Example 5
Effect of Mecamylamine, 18-Methoxycoronaridine, Dextromethorphan, Mecamylamine/18-Methoxycoronaridine, Mecamylamine/Dextromethorphan, and Dextromethorphan/18-Methoxycoronaridine Drug Treatments on Morphine and Methamphetamine Self-administration
FIGS. 5-7 show the effects of mecamylamine, 18-methoxycoronaridine, dextromethorphan, mecamylamine/18-methoxycoronaridine, mecamylamine/dextromethorphan, and dextromethorphan/18-methoxycoronaridine drug treatments on morphine and methamphetamine self-administration and on responding for water.
More particularly, FIG. 5 shows the effects of the drugs and drug combinations on morphine self-administration. Rats were administered two of the following treatments before testing: mecamylamine (1 mg/kg i.p., 30 min) (“Mec 1”), 18-methoxycoronaridine (1 mg/kg i.p., 15 min) (“18MC 1”), dextromethorphan (5 mg/kg s.c., 20 min) (“DM 5”), or vehicle (saline for mecamylamine and dextromethorphan; phosphate buffer for 18-methoxycoronaridine). Each data point represents the mean (±S.E.M.) percent of baseline of 6-8 rats. Significant differences between baseline and treatment are indicated by an asterisk (paired t-test, P<0.01-0.001).
FIG. 6 shows the effects of the drugs and drug combinations on methamphetamine self-administration. Rats were administered two of the following treatments before testing: mecamylamine (1 mg/kg i.p., 30 min) (“Mec 1”), 18-methoxycoronaridine (2 mg/kg i.p., 15 min) (“18MC 2”), dextromethorphan (5 mg/kg s.c., 20 min) (“DM 5”), or vehicle (saline for mecamylamine and dextromethorphan; phosphate buffer for 18-methoxycoronaridine). Each data point represents the mean (±S.E.M.) percent of baseline of 6-7 rats. Significant differences between baseline and treatment are indicated by an asterisk (paired t-test, P<0.01).
FIG. 7 shows the effects of the drugs and drug combinations on responding for water. Rats were administered two of the following treatments before testing: mecamylamine (1 mg/kg i.p., 30 min) (“Mec 1”), 18-methoxycoronaridine (2 mg/kg i.p., 15 min) (“18MC 2”), dextromethorphan (5 mg/kg s.c., 20 min) (“DM 5”), or vehicle (saline for mecamylamine and dextromethorphan; phosphate buffer for 18-methoxycoronaridine). Each data point represents the mean (±S.E.M.) percent of baseline of 6 rats.
All three drug combinations (i.e., mecamylamine/18-methoxycoronaridine, mecamylamine/dextromethorphan, and dextromethorphan/18-methoxycoronaridine), but none of the drugs administered alone, significantly decreased morphine and methamphetamine self-administration while having no effect on responding for water. The particular doses of 18-methoxycoronaridine, dextromethorphan, and mecamylamine selected for study were, in each instance, based on the respective dose-response functions. The doses of 18-methoxycoronaridine (1 and 2 mg/kg) were approximately one-fifth of those required to decrease morphine (Glick et al., “18-Methoxycoronaridine, a Non-toxic Iboga Alkaloid Congener: Effects on Morphine and Cocaine Self-administration and on Mesolimbic Dopamine Release in Rats,” Brain Res., 719:29-35 (1996), which is hereby incorporated by reference) and methamphetamine (Glick I, which is hereby incorporated by reference) self-administration, respectively, when administered alone. The dose of dextromethorphan (5 mg/kg) was one-half to one-fourth of that necessary to decrease morphine and methamphetamine self-administration (Glick et al., “Comparative Effects of Dextromethorphan and Dextrorphan on Morphine, Methamphetamine, and Nicotine Self-administration in Rats,” Europ. J. Pharmacol., 422:87-90 (2001), which is hereby incorporated by reference), respectively, when administered alone. The dose of mecamylamine (1 mg/kg) was one-third of that required to decrease either morphine or methamphetamine self-administration, and, at a dose of 3 mg/kg, mecamylamine also decreases responding for water (data not shown). Lastly, although FIG. 7 only shows results with the 2 mg/kg dosage of 18-methoxycoronaridine, virtually identical results were found with 1 mg/kg.
Example 6
Effect of Mecamylamine, 18-Methoxycoronaridine, Dextromethorphan, Bupropion, Mecamylamine/Bupropion, Dextromethorphan/Bupropion, and 18-Methoxycoronaridine/Bupropion Drug Treatments on Morphine and Methamphetamine Self-administration
FIGS. 8-10 show the effects of mecamylamine, 18-methoxycoronaridine, dextromethorphan, bupropion, mecamylamine/bupropion, dextromethorphan/bupropion, and 18-methoxycoronaridine/bupropion drug treatments on morphine and methamphetamine self-administration and on responding for water.
