Potentiation of morphine analgesia by d-amphetamine

Rats were trained to escape from aversive electrical brain stimulation delivered to the mesencephalic reticular formation (MRF). The threshold for this escape behavior was determined by a modification of the classic psychophysical method of limits. Escape thresholds were determined after the administration of morphine alone, d-amphetamine alone, and the combination of d-amphetamine and an ineffective dose of morphine. Morphine alone caused a dose-dependent raising of the escape threshold (1.0–16.0 mg/kg IP) while d-amphetamine alone (0.06–2.0 mg/kg IP) had no effect or caused a slight lowering of threshold. For each animal, a dose of morphine that produced no change in escape threshold was then selected to be administered concomitantly with various doses of d-amphetamine. The co-administration of morphine and d-amphetamine resulted in a significant, dose-dependent increase in the escape threshold, which was not seen with d-amphetamine alone and was as great or greater in magnitude than the increase seen with the highest dose of morphine tested. The results of this study clearly demonstrate that opiate analgesia is potentiated by concomitant d-amphetamine administration. The mechanisms involved in this potentiation warrant further investigation for the clinical management of pain.     

Effects of morphine alone and in combination with naloxone or d-amphetamine on shock-maintained behavior in the squirrel monkey

Key-pressing behavior in the squirrel monkey was maintained under an 8-min fixed-interval (FI) schedule of electric-shock delivery. The acute i.m. administration of morphine prior to a daily session decreased response rates at doses of 1.0–3.0 mg/kg but had little systematic effect on rate at doses of 0.03–0.3 mg/kg. When naloxone was administered concomitantly with morphine prior to a session, 0.01 mg/kg naloxone required a three-fold increase in the dose of morphine necessary to obtain decreased response rates, 0.1 mg/kg naloxone required a 30-fold increase in morphine, and 1.0 mg/kg required more than a 30-fold increase in morphine. Moreover, the administration of naloxone with morphine resulted in increased rates of responding at certain combinations of doses of the two drugs. The administration of d-amphetamine (0.03 or 0.1 mg/kg) alone increased mean response rates under the FI schedule; when combined with 0.03–0.3 mg/kg morphine the increases in responding were greater than obtained with d-amphetamine alone. The negative slope of the linear regression lines relating the effects of morphine to control rates of responding engendered under the FI schedule was decreased when morphine was combined with naloxone, but not with d-amphetamine. These results show that naloxone, but not d-amphetamine, can antagonize the response-rate decreasing effect of morphine when responding in the squirrel monkey is maintained by response-produced electric shock.     

Failure of naloxone to modify the effects of chlorpromazine and d-amphetamine on avoidance behavior in the squirrel monkey

Lever-pressing by squirrel monkeys was maintained under a continuous avoidance schedule in which each response postponed for 30 s the delivery of an electric shock to the tail. Dose-response curves were determined for chlorpromazine (0.03–0.3 mg/kg) and d-amphetamine (0.03–1.0 mg/kg) administered alone and administered concomitantly with 1.0 or 10 mg/kg of aaloxone. The dose-response curves for chlorpromazine and d-amphetamine were similar to those previously reported for monkeys under other schedules of shock-maintained behavior: Chlorpromazine decreased responding in a dose-related manner while d-amphetamine increased responding at low doses and disrupted behavior at the highest dose. Naloxone did not modify the effects of chlorpromazine, and d-amphetamine. These results suggest that interactions observed previously between naloxone and nonopiate drugs on behavior in pigeons and rodents are not general phenomena in all animal species.     

