G.R. King

Intermittent and Continuous cocaine Administration: Residual Behavioral states during withdrawal

Rats were pretreated with 40 mg/kg/day cocaine for 14 days by either subcutaneous injections or osmotic minipumps. Rats were then withdrawn from the pretreatment regime for 1 or 7 days and given a 20-mg/kg IP cocaine challenge (day 1) or a 0-, 10-, 20-, or 40-mg/kg IP cocaine challenge (day 7). The results indicate that rats receiving intermittent, daily injections exhibited sensitization to the behavioral effects of a cocaine challenge on days 1 and 7 of withdrawal. In contrast, rats receiving continuous cocaine exhibited tolerance to the behavioral effects of a cocaine challenge on days 1 and 7 of withdrawal. The present results support and extend previous research that indicates that the route and temporal pattern of administration influences the effects of chronic cocaine. Furthermore, the present results indicate that the continuous infusion paradigm may represent an alternative animal model of some aspects of high-dose cocaine abuse, as compared to the typical procedure of single, or multiple, daily cocaine injections.

Long-term blockade of the expression of cocaine sensitization by ondansetron, a 5-HT3 receptor antagonist

Intermittent cocaine administration induces sensitization (reverse tolerance) to its behavioral effects. The mechanism(s) mediating sensitization is not clear, however, previous research has implicated 5-HT(3) receptors in the expression of sensitization. The present experiment evaluated the ability of the 5-HT(3) receptor antagonist, ondansetron, administered during withdrawal from chronic intermittent cocaine administration, to block the expression of sensitization. Rats were pretreated for 14 days by daily subcutaneous injections of either 40 mg/kg cocaine or 0.9% saline. During the first 5 days of withdrawal from this pretreatment regimen, all rats received a daily subcutaneous injection of 0-1.0 mg/kg ondansetron. On days 7, 14 or 28 of withdrawal from the cocaine pretreatment, the rats received a 15.0-mg/kg cocaine challenge. Ambulatory behavior was automatically recorded for 60 min. Ondansetron had no significant effect on the subsequent behavioral response to cocaine in the saline control subjects. In contrast, daily injections of ondansetron blocked the expression of sensitization at all withdrawal times. We thus report that it is possible to permanently block the expression of sensitization once it has developed by administering a 5-HT(3) receptor antagonist.

Blockade of cocaine sensitization and tolerance by the co-administration of odansetron, a 5-HT3 receptor antagonist, and cocaine

Abstract The present experiment evaluated the ability of the 5-HT3 antagonist, ondansetron, administered during chronic cocaine administration, to block the development of sensitization and tolerance induced by the intermittent or continuous administration of cocaine, respectively. Rats were pretreated with 40 mg/kg per day cocaine for 14 days by either SC injections or osmotic minipumps, or 0.9% saline, administered by SC injection. During this chronic (cocaine) treatment, all rats received a daily SC injection of 0–1.0 mg/kg ondansetron. The rats were then withdrawn from the pretreatment regimen for 7 days. On day 7 of withdrawal from the cocaine pretreatment all subjects received a 15.0 mg/kg IP cocaine challenge, and their behavior was then rated according to the modified Ellinwood and Balster scale for 60 min. The results indicated that daily injections of ondansetron had no consistent or significant effect on the subsequent behavioral response to cocaine in the saline control subjects. In contrast, daily injections of ondansetron with cocaine significantly blocked the development of sensitization with an inverted U-shape dose-response curve. In the continuous cocaine group ondansetron injections also attenuated the development of behavioral tolerance. The results therefore indicate that 5-HT3 receptor stimulation during continuous and intermittent cocaine administration is an important link in the development of behavioral tolerance and sensitization.