More particularly, FIG. 8 shows the effects of the drugs and drug combinations on morphine self-administration. Rats were administered two of the following treatments before testing: mecamylamine (1 mg/kg i.p., 30 min) (“Mec 1”), 18-methoxycoronaridine (1 mg/kg i.p., 15 min) (“18MC1”), dextromethorphan (5 mg/kg s.c., 20 min) (“DM5”), bupropion (5 mg/kg i.p., 15 min) (“Bup5”), or vehicle (saline for mecamylamine, dextromethorphan and bupropion; phosphate buffer for 18-methoxycoronaridine). Each data point represents the mean (±S.E.M.) percent of baseline of 5-8 rats. Significant differences between baseline and treatment are indicated by an asterisk (paired t-test), P<0.05-0.01).
FIG. 9 shows the effects of the drugs and drug combinations on methamphetamine self-administration. Rats were administered two of the following treatments before testing: mecamylamine (1 mg/kg i.p., 30 min) (“Mec 1”), 18-methoxycoronaridine (5 mg/kg i.p., 15 min) (“18MC5”), dextromethorphan (10 mg/kg s.c., 20 min) (“DM10”), bupropion (10 mg/kg i.p., 15 min) (“Bup10”), or vehicle (saline for mecamylamine, dextromethorphan and bupropion; phosphate buffer for 18-methoxycoronaridine). Each data point represents the mean (±S.E.M.) percent of baseline of 5-9 rats. Significant differences between baseline and treatment are indicated by an asterisk (paired t-test, P<0.01).
FIG. 10 shows the effects of the drugs and drug combinations on responding for water. Rats were administered two of the following treatments before testing: mecamylamine (1 mg/kg i.p., 30 min) (“Mec 1”), 18-methoxycoronaridine (5 mg/kg i.p., 15 min) (“18MC5”), dextromethorphan (10 mg/kg s.c., 20 min) (“DM10”), bupropion (10 mg/kg i.p., 15 min) (“Bup10”), or vehicle (saline for mecamylamine, dextromethorphan and bupropion; phosphate buffer for 18-methoxycoronaridine). Each data point represents the mean (±S.E.M.) percent of baseline of 6-7 rats.
All three drug combinations (i.e., mecamylamine/bupropion, dextromethorphan/bupropion, and 18-methoxycoronaridine/bupropion), but none of the drugs administered alone, significantly decreased morphine and methamphetamine self-administration while having no effect on responding for water.
Example 7
Effect of Drugs and Drug Combinations on Nicotine Self-administration
FIGS. 11 and 12 show the effects of mecamylamine, 18-methoxycoronaridine, dextromethorphan, bupropion, mecamylamine/18-methoxycoronaridine, mecamylamine/dextromethorphan, and dextromethorphan/18-methoxycoronaridine, mecamylamine/bupropion, dextromethorphan/bupropion, and 18-methoxycoronaridine/bupropion drug treatments on nicotine self-administration.
More particularly, FIG. 11 shows the effects of mecamylamine, 18-methoxycoronaridine, dextromethorphan, mecamylamine/18-methoxycoronaridine, mecamylamine/dextromethorphan, and dextromethorphan/18-methoxycoronaridine, on nicotine self-administration. Rats were administered two of the following treatments before testing: mecamylamine (0.1 mg/kg i.p., 30 min) (“Mec 0.1”), 18-methoxycoronaridine (0.5 mg/kg i.p., 15 min) (“18MC 0.5”), dextromethorphan (0.5 mg/kg s.c., 20 min) (“DM 0.5”), or vehicle (saline for mecamylamine and dextromethorphan; phosphate buffer for 18-methoxycoronaridine). Each data point represents the mean (±S.E.M.) percent of baseline of 5-7 rats. Significant differences between baseline and treatment are indicated by an asterisk (paired t-test, P<0.01).
FIG. 12 shows the effects of mecamylamine, 18-methoxycoronaridine, dextromethorphan, bupropion, mecamylamine/bupropion, dextromethorphan/bupropion, and 18-methoxycoronaridine/bupropion drug treatments on nicotine self-administration. Rats were administered two of the following treatments before testing: mecamylamine (0.1 mg/kg i.p., 30 min) (“Mec 0.1”), 18-methoxycoronaridine (0.5 mg/kg i.p., 15 min) (“18MC 0.5”), dextromethorphan (0.5 mg/kg s.c., 20 min) (“DM 0.5”), bupropion (5 mg/kg i.p., 15 min) (“Bup5”), or vehicle (saline for mecamylamine, dextromethorphan and bupropion; phosphate buffer for 18-methoxycoronaridine). Each data point represents the mean (±S.E.M.) percent of baseline of 5-8 rats. Significant differences between baseline and treatment are indicated by an asterisk (paired t-test, P<0.01).
All six drug combinations (i.e., mecamylamine/18-methoxycoronaridine, mecamylamine/dextromethorphan, dextromethorphan/18-methoxycoronaridine, mecamylamine/bupropion, dextromethorphan/bupropion, and 18-methoxycoronaridine/bupropion), but none of the drugs administered alone, significantly decreased nicotine self-administration. Control experiments showed that these drug combinations had no significant effect on responding for water.
Although the invention has been described in detail for the purpose of illustration, it is understood that such detail is solely for that purpose, and variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention which is defined by the following claims.