Interactions of naloxone with morphine,amphetamine and phencyclidine on fixed interval responding for intracranial self-stimulation in rats

Rats were implanted with stimulating electrodes aimed at the medial forebrain bundle-lateral hypothalamus (MFB-LH) and were trained to lever-press for brain self-stimulation on a fixed interval: 60 s schedule of reinforcement. The effects of graded doses of naloxone (0.1–30 mg/kg), morphine (0.3–5.6 mg/kg), naloxone plus morphine,d-amphetamine (0.03–1.0 mg/kg), naloxone plusd-amphetamine, phencyclidine (0.3–5.6 mg/kg), and naloxone plus phencyclidine were tested. Naloxone produced a significant decrease in rates at 30 mg/kg. Naloxone (0.1–1.0 mg/kg) plus morphine blocked the dose-dependent decrease produced by morphine alone. In contrast, naloxone (1.0–10 mg/kg) plusd-amphetamine attenuated the graded increase in response rates produced byd-amphetamine. Naloxone (1.0–10 mg/kg) plus phencyclidine did not reliably change the increase in response rates produced by phencyclidine alone. The use of the fixed interval schedule of brain self-stimulation to study these drug interactions is novel, and further demonstrates that the highly reinforcing aspects of brain stimulation, known to be influenced by dopamine, may also be modulated by the endogenous opiate system.     

Shifting of the d-amphetamine dose-response curve in rats with frontal cortical ablations

Rats trained to bar-press on a FI 15 sec schedule for water reinforcement were administered various doses of d-amphetamine (0.25–4.0 mg/kg) both before and 6–8 weeks after bilateral ablation of frontal cortex. Preoperatively, low doses (e.g. 0.25–0.5 mg/kg) of (d-amphetamine increased responding and high doses (e.g. 2.0–4.0 mg/kg) of d-amphetamine depressed responding. Postoperatively, frontal rats showed larger facilitatory effects in response to low doses of d-amphet-amine but lesser depressant effects in response to high doses of d-amphetamine; the whole dose-response curve was generally shifted higher by the frontal lesions. These results indicate that frontal lesions differentially influence mechanisms mediating two different actions of d-amphetamine.This research was supported by NIMH grant MH21156 and NIMH Research Scientist Development Award (Type 2) DA70082 to S. D. Glick.     

Effects of d-amphetamine and ethanol alone and in combination on schedule-controlled responding of pigeons

Key pecking by pigeons was maintained under either a 5-min fixed-interval or a 30-response fixed-ratio schedule of food delivery. d-Amphetamine (0.1–1.0 mg/kg) either increased or did not affect overall rates of responding under the fixed-interval schedule; the lowest dose of ethanol (0.5 g/kg) did not affect or slightly decreased response rates, whereas higher doses (1.0–2.0 g/kg) substantially decreased rates. Combinations of low noneffective ethanol doses with most doses of d-amphetamine increased rates of responding under the fixed-interval schedule above those obtained with d-amphetamine alone; decreases produced by the higher doses of ethanol were attenuated by most doses of d-amphetamine. Doses of d-amphetamine (0.1–1.0 mg/kg) and ethanol (0.5–1.5 g/kg) alone generally had no effect on responding maintained under the fixed-ratio schedule; higher doses of these drugs decreased responding. The effects of dose combinations other than the highest ones generally differed little from those obtained with ethanol alone; the effects of high doses of each drug were antagonized by low to moderate doses of the other. Combinations of ethanol with d-amphetamine can result in higher rates of responding than are obtained with either drug alone. Further, effects of the drugs alone and in combination depend on the schedule under which behavior is maintained.     

Comparison of the effects of morphine,pentazocine, cyclazocine and amphetamine on intracranial self-stimulation in the rat

Rats were trained to press a lever in order to stimulate their lateral hypothalamus through a chronically implanted electrode. Dose-response curves were determined for the effects of morphine (0.3–10 mg/kg), pentazocine (1.0–30 mg/kg), cyclazocine (0.03–3.0 mg/kg) and d-amphetamine (0.1–3.0 mg/kg) on responding for intracranial stimulation, and then were redetermined in the presence of one or two doses of naloxone. The three analgesics produced only dose-related decreases in responding with the following relative potencies: cyclazocine>morphine>pentazocine. The well-documented rate-increasing effects of d-amphetamine on intracranial self-stimulation were observed at 0.3 and 1.0 mg/kg of the drug; decreases in responding at 3.0 mg/kg were associated with stereotyped behavior. Naloxone, which had no effect of its own on self-stimulation, increased the dose of the analgesics required to depress response rate in a manner consistent with a competitive antagonism. In contrast, response rates were reduced at all doses of d-amphetamine tested in the presence of naloxone. Thus, the interaction between naloxone and d-amphetamine is qualitatively different from the one between naloxone and the analgesics. This finding extends to intracranial self-stimulation the generality of a previous report of interactions between d-amphetamine and naloxone on behavior in the rat.Publication No. 1303 of the Division of Basic Health Sciences of Emory University. This investigation was supported by USPHS Grant DA-00541.Recipient of Research Scientist Development Award K02-DA00008.     

