Time-dependent changes in sensitivity to apomorphine and monoamine receptors following withdrawal from continuous cocaine administration in rats

The effects of withdrawal from continuous administration of cocaine on behavioral sensitivity to apomorphine and monoamine receptor density were examined in rats. Subdermal minipumps that delivered either saline or 20 mg/kg/day cocaine hydrochloride were implanted for 2 weeks. Apomorphine-induced stereotypy (0.5 mg/kg, SC) was examined in separate groups of rats either 4 hr or 7, 28, or 60 days after removal of the minipumps. Transient enhanced sensitivity to apomorphine-induced stereotypy occurred during the course of withdrawal. Animals withdrawn from cocaine for 4 hours did not differ from controls in their sensitivity to apomorphine, whereas animals withdrawn from cocaine for 7 days exhibited an increase in apomorphine-induced oral stereotypy relative to controls. However, the enhanced stereotypy response was no longer evident in animals withdrawn for 28–60 days. The animals were sacrificed after behavioral testing, and their brains were assayed for changes in monoamine receptor density in the frontal cortex, caudate-putamen, and nucleus accumbens. The density of ³H-SCH-23390-labeled D1 receptors was altered in all three regions examined in a time-dependent manner that paralleled the changes in behavioral sensitivity to apomorphine. There was a transient decrease in D1 receptor density that was evident by 7 days following withdrawal from continuous cocaine administration and was no longer evident 28 or 60 days posttreatment. There were no changes in ³H-spiroperidol-labeled D2 receptors, ¹²⁵-pindolol-labeled β-adrenergic receptors, or ³H-ketanserin-labeled 5-HT₂ receptors in any of the regions examined at both 4 hr and 7 days after termination of the cocaine infusion. These findings are discussed in terms of their relevance to developing pharmacologic treatments for withdrawal from cocaine. © 1994 Wiley-Liss, Inc.     

Effects of cocaine on the EEG power spectrum of rats are significantly altered after its repeated administration: do they reflect sensitization phenomena?

It was previously shown that a moderate dose of cocaine (10 mg/kg i.p.) produces a pattern in the EEG power spectrum which indicates a preferential activation of dopamine D₁-like receptors, namely a decrease of power in most of the frequency bands. In contrast, a large dose of cocaine (30 mg/kg i.p.) produces a decrease of power in most of the frequency bands as well, but a selective increase in the alpha-1 band, characteristic for an additional activation of dopamine D₂-like receptors.In the present experiments, it was studied in rats, if in the course of sensitization, a shift from D₁-like to additional D₂-like receptor activation will occur or not. For this study, the animals were treated 10 times with cocaine (either 10 or 20 mg/kg) and, after a drug free interval of 4 days, tested with the same dose administered previously. Acute administration of 10 mg/kg of cocaine increased the Locomotor activity slightly and its effect tended to be enhanced after repeated administration. Twenty mg/kg cocaine increased the locomotor activity more than the 10 mg/kg dose and its effect was significantly enhanced after repeated treatment. In addition, it was shown that the dose of 10 mg/kg of cocaine which activates D₁- but not D₂-like receptors is sufficient to elicit conditioned place preference.Ten mg/kg of cocaine produced a decrease of power in most of the frequency bands and this effect was slightly more pronounced after repeated treatment. Twenty mg/kg of cocaine acutely also produced a decrease in power in most of the frequency bands, but did not decrease the power in the alpha-1 band, being just at the threshold of activating D₂-like receptors as well. Repeated administration led to a significant increase in power in the alpha-1 band and a less pronounced one in the alpha-2 band. This observation demonstrates that sensitization to cocaine can be manifest in the EEG and that after a certain dosage, a shift from an activation of D₁-like dopamine receptors to an additional activation of D₂-like receptors becomes obvious.     

Chronic administration of a selective dopamine D-2 agonist: factors determining behavioral tolerance and sensitization

The locomotor stimulant effects of sustained administration of a potent and selective dopamine (DA) D-2 receptor agonist, [+]-4-propyl-9-hydroxynaphthoxazine (PHNO), in rats were assessed 24 h a day during 12 h light-dark cycles. PHNO was administered continuously with subcutaneous implants of Alzet osmotic minipumps (5 g/h), for 12 h a day with modified osmotic minipumps (5 g/h), or by daily injections (15 g, SC). Tolerance was observed to occur only with 24 h continuous infusions and only during the light period. The other treatment regimens produced sensitization of the locomotor response. Daytime tolerance to continuous infusions of PHNO was reversed following reversal of the light-dark cycle. A normally arousing stimulus also reversed (temporarily) daytime tolerance. The present results indicate that the temporal pattern of administration of DA agonists, the phase of the circadian cycle and environmental stimuli associated with arousal are important determinants of the behavioral consequences of long-term treatment.     