Dopamine efflux during withdrawal from continuous or intermittent cocaine

Daily, intermittent, subcutaneous cocaine injections produce sensitization, while the continuous administration of cocaine produces tolerance to the behavioral effects of subsequent cocaine injections. The present experiments examined whether these behavioral differences are related to differences in the ability of cocaine to increase extracellular dopamine. Increases in perfusate DA, in response to different concentrations of cocaine, were measured in caudate-putamen slices obtained from rats withdrawn for 7 days from a 14-day treatment of either continuous or daily subcutaneous cocaine injections. Compared to saline controls, cocaine-induced DA efflux was increased in subjects receiving daily injections and markedly decreased in subjects receiving continuous cocaine. Thus, different temporal patterns of cocaine administration produce dramatically different alterations in DA neurotransmission. Such changes in dopamine release may be related to the withdrawal symptoms experienced by human cocaine abusers.

Alterations in Baseline Activity and Quinpirole Sensitivity in Putative Dopamine Neurons in the Substantia Nigra and Ventral Tegmental Area after Withdrawal from Cocaine Pretreatment

Using in vivo single-unit recording, we compared in rats the effects of continuous infusion and once-a-day injections of cocaine on the activity of single putative dopamine neurons in the substantia nigra and ventral tegmental area. After a 7-day withdrawal, we determined: (1) the number of spontaneously active neurons and their bursting patterns and (2) sensitivity of these neurons to intravenous quinpirole. In the substantia nigra, continuous cocaine infusion reduced the number of neurons without affecting the bursting patterns; daily injections were without effects. In the ventral tegmental area, continuous infusion reduced the bursting activity without affecting the number of neurons, whereas infections increased number of neurons without changes in the bursting pattern. Acute sulpiride normalized all the changes in both cell body areas. The quinpirole sensitivity was selectively increased in the nigral neurons following withdrawal from continuous infusion. Possible role of D2/autoreceptor mechanisms in these changes is discussed.

Continuous or intermittent cocaine administration: Effects of amantadine treatment during withdrawal

Research indicates that daily cocaine injections produce sensitization to, while the continuous infusion of cocaine produces tolerance to, its behavioral and neurochemical effects. The effects of the continuous infusion of cocaine are consistent with the withdrawal syndrome reported by human cocaine abusers. The present experiment examined whether amantadine administrations during withdrawal from continuous or intermittent cocaine attenuate and/or eliminate the behavioral effects produced by these administration regimens. The rats were pretreated for 14 days with either continuous or intermittent daily injections of cocaine, and were then withdrawn from the pretreatment regimen for 7 days. On days 1-5 of the withdrawal period, half the subjects received a 5.0 mg/kg IP injection of amantadine, and the other half received a 20.0 mg/kg IP injection of amantadine. On day 7 of withdrawal from the cocaine pretreatment, all rats were given a 15.0 mg/kg IP injection of cocaine. Their behavior was rated according to the modified Ellinwood and Balster (6) scale for 60 min. The results indicated that amantadine treatment during withdrawal eliminated the tolerance normally associated with the continuous infusion of cocaine. In contrast, in both the saline control and daily injection subjects amantadine treatment during withdrawal resulted in a slight, but statistically significant, reduction in the behavioral effects of cocaine. The present results therefore indicate that low doses of amantadine should be considered as a potential pharmacotherapy for the early stages of cocaine withdrawal. Furthermore, the present experimental procedures may represent an effective screening methodology for potential cocaine pharmacotherapies.

Blockade of the expression of sensitization and tolerance by ondansetron, a 5-HT3 receptor antagonist, administered during withdrawal from intermittent and continuous cocaine