Role of specific dopamine receptor subtypes in amphetamine discrimination

Biochemical, electrophysiological, and behavioral experiments suggest that the dopamine D-1 and D-2 receptor subtypes functionally interact. In rats trained to discriminate 1.0 mg/kg d-amphetamine, substitution with the D-2 agonist quinpirole (0.1–2.0 mg/kg) produces amphetaminelever responding, whereas the D-1 agonist SKF 38393 (0.3–10.0 mg/kg) elicits only saline-appropriate responding. Combining either quinpirole (0.05–0.5 mg/kg) or SKF 38393 (0.5–10.0 mg/kg) with 0.3 mg/kg d-amphetamine results in dose-dependent increases in amphetamine-lever responding. Conversely, the D-1 antagonist SCH 23390 (0.02–0.1 mg/kg) antagonizes the discrimination produced by 0.7 mg/kg d-amphetamine. Additional combination studies examined the effect of DA receptor drugs on discrimination when quinpirole is substituted in d-amphetamine trained rats. SKF 38393 (0.5–7.0 mg/kg) fails to increase the amphetamine-appropriate lever response produced by either 0.05 or 0.2 mg/kg quinpirole. Similarly, SCH 23390 (0.01–0.1 mg/kg) fails to antagonize the amphetamine-lever responding produced by either 0.2 or 0.5 mg/kg quinpirole. Haloperidol (0.02–0.2 mg/kg) does antagonize the amphetamine-appropriate response produced by quinpirole substitution. The d-amphetamine discrimination studies indicate that stimulating D-2 receptors alone or D-1 receptors in the presence of d-amphetamine yields d-amphetamine-lever responding, and suggests that D-1/D-2 receptors can functionally interact to alter discrimination behavior. Quinpirole substitution, on the other hand, shows an insensitivity to D-1 receptor manipulations.     

Effects of triadimefon on a multiple schedule of fixed-interval performance: Comparison with methylphenidate, d-amphetamine and chlorpromazine

Triadimefon is a fungicide that has recently been shown to increase motor activity and rates of schedule-controlled responding. These findings indicate that triadimefon resembles psychomotor stimulants and in this respect is a unique pesticide. The present experiment was designed to evaluate triadimefon's effects on performance maintained by a multiple schedule of reinforcement and to compare triadimefon to known psychomotor stimulants. Four rats were trained to perform under a mult FI 1-min FI 5-min schedule of milk reinforcement. They then received a series of dosages of triadimefon (10–170 mg/kg, IP) and of methylphenidate (1–17.3 mg/kg, IP) in a counterbalanced order. Triadimefon increased response rates in both the FI 1-min and FI 5-min components. Methylphenidate did not consistently alter response rates in either component. Temporal patterns of responding were disrupted much more in the FI 5-min component than in the FI 1-min component by both triadimefon and methylphenidate. Performances were then evaluated following a series of dosages of d-amphetamine (0.3–3.0 mg/kg, IP) and chlorpromazine (0.5–2.0 mg/kg, IP). Response rates were increased d-amphetamine in the FI 1-min component but not in the FI 5-min component. Like triadimefon and methylphenidate, d-amphetamine produced a greater disruption of response patterning in FI 5-min than in FI 1-min. Only chlorpromazine decreased response rates in both components. Chlorpromazine also disrupted FI 5-min response patterning, but left FI 1-min patterning intact. Although triadimefon did not closely resemble any of the comparison drugs, it had opposite effects on response rates from chlorpromazine in both components of the schedule and resembled d-amphetamine in its effects on FI 1-min response rates. The rate-increasing effects frequently obtained with psychomotor stimulants were more evident for triadimefon than for either methylphenidate or d-amphetamine.     