Desensitization protocols improving access and outcome in transplantation

Sensitization to antigens of the HLA and ABO system has been the biggest barrier to access in renal transplantation and, increasingly, in transplantation of other organs. Additionally, antibody to donor antigens has been shown to result in injury to the graft ranging from catastrophic, irreversible hyperacute rejection to the slower, more insidious, chronic form of rejection. The problem of access has been recognized globally and has been the incentive for measures to overcome the disadvantage experienced by the sensitized patient. However, early attempts to reduce sensitization achieved only transient success. Newer immunosuppressive agents that affect B-cell function or viability have permitted the development of treatment protocols to eliminate and, potentially, downregulate donor-specific antibodies. The use of these protocols has achieved successful transplants that were HLA and/or ABO incompatible prior to treatment and, as such, has provided some patients with their only opportunity for transplantation.     

Sensitization of nociceptive cutaneous nerve fibers from the rat's tail by noxious mechanical stimulation

Summary This single fiber study on rat tail nerve afferents attempts to establish a peripheral neural correlate for the hyperalgesia to mechanical stimulation which follows injury to the skin. Mechano-heat sensitive C fibers (MH-C or polymodal nociceptors) and high-threshold mechanoreceptive A delta fibers (HTM-A delta) were examined with a series of constant noxious pressure stimulations (4-6-8-4 N on 25 mm², 120 s each, 5 min intervals). These injurious stimuli were either directed to the most sensitive spot of the receptive fields (central stimulation) or closely outside their borders (1–5 mm). With this protocol no clear sensitization was seen in MH-C fibers apart from a stronger dynamic response to central stimulation in some of them. In contrast, most HTM-A delta units, irrespective of the site of noxious stimulation, developed spontaneous activity, lowering of their von Frey thresholds and expansion of their receptive fields. All HTM-A delta units responded to outside stimulation: upon the first stimulus (4 N) there was a delayed discharge of continuously increasing frequency (recruited response), but the onset of the last stimulation (4 N repeated) evoked vigorous dynamic responses in many fibers. The recruitment of HTM-A delta nociceptor activity may contribute to post-injury hyperalgesia to mechanical stimulation and it may counteract adaptation of the single afferent fiber during prolonged noxious influence.On leave from the Laboratoire de Physiologie, Faculté de Médecine Lyon-Sud, Chemin du Petit Revoyet, F-69600 Ouillins, France     

Caffeine enhances the stimulant effect of methamphetamine,but may not affect induction of methamphetamine sensitization of ambulation in mice

Methamphetamine (MAP: 1 and 2 mg/kg SC) and caffeine (CAF: 1, 3, 10 and 30 mg/kg SC) dose-dependently increased ambulation in mice. Repeated administration (5 times at 3 to 4-day intervals) of MAP, but not CAF, induced sensitization to its effect. Furthermore, the mice repeatedly receiving CAF showed no significant change in the sensitivity to MAP. Combined administration of MAP with CAF increased the effect. In the combinations of MAP (1 mg/kg) with CAF (3, 10 and 30 mg/kg), and MAP (2 mg/kg) with CAF (1 and 3 mg/kg), the effect was enhanced by the repeated administration. However, MAP sensitization was not modified by the combination with CAF in the repeated administration schedule, except in the combination of MAP (1 mg/kg) with CAF (30 mg/kg). The ambulation-increasing effects of MAP (1 mg/kg), CAF (10 mg/kg) and combination of MAP with CAF were almost equivalently inhibited by SCH 23390 (0.01 and 0.1 mg/kg SC) and YM-09151-2 (0.01 and 0.1 mg/kg SC). However, the inhibitory effects of apomorphine (0.05 mg/kg SC) andN ⁶-(L-phenylisopropyl)-adenosine (0.1 and 0.2 mg/kg SC) were stronger for CAF than for MAP and the combination, and those of -methyl-p-tyrosine (200 mg/kg IP, 4 h before) and reserpine (1 mg/kg SC, 4 h before) were stronger for MAP and CAF alone than for the combination. The present results suggest that, although the combination of MAP and CAF enhances the ambulation-increasing effect through an interaction at dopaminergic system, CAF may not significantly modify the induction of MAP sensitization in mice.     

Pretreatment with the putative anti-addictive drug, ibogaine, increases the potency of cocaine to elicit locomotor responding: a study with acute and chronic cocaine-treated rats

Rationale: Results of single-dose studies suggest that the effects of pretreatment with the putative anti-addictive compound, ibogaine, on drug-induced locomotor behavior depends on the previous drug history of the animal. Objectives: To compare the effects of ibogaine pretreatment on the dose-locomotor response function for cocaine in rats treated chronically with either saline or cocaine. Methods: Rats were chronically treated with either cocaine (15 mg/kg, IP, once daily for 5 days, followed by 2 week withdrawal) or saline. Ibogaine (40 mg/kg, IP) or vehicle was administered and 19 h later, a cocaine dose-locomotor response test was conducted (0, 5, 10, 20 and 40 mg/kg, IP). Results: Chronic cocaine administration augmented the locomotor response to cocaine in chronic cocaine-treated rats, compared to acutely treated controls. Ibogaine pretreatment enhanced the locomotor effects of cocaine in both chronic and acute cocaine groups. Furthermore, due to the shape of the dose-response curve, in chronic cocaine but not in acute cocaine rats, ibogaine pretreatment enhanced the locomotor response to 5 and 10 mg/kg cocaine while decreasing the locomotor response to 40 mg/kg cocaine. Conclusions: These data demonstrate definitively that ibogaine can enhance sensitivity to the locomotor stimulant effects of cocaine, an effect which depends, in part, on the previous cocaine history of the animal. Received: 19 December 1998 / Final version: 2 March 1999     