Abstract The present experiment evaluated the ability of the 5-HT3 antagonist, ondansetron, administered during withdrawal from chronic cocaine administration, to block the expression of sensitization and tolerance induced by the intermittent or continuous administration of cocaine, respectively. Rats were pretreated with 40 mg/kg/per day cocaine for 14 days by either SC injections or osmotic minipumps, or 0.9% saline, administered via osmotic minipump. During the first 5 days of withdrawal from this pretreatment regimen, all rats received a daily SC injection of 0–1.0 mg/kg ondansetron. On day seven of with-drawal from the cocaine pretreatment (2 days after the final ondansetron injection) all subjects received a 15.0 mg/kg IP cocaine challenge. Their behavior was then rated according to the Ellinwood and Balster (1974) scale for 60 min. The results indicated that daily injections of ondansetron, on days 1–5 of withdrawal from the pretreatment regimen, had no significant effect on the subsequent behavioral response to cocaine in the saline control subjects. In contrast, daily injections of ondansetron, on days 1–5 of withdrawal from intermittent cocaine administration, significantly blocked the expression of sensitization. In the continuous cocaine group, ondansetron injections, on days 1–5 of withdrawal from continuous cocaine administration, also blocked the expression of behavioral tolerance. The results therefore indicate that changes in 5-HT3 receptor function are associated with the expression of tolerance and sensitization, respectively.

Technique for the continuous infusion of high doses of cocaine by osmotic minipump

The present article describes a procedure for modifying osmotic minipumps to avoid the local, toxic, necrotic effects of high concentrations of drug at the exit portal during the chronic, continuous infusion of cocaine. The present procedure eliminates the occurrence of necrotic skin lesions otherwise produced by SC administration of cocaine and/or other vasoconstrictive agents. The method of administration will therefore be useful for administration of other chronic drug regimens.

Withdrawal from continuous or intermittent cocaine: behavioral responsivity to 5-HT1 receptor agonists.

Research on chronic cocaine administration indicates that both the dose and route of administration influences the effects of chronic cocaine. Rats were pretreated with 40 mg/kg/day cocaine for 14 days by either SC injections or osmotic minipumps. Rats were then withdrawn from the pretreatment regimen for 7 days and their behavior rated following injections of 5-hydroxytryptamine1A (5-HT1A) or 5-HT1B agonists. In Experiment 1, rats received 0- to 4.0-mg/kg IP injections of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-HT1A receptor agonist. In Experiment 2, rats received 0- to 16.0-mg/kg IP injections of 7-trifluoromethyl-4(4-methyl-1-piperazinyl)- pyrrolo[1,2a]quinoxaline (CGS 12066B), a selective 5-HT1B receptor agonist. The results of Experiment 1 indicated that rats receiving cocaine via osmotic minipumps exhibited marked 5-HT1A receptor subsensitivity. In contrast, rats receiving daily cocaine injections sometimes demonstrated evidence of 5-HT1A supersensitivity and sometimes demonstrated evidence of 5-HT1A normosensitivity. The results of Experiment 2 indicated there were no consistent differences between the pretreatment groups in the behavioral response to CGS 12066B, although there were significant differences at single, isolated time points. Overall, the results indicate that, at least in the present behavioral paradigm, the effects of chronic cocaine administration are mediated by changes in 5-HT1A receptor sensitivity but not by changes in 5-HT1B receptor sensitivity.

Withdrawal from continuous or intermittent cocaine: Effects of NAN-190 on cocaine-induced locomotion

Rats were pretreated with 40 mg/kg/day cocaine for 14 days by either SC injections or osmotic minipumps. Rats were then withdrawn from the pretreatment regimen for 7 days. In Experiment 1, rats received 0- to 2.0-mg/kg IP injections of 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine (NAN-190), a putative 5-hydroxytryptamine1A (5-HT1A) receptor antagonist. In Experiment 2, rats received the same doses of NAN-190 in combination with a 15-mg/kg IP injection of cocaine. The results of Experiment 1 indicate that the continuous-infusion group demonstrated a dose-dependent suppression of locomotor behavior by single doses of NAN-190. NAN-190 had no consistent dose-dependent effect on the locomotor behavior of subjects in the other pretreatment groups. The results of Experiment 2 indicate that rats receiving intermittent, daily injections tended to exhibit behavior consistent with 5-HT1A receptor supersensitivity. In contrast, rats receiving continuous cocaine tended to exhibit behavior consistent with 5-HT1A receptor subsensitivity. Changes in 5-HT1A receptor sensitivity may contribute to some of the anxiety and depressive symptoms exhibited by human cocaine abusers.