Drug level of d- and l-amphetamine during intravenous self-administration

Rats were allowed to self-administer dextro and levo isomers of amphetamine in doses of 0.25, 0.50, 0.75 and 1.0 mg/kg/injection for 6 h/day. Total body level of drug was calculated at the time of responding for each drug injection. Body level of amphetamine initially increased and then decreased (0–2 h), and thereafter remained relatively constant for the remainder of the experimental session (2–6 h). During 2–6 h of self-administration, calculated whole body levels of both d- and l-amphetamine remained relatively constant across injection doses. In another study, blood was removed several times during 2–6 h at the time of responding for drug injection. Again, no difference in blood level of ¹⁴C-amphetamine was found across a range of injection doses. Mean blood levels were 0.48 g/ml for l-amphetamine and 0.18 g/ml for d-amphetamine. Drug intake averaged 2.0 mg/kg/h for l-amphetamine and 0.79 mg/kg/h for d-amphetamine.     

Effects of dopamine D1 and D2 receptor blockade on MK-801-induced hyperlocomotion in rats

Blocking glutamatergic transmission at the N-methyl-d-aspartate (NMDA) receptor complex with MK-801 (0.15–0.5 mg/kg, IP) was found to induce a robust, dose-dependent increase in locomotor activity. This behavioural activation was similar in intensity to that observed afterd-amphetamine (1 mg/kg, SC). The locomotor stimulation induced by MK-801 at 0.3 mg/kg was significantly inhibited by the D₂ dopamine receptor antagonist raclopride (0.1–0.3 mg/kg, SC) and by the D₁ receptor antagonist SCH 23390 (0.04 mg/kg, SC). The locomotor activity induced by a higher dose of MK-801 (0.5 mg/kg) was reduced by higher doses of raclopride or SCH 23390 administered alone (0.3 and 0.08 mg/kg, respectively), and was inhibited by simultaneous administration of ineffective doses. Raclopride significantly reducedd-amphetamine-induced locomotor activity at a dose (0.2 mg/kg) that also blocked the effects of a low dose of MK-801. In contrast, SCH 23390 blocked the effects ofd-amphetamine at a dose (i.e. 0.01 mg/kg) lower than that needed to block MK-801. These results suggest that the dopaminergic system may in part mediate the locomotor effects induced by the NMDA antagonist, MK-801, in rats. However, the locomotor activity induced by MK-801 appears to be less sensitive to dopaminergic receptor blockade than that induced byd-amphetamine, suggesting that the underlying mechanisms, although similar, are not identical.     

Specific opioid-amphetamine interactions in the caudate putamen

Bilateral microinjection of morphine (0.003–3 g/side) into the caudate putamen enhances the behavior induced by the IP injection of 1 mg/kg d-amphetamine phosphate in a dose-related manner. The duration of activity was prolonged and ambulation was changed to d-amphetamine stereotypy, a behavior normally associated with higher doses of d-amphetamine. The opioid activity was stereospecific in that levorphanol was active, whereas dextrorphan was not. The enhancement of d-amphetamine-induced behavior by the opioids was blocked by naloxone. d-ala²-met-Enkephalin also enhanced the amphetamine-induced behavior. This enhancement appears to be specific to the caudate putamen because the oral stereotypy observed appears to be a unique action of amphetamine in this region of the brain.     

