in the different conditions (mean basal NE values, 0.67 pg NE/20 min ± 0.08). B, Locomotor response to d-amphetamine (2 mg/kg) is measured in the same experimental conditions as in A. C, Cortical extracellular 5-HT levels are expressed as a percentage of the respective mean basal value. There was no significant difference in basal cortical extracellular 5-HT levels in the different conditions (mean basal 5-HT values, 0.81 pg 5-HT/20 min ± 0.06). D, Locomotor response to PCA (7 mg/kg) was measured in the same experimental conditions as in C. Error bars indicate SEM. nico, Nicotine; tranyl, tranylcypromine.

Development of neurochemical and behavioral sensitizations induced by repeated tranylcypromine plus nicotine is blocked by prazosin and SR46349B but not by SCH23390. Experimental conditions were identical with those of Figure 2 for determinations of extracellular NE and 5-HT levels as well as for monitoring locomotor activity (A–D). Each group consisted of at least five and eight animals for microdialysis and locomotor activity, respectively. It was verified that data obtained with repeated SR46349B plus prazosin or repeated SCH233890 were not significantly different from that of repeated saline. Amph, d-Amphetamine; SR, SR46349B; Pz, prazosin; SCH, SCH23390. Error bars indicate SEM.

Locomotor activity and cortical extracellular NE and 5-HT levels in response to nicotine in presence or absence of tranylcypromine. Animals received tranylcypromine (6 mg/kg) or saline (first arrow) and, 100 min later, an injection of nicotine (1 mg/kg) or saline (second arrow), and locomotor activity (A) and extracellular NE (B) and 5-HT (C) levels were monitored. Each group consisted of at least five and eight animals for microdialysis and locomotor activity, respectively. Mean basal cortical extracellular NE and 5-HT levels were similar to those of Figure 2. Error bars indicate SEM. nico, Nicotine; tranyl, tranylcypromine.

Effects of 8-OHDPAT, a 5-HT_1A receptor agonist, on locomotor activity induced by nicotine. Three groups of eight animals received an injection of 8-OHDPAT (1 mg/kg) and 60 min (A), 100 min (B), or 120 min (C) later, an injection of nicotine (1 mg/kg) or of saline, and locomotor activity was monitored. Error bars indicate SEM. nico, Nicotine.

Effects of WAY 100635, a 5-HT_1A receptor antagonist, on locomotor activity induced by nicotine after acute or repeated treatments. A, C, Acute, Animals received an injection of WAY 100635 (1 mg/kg) or saline and, 30 min later, an injection of nicotine (1 mg/kg) or saline, and locomotor activity was monitored. B, D, Pretreated, Animals received 4 consecutive days, once a day, either repeated saline plus saline, saline plus nicotine, WAY 100635 plus saline, or WAY plus nicotine. Then, 4 d later, all animals received an injection of WAY 100635 and, 30 min later, an injection of nicotine, and locomotor activity was measured. C, Histograms of acute locomotor responses after different conditions (white rectangles). ***p < 0.0001 from corresponding saline, WAY 100635, or nicotine controls. D, Histograms of locomotor responses to WAY 100635 plus nicotine after different repeated pretreatments. ***p < 0.0001 from acute WAY 100635 plus nicotine and repeated saline plus saline, WAY 100635 plus saline, or saline plus nicotine. Each group contained at least eight animals. sal, Saline; nico, nicotine; WAY, WAY 100635. Error bars indicate SEM.

Effects of repeated WAY 100635 plus nicotine on sensitization of noradrenergic and serotonergic neurons and behavioral sensitization. Animals were repeatedly treated once a day during 4 d by WAY 100635 (1 mg/kg) and nicotine (1 mg/kg), and WAY 100635 and saline. Four days after the last injection, d-amphetamine (2 mg/kg) or PCA (7 mg/kg) was administered and cortical extracellular NE (A) or 5-HT (C) levels, respectively, or locomotor responses (B, D, respectively) were analyzed. Data of repeated nicotine, presented in Figure 2, have been omitted for sake of clarity. Each group contained at least five animals for microdialysis experiments and eight animals for locomotor activity determination. Mean basal extracellular NE and 5-HT levels were similar to those of Figure 2. Amph, d-Amphetamine; nico, nicotine; WAY, WAY 100635. Error bars indicate SEM.