Effects of early handling on amphetamine-induced locomotor activation and conditioned place preference in the adult rat

  Rationale: Altered hormonal stress responsiveness has been implicated in psychostimulant responsivity, and early handling represents a mild environmental manipulation which alters the hormonal profile following stress exposure. Objective: The present experiments examined whether early handling in rats would alter locomotor effects of amphetamine, as well as cross-sensitization of locomotor responsiveness after chronic stress. Conditioned place preference (CPP) for amphetamine was also measured. Methods: Handling consisted of daily 15-min isolation periods from days 1–12 postnatally. Novelty- and amphetamine (0, 1.5 mg/kg)-induced locomotion were examined using circular corridors in adult rats that were either restrained repeatedly over 8 days or not disturbed prior to testing. The effects of handling on amphetamine (0, 1, 2, 5 mg/kg) conditioned place preference (CPP) were also examined following 3 days of drug-compartment pairings. Results: Early handling produced a more rapid post-stress recovery in corticosterone levels. Handled animals also exhibited a significant attenuation in amphetamine-induced CPP compared to non-handled controls. Locomotor responsiveness to novelty and amphetamine was not altered by early handling. Although no cross-sensitization was observed, evidence for stress sensitization was seen, but was unaffected by early handling. Conclusions: Handled animals showed an attenuated CPP for amphetamine, data suggesting that sensitivity to the reward value of drugs of abuse in adulthood may be susceptible to relatively minor environmental manipulations early in life. This effect of handling on CPP does not seem to reflect differences in locomotor sensitivity to amphetamine. Received: 5 August 1998 / Final version: 2 November 1998     

Does crossing over repeated treatment with the dopamine reuptake inhibitors cocaine and BTCP modify their effects on cocaine-induced locomotion?

Because the dopamine reuptake inhibitors cocaine and BTCP produce different behavioral effects after repeated administration, we studied whether they could alter each other’s effects by examining the effects of crossing over repeated treatment with cocaine and BTCP on cocaine-induced locomotion. Male C57BL/6 mice were treated repeatedly with cocaine or BTCP during a first phase (days 1–3) and 3 days later, treated repeatedly with the same or the other compound during a second phase (days 7–9), after which they were administered one of several doses of cocaine on the next day. Locomotor activity was assessed after every daily treatment. The results show that 1) cocaine induced sensitization to its locomotor effects, 2) cocaine-induced sensitization was not altered by subsequent repeated treatment with BTCP, 3) initial repeated treatment with BTCP induced apparent cross-tolerance to cocaine, and 4) the initial effects of repeated BTCP were not markedly altered by subsequent repeated treatment with cocaine. The results indicate that the initial effects produced by repeated cocaine or BTCP are enduring and relatively difficult to alter by crossing over repeated treatment with the other compound. Thus, sensitization to the locomotor effects of cocaine in mice appeared to be attenuated by prior repeated treatment with BTCP but not reversed when followed by repeated treatment with BTCP. Received: 11 January 1998/Final version: 17 September 1998     

Loss of tolerance to morphine after a change in route of administration: control of within-session tolerance by interoceptive conditioned stimuli

Tolerance to morphine analgesia (tail-immersion test) was examined after manipulation of two aspects of a tolerance test: 1) the route of drug administration and 2) the time interval between the test dosing and the tolerance test. The intravenous (IV) and intraperitoneal (IP) routes were used, together with a novel test for tolerance in which the test morphine was infused IV just 2 min before measuring the opiate effect. The first experiment validated this test as an assay for tolerance by examining the log dose-response (LDR) curve changes produced by daily IP injection with 0, 20 or 200 mg/kg morphine; the IV test confirmed the expected parallel shift to the right and flattening of the LDR curve. In the second experiment, all rats of two groups were injected once daily for 3 weeks with 20 mg/kg morphine and with saline except that one group received the morphine IV (and saline IP), the other morphine IP (saline IV). The results indicated route-specific tolerance. On a test using 20 mg/kg given IV morphine, tolerance was significantly greater in rats treated with IV morphine than in those treated IP. However, a larger effect on tolerance was produced by a pretest application of 5 mg/kg morphine 30 min before the actual tolerance test. This manipulation was designed to prime short-term, adaptive processes hypothesized to occur within a normal tolerance test session as morphine is taking effect. The tolerance on the test increased (equivalent to 2 to 3 fold shift in the LDR curve) when the pretest morphine was given with the same route as the chronic morphine, regardless of treatment group. It was concluded that opiate tolerance may be modulated by conditioned stimuli produced by morphine acting through different routes. These interoceptive cues appear to modulate rapidly acquired and short-lived adaptive processes taking place within a given test session.