Antagonism of the behavioral effects of cocaine and d-amphetamine by prazosin

Key pecking by pigeons was maintained under a 30-response fixed-ratio schedule of food delivery; lever pressing by squirrel monkeys was maintained under a 3-min fixed-interval schedule of food delivery. Administered alone, d-amphetamine (0.1–3.0 mg/kg), cocaine (1.0–3.0 mg/kg) and bupropion (1.0–30 mg/kg) either did not affect or decreased fixed-ratio responding of pigeons, whereas d-amphetamine (0.056–0.3 mg/kg) either increased or decreased (0.56 mg/kg) responding of monkeys maintained under the fixed-interval schedule. Prazosin, a selective centrally-active alpha₁ antagonist, produced a dose-dependent reversal of the rate-decreasing effects of d-amphetamine and cocaine but not of bupropion on fixed-ratio responding in pigeons. Prazosin also reversed both the rate-increasing and rate-decreasing effects of d-amphetamine on fixed-interval responding of squirrel monkeys. In contrast, the non-selective alpha-antagonist phentolamine enhanced d-amphetamine-induced decreases in fixed-ratio responding. These findings suggest that the behavioral effects of d-amphetamine and cocaine are produced at least in part by activation of central alpha₁ receptors. Prazosin may be a useful tool for better understanding the mechanisms through which cocaine, amphetamine, and other abused stimulant drugs exert their potent behavioral effects.     

Some behavioural and EEG effects of ascorbic acid in rats

Ascorbic acid (50–200 mg/kg IP) activated gross behaviour and EEG of rats. The behavioural excitation induced by d-amphetamine (2.5 mg/kg SC) was significantly potentiated by ascorbic acid (100–200 mg/kg IP). Catalepsy induced by haloperidol (0.25 mg/kg IP) was attenuated by ascorbic acid (50–200 mg/kg IP) while pentobarbitone (20 mg/kg IP)-induced sleep in rats was dose-dependently antagonised by ascorbic acid (50–400 mg/kg IP). Ascorbic acid (50–400 mg/kg IP) desynchronized the EEG of the frontal cortex and optic cortex while the EMG activity was slightly enhanced in the rat. Ascorbic acid (100 mg/kg IP) potentiated d-amphetamine (2.5 mg/kg SC)-induced EEG desynchronization and EMG activation in the rat. These results indicate that ascorbic acid exerts stimulatory effects in rats. The results also suggest that dopaminergic mechanism may contribute indirectly or directly to the observed behavioural and EEG effects of ascorbic acid.     

Effects of d-amphetamine,scopolamine, chlordiazepoxide and diphenylhydantoin on self-stimulation behavior and brain acetylcholine

The effects of d-amphetamine (0.25–8), scopolamine (0.25–8), chlordiazepoxide (2.5–40), and diphenylhydantoin (25–75), given i.p. or s.c. on a mg/kg basis, were studied on self-stimulation behavior in the male albino rat. The dose-effect relationships, the role of baseline rates of responding and their effects on brain acetylcholine (ACh) were determined in rats trained to self-stimulate for electrical reward in the lateral posterior hypothalamus. The effects of d-amphetamine were both dose and baseline-rate dependent. Low-moderate doses (0.5–2.0 mg/kg inclusive) facilitated self-stimulation and larger doses (2.0 to 8.0 mg/kg) depressed responding. Baseline rates before d-amphetamine administration were extremely important in the effect observed. Low rates of responding were facilitated and high rates were depressed by this agent. The effects of scopolamine in a wide range of dosage were less consistent. A small dose (0.5 mg/kg) facilitated only transiently self-stimulation and larger doses (1–8 mg/kg) tended to depress this behavior. Baseline rate effects were less important but high-rate responders were usually depressed by scopolamine.The effects of chlordiazepoxide were dose-dependent. A dose of (5 mg/kg) caused facilitation but larger doses (10–40 mg/kg) produced depression of selfstimulation irrespective of baseline rates. However, high-rate stimulators showed the most dramatic increases with 5 mg/kg of chlordiazepoxide. In contrast, diphenylhydantoin (25–75 mg/kg) usually depressed self-stimulation. Low rate self-stimulators showed the most marked depressant effects.Brain ACh was progressively reduced by handling of naive animals, injection of saline, and 1/2 h of self-stimulation and escape behavior. Animals not allowed to self-stimulate but given d-amphetamine (2.0 mg/kg), scopolamine (2.0 mg/kg) showed a significant decrease in brain ACh. Self-stimulation, in addition to medication with the various drugs, showed a trend for further reduction in brain ACh but the differences were not statistically significant.Supported in part by Grant MH-11846 (to EID) and MH-11627 (to JO), U.S. Public Health Service.     

