Cocaine-induced Sensitization Research Articles

Sensitization to stress and psychostimulants. Involvement of dopamine transmission versus the HPA axis.

Rats exposed to chronic stress demonstrate an enhanced motor response to psychostimulants, such as cocaine. This behavioral cross-sensitization between stress (repeated mild footshock) and cocaine (15 mg/kg, ip) is associated with an increase in extracellular dopamine in the nucleus accumbens, but a decrease in the prefrontal cortex. To determine a role for the hypothalamic-pituitary-adrenal axis in sensitization, rats were adrenalectomized prior to administering repeated cocaine injections. One and twelve days after discontinuing repeated cocaine, rats were challenged with acute cocaine. Adrenalectomy blocked the cocaine-induced sensitization observed in sham animals, but both the sham and adrenalectomized rats demonstrated behavioral sensitization to cocaine after twelve days of withdrawal. These data argue that while long-term alterations in dopamine transmission may be an important neurochemical substrate of stress and psychostimulant-induced sensitization, the hypothalamic-pituitary-adrenal axis may not have a necessary role.

Lack of evidence for context-dependent cocaine-induced sensitization in humans: Preliminary studies

Cocaine-induced behavioral sensitization is the well-documented phenomenon where repeated doses of cocaine elicit increasingly greater effects on motoric activity in rats. Some observations suggest that behavioral sensitization may provide a model for understanding the mechanisms of drug-craving elicited by environmental triggers or cues. The process of fully validating such an animal model for its ability to detect effective anticraving medicines is a difficult and long-term undertaking. As a first step in that direction, we decided to determine if cocaine can produce conditioned behavioral sensitization in humans using a paradigm fairly similar to that used for rodents. Because humans do not react to cocaine with the pronounced motor activation observed in rodents, we measured a variety of end points, including blood pressure (BP), heart rate (HR), respiratory rate, pupil diameter, hormones (prolactin and cortisol), and subjective responses using the questionnaire for drug-related feelings (QDRF) and the EEG. To mimic the home and test cages used in rodent studies, two rooms were used: a small test chamber and a regular room with a window and furnishings. On day 1 each subject received a drug infusion (either saline or 40 mg cocaine IV) in both locations. On day 2, all subjects received an infusion (saline or 25 mg cocaine IV) in the test chamber. All drug infusions were conducted double blind. The paired group received cocaine on both days in the test chamber. The unpaired group received cocaine in regular room on day 1, and cocaine in the test chamber on day 2. A control-1 group received saline at both locations on day 1, and cocaine on day 2 in the test chamber. A control-2 group [4] received cocaine in the test chamber on day 1 and saline in the test chamber on day 2. Conditioned-sensitization was not observed. However, conditioned tolerance was observed for cocaine-induced changes in plasma prolactin levels and diastolic blood pressure. Because rodent studies use cocaine-naive subjects and this study used cocaine-experienced subjects, these data suggest that prior experience with cocaine may alter it ability to poduce sensitization. Viewed collectively, the present investigation suggests caution in the design of both human and animal studies.

Inhibition of cocaine-induced sensitization by the δ-opioid receptor antagonist naltrindole

The influence of the δ-opioid receptor antagonist naltrindole upon sensitization to the locomotor activating effects of cocaine was assessed. Activity in response to a challenge dose of cocaine (20 mg/kg, i.p.) was significantly increased in rats which had received cocaine (20 mg/kg, i.p.) once daily for 3 days as compared to those which had previously received saline. The repeated administration of naltrindole (0.3–3.0 mg/kg, s.c.) alone did not affect activity. However, in animals which had received both naltrindole and cocaine for 3 days, no sensitization to the locomotor activating effects of cocaine was observed. These data demonstrate that the selective blockade of δ-opioid receptors modifies the development of cocaine-induced sensitization and suggest an important role of δ-opioid receptor systems in modulating the development of drug-induced sensitization.

Mechanisms of cocaine-induced sensitization

Sorg, Barbara A. and Jeffery D. Steketee: Mechanisms of Cocaine-Induced Sensitization. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1992, 16(6): 1003–1012. 1. 1. Rats pretreated with repeated footshock demonstrated an augmentation in cocaineinduced locomotor activity and extracellular dopamine concentrations in the nucleus accumbens. 2. 2. Pertussis toxin injections into the A10 region also led to cocaine- induced enhancement in extracellular dopamine levels in the nucleus accumbens and a strong trend towards elevated locomotor activity. 3. 3. Repeated treatment with cocaine led to a blockade of the footshock-induced increase in extracellular dopamine in the medial prefrontal cortex. 4. 4. Prior treatment with pertussis toxin microinjection into the A10 region resulted in enhanced levels of tissue dopamine metabolites in the medial prefrontal cortex following footshock stress. 5. 5. The pertussis toxin- and daily stress-induced behavioral and neurochemical sensitization suggest that behavioral sensitization to these stimuli involves a loss of inhibitory tone on A10 dopamine cells.

Errors in the measurement of agonist potency-ratios produced by uptake processes: a general model applied to beta-adrenoceptor agonists.

1. The sensitization of guinea-pig atria and trachea to noradrenaline, isoprenaline, and salbutamol, produced by an inhibitor of neuronal (cocaine) and extraneuronal (metanephrine) uptake, was studied quantitatively. The data were compared to a theoretical model. 2. Cocaine produced near maximal sensitization to noradrenaline in guinea-pig atria (5 fold) at concentrations which produced only partial sensitization in guinea-pig trachea (4.7 fold sensitization of a maximum 11 fold). These results agreed with the model which predicts that there is a direct relationship between the amount of uptake inhibitor required to produce full sensitization and the magnitude of maximal sensitization demonstrable in the tissue. This makes extrapolation of uptake inhibition concentrations from tissue to tissue a potentially erroneous practice. 3. In normal trachea, salbutamol is 20 times more potent than noradrenaline but this difference is abolished (to 0.9 times) by cocaine (100 microM). This reduction of potency-ratio is due to the selective cocaine-induced sensitization of trachea to noradrenaline and raises a serious objection to the classification of salbutamol as a beta 2 selective agonist. 4. Metanephrine produced very little sensitization of trachea to isoprenaline. Experiments with salbutamol showed metanephrine to be a simple competitive antagonist of beta-adrenoceptors (pKb = 4.3) and that this receptor antagonism masked sensitization to isoprenaline. 5. A theoretical model indicates that an inhibitor of agonist uptake requires a remarkable degree of selectivity for the uptake mechanism (i.e. Kb for receptors 10(4) x KI for uptake sites) to demonstrate tissue sensitization to the agonist. This analysis and the data with metanephrine indicate that a sinistral shift of the concentration-response curve is a poor indicator of the importance of uptake mechanisms in an isolated tissue. 6. An alternate method to determine the importance of agonist-uptake effects on concentration-response curves is described which utilizes agonist potency ratios. Agonist potency ratios in guinea-pig atria and trachea showed that the bronchoselectivity demonstrated by salbutamol (with respect to isoprenaline) is reduced from 54 to 7.8 by metanephrine reflecting the importance of extraneuronal uptake in trachea.