Intravenous self-administration of cocaine and norcocaine by dogs

The potency of cocaine, relative to d-amphetamine, to initiate and maintain intravenous self-administration behavior by dogs (n=5) was determined. Response-contingent infusions of cocaine (at unit doses of 0.15, 0.30 and 0.60 mg/kg/infusion) and d-amphetamine (at unit doses of 0.05 and 0.10 mg/kg/infusion) were available during daily 4-h sessions on a FR1 reinforcement schedule. By comparing the dose-response curves of the two drugs, it was found that 1 mg of amphetamine is equivalent to 5.3 mg of cocaine (95% confidence limits=3.8–9.1 mg). In a second experiment, pretreatment with the -adrenergic antagonist phenoxybenzamine (in doses ranging from 0.125–2.0 mg/kg, IV) did not produce any appreciable changes in responding for cocaine (0.2 mg/kg/infusion) by dogs (n=9). In contrast, when the same animals were pretreated with the dopaminergic antagonist pimozide (in doses ranging from 5–40 mg/kg, IV), subsequent responding for cocaine was increased in a dose-dependent manner. In a third experiment it was determined that norcocaine, the N-demethylated metabolite of cocaine, would maintain self-administration behavior by dogs (n=4) when it was substituted for cocaine. As expected, when saline was substituted for cocaine, responding was not maintained.A preliminary report of these studies was presented at the 61st Annual Meeting, Federation of American Societies for Experimental Biology, April 1977 (Fed. Proc. 36: 1040, 1977)     

Effects of d-amphetamine,morphine, naloxone,and drug combinations on visual discrimination in rats

The effects of d-amphetamine, morphine, and naloxone on visual discrimination were investigated using a two-choice discrete-trial procedure in which rats were trained to discriminate the position of a lightflash. Morphine (0.3–5.6 mg/kg) but not amphetamine (0.1–1.0 mg/kg) caused a significant dose-dependent disruption in discriminative performance. Both amphetamine and morphine increased response latencies. Naloxone (1.0 mg/kg) prevented the disruption of any aspect of performance by up to 100 mg/kg morphine. Performance after naloxone/amphetamine co-administration was not significantly different from that observed after amphetamine alone. Naloxone alone (0.3–10 mg/kg) had no effect on discrimination, spatial bias or response latencies. These results suggest that morphine and amphetamine affect different components of discrimination performance. Offprint requests to: S.G. Holzman     

Amphetamine and maternal behavior: Dose response relationships

Primiparous rats received 0.05, 0.25, 0.50, or 1.50 mg d-amphetamine/kg body weight, injected IP, when offspring reached 3–4 and 10–11 days of age. A multidimensional analysis of their maternal behavior revealed that at doses as low as 0.25 mg/kg, amphetamine had a disruptive effect on mother-pup intercontact interval, retrieval latency, inter-retrieval interval, number of pup retrieved and number of corners to which they were retrieved, time nest building, number of paper strips used, nursing time, time in motion, and number of squares entered. Disruption was dose-dependent for all the preceding except number of corners and time nest building. Amphetamine had no effect on the rate of maternal locomotion. The impact of amphetamine on nursing was significantly greater at pup ages of 3–4 days than at 10–11 days. Drug-induced augmentation of arousal exceeding optimal levels for adequate care-giving and locomotor stimulation incompatible with elements of maternal behavior may account for dose-dependent impairment in the range of 0.25 to 1.50 mg/kg d-amphetamine.     

Quantitative assessment of the microstructure of rat behavior: II. Distinctive effects of dopamine releasers and uptake inhibitors

The effects of four indirect dopamine agonists,d-amphetamine (0.25–4.0 mg/kg), cocaine (2.5–40.0 mg/kg), GBR 12909 (10.0–30.0 mg/kg), and nomifensine (5.0–20.0 mg/kg), on the behavioral organization of movements in an unconditioned motor paradigm were investigated in rats. The extended scaling hypothesis using the fluctuation spectrum of local spatial scaling exponents was used to quantify the geometrical characteristics of movements. The results reveal a qualitatively similar disruption of behavioral organization by lower doses of these drugs. Specifically, rats treated withd-amphetamine (<2.0 mg/kg), cocaine (<20.0 mg/kg), GBR 12909 (<20.0 mg/kg), or nomifensine (<10.0 mg/kg) exhibited a reduced range in the fluctuation spectrum, reflecting a predominance of meandering movements with local spatial scaling exponents between 1.3 and 1.7. This reduction was accompanied dynamically by a reduced predictability of movement sequences as measured by the dynamical entropy,h. By contrast, higher doses of these drugs produced distinctly different changes in behavioral organization. In particular, 4.0 mg/kgd-amphetamine and 40.0 mg/kg cocaine increased the fluctuation range, reflecting relative increases in both straight and circumscribed movements that are interpreted as a combination of spatially extended and local perseveration. In contrast, high doses of 30.0 mg/kg GBR 12909 and 20.0 mg/kg nomifensine induced only local perseveration. High doses ofd-amphetamine, cocaine, GBR 12909 and nomifensine reduced the dynamical entropy,h, indicating an increased predictability of the movement sequences. These results suggest that the generic behavioral change induced by low doses of dopamine agonists is characterized by a reduced variety of path patterns coupled with an increased variability in sequential movement sequences. The differential effects of higher doses of these drugs may be due to their influences on other neurotransmitter systems or differential affinities for different dopamine subsystems.     

A comparison of the effects of sibutramine hydrochloride,bupropion and methamphetamine on dopaminergic function: evidence that dopamine is not a pharmacological target for sibutramine

Sibutramine hydrochloride, a novel monoamine reuptake inhibitor antidepressant, has been studied to determine whether it alters dopaminergic function in the brain. Its effects have been compared with bupropion, a dopamine reuptake inhibitor, and methamphetamine, a dopamine reuptake inhibitor and releasing agent. Sibutramine (0.1–3 mg/kg PO) and methamphetamine (0.3–30 mg/kg PO) both prevented reserpine (0.75 mg/kg IV) ptosis in rats with ED₅₀ values of 0.6 mg/kg and 4.2 mg/kg, respectively. Bupropion (10–100 mg/kg PO) was ineffective against reserpine ptosis. The efflux of [³H]-dopamine from preloaded rat striatal slices was not altered by 10^–7–10^–5 M concentrations of sibutramine, BTS 54 354, BTS 54 505 (secondary and primary amine metabolites, respectively) or bupropion. In contrast, methamphetamine (10^–8–10^–4 M) caused a significant concentration-dependent increase in [³H]-dopamine release. Sibutramine (3 mg/kg IP or 6 mg/kg PO) and bupropion (10 mg/kg IP or 430 mg/kg PO) did not alter 3-methoxy-tyramine (3-MT) levels in rat striatum. Striatal 3-MT concentrations were, however, dose-dependently increased by methamphetamine (0.3–10 mg/kg IP or 0.42–4.2 mg/kg PO). Sibutramine (6 mg/kg PO) did not induce circling in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopaminergic neuronal tract. Bupropion (10–100 mg/kg PO) did not induce circling at the lowest dose, but caused increasing ipsilateral rotation at higher doses. Methamphetamine (0.42 or 4.2 mg/kg PO) induced ipsilateral circling with marked effects at the higher dose. In a two-choice lever pressing model using rats trained to discriminated-amphetamine (0.5 mg/kg IP) from saline, sibutramine (0.3–3 mg/kg IP) generalised to the saline lever. Bupropion (3–30 mg/kg IP) generalised tod-amphetamine at the highest dose, while methamphetamine (0.1–5 mg/kg IP) generalised to this lever at doses as low as 0.3 mg/kg. Overall, the rank order of potency for enhancing central dopaminergic function is methamphetamine > bupropion >> sibutramine. The data therefore indicate that dopamine is unlikely to be an important pharmacological target for reuptake inhibition by sibutramine.