Behavioral sensitization and tolerance to cocaine and the occupation of dopamine receptors by dopamine.

Data from the authors' laboratory on the neural substrates of Pavlovian conditioning and behavioral sensitization to psychomotor stimulants are reviewed. The findings of a recent experiment on the role of occupation of dopamine receptors by dopamine and its association to behavioral sensitization are reported. Daily intermittent injections of cocaine produced behavioral sensitization to the locomotor response in rats, whereas continuous cocaine infusions produced behavioral tolerance. Behavioral sensitization to cocaine was blocked by coadministration of nimodipine, an L-type calcium channel blocker. The increase in locomotion produced by cocaine was associated with an increase in the occupation of striatal dopamine D1 and D2 receptors, measured as the density of receptors protected from denaturation by N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ). This association was not observed when rats were given a challenge injection of cocaine 10 d after withdrawal from similar treatment regimens. Rats given a cocaine challenge after withdrawal from either intermittent or continuous cocaine treatments regimens exhibited increased occupation of striatal D1 and D2 receptors. This increase was similar in magnitude to that observed in rats without a history of cocaine treatments after a challenge injection of cocaine. This suggests that the differences in occupancy of striatal dopamine receptors by dopamine observed in the prewithdrawal condition are likely the results of differences in brain levels of cocaine achieved by the two treatment regimens. Occupancy of striatal dopamine D1 and D2 receptors does not appear to be related to the development of sensitization to the motor-stimulating effects of cocaine.

Increased occupation of D1 and D2 dopamine receptors accompanies cocaine-induced behavioral sensitization.

In rats exhibiting behavioural sensitization after daily cocaine (10 mg/kg, i.p.) injections, the occupation of D1 and D2 dopamine receptors by dopamine, measured as protection from N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) receptor denaturation, was increased by about 100% compared to animals receiving cocaine in a treatment regimen that produced behavioural tolerance. Co-administration with nimodipine, an agent that blocks the impulse-dependent increase in synaptic concentrations of dopamine caused by cocaine, not only blocked sensitization but also blocked the increase in occupation of receptors. These findings strongly support the hypothesis that enhanced dopamine release and subsequent interaction with dopamine receptors is a substrate for behavioural sensitization to cocaine and have implications for the pharmacotherapy of cocaine abuse.

Day/night differences in D1 but not D2 DA receptor protection from EEDQ denaturation in rats treated with continuous cocaine.

The effect of chronic cocaine administration on the in vivo occupation of dopamine (DA) receptor subtypes was examined using the irreversible receptor blocker N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). Rats were given continuous infusions of cocaine (vehicle, 2.5, 7.5, or 22.5 mg/day) via subcutaneous implants of Alzet osmotic minipumps for 14 days. Some groups were also given the D1 antagonist SCH 23390 and/or the D2 antagonist raclopride for this same time period. DA receptor binding techniques were used 24 hours post-EEDQ injection (Day 15, 5 mg/kg, intraperitoneally [ip]) in order to examine changes in D1 and D2 receptor densities in the striatum. Half of the rats were killed in the day with the other half killed at night in order to examine day/night differences in the effects of cocaine treatment. Results showed that chronic cocaine increased the protection of D1 receptors from EEDQ inactivation in a dose-dependent fashion during the day, and decreased D1 protection from EEDQ at night. Since EEDQ has a low affinity for the DA receptor relative to endogenous DA or the exogenous ligands in this study, only receptors that are vacant are inactivated thereby allowing for an estimate of DA receptor occupation in vivo. Cocaine can therefore be said to increase D1 receptor occupation by DA in vivo during the day and decrease it at night. Coadministration of the DA antagonists eliminated this cocaine-induced day/night difference and, in the case of the D1 antagonist, produced opposite D1 receptor effects when administered alone. Chronic SCH 23390 treatment protected D1 receptors from EEDQ denaturation while D2 receptors were protected by chronic raclopride. In addition, raclopride was found to affect the affinity of both the D1 and the D2 receptors to the [3H] SCH 23390 and [3H] spiperone ligands, respectively. Since no day/night differences were found in D2 receptor density with respect to chronic cocaine treatment these findings have implications for a phasic D1/tonic D2 receptor hypothesis such that cocaine treatment selectively alters the level of DA at sites containing D1 receptors with differential effects depending on the day/night cycle.

Food granules elicit heavy drinking in polydipsic rats independently of meal duration.

Excessive drinking, in rats made polydipsic on intermittent delivery of food pellets, is inversely related to the time the rat spends with its head in the feeder, early in the interfood interval. In a sensitization model, this explains why food textures that induce more oral activity, e.g., powder, do not elicit drinking. This hypothesis was examined by coding the behavior of polydipsic rats and varying the duration of the meal delivered in each interval, while holding texture constant. Polydipsic rats were presented with pellets, food granules, or food powder. The food granules were dispensed over periods lasting 1, 14, 21, and 28 s. All food deliveries were of the same mass. The food was delivered periodically at 60-s intervals in each condition. The 14 rats in the experiment served as their own controls by experiencing every condition. The food granule conditions induced the expected increases in feeding early in the interval. However, instead of progressively reducing drinking, the excessive drinking simply occurred later in the interval. By contrast, the powder condition resulted in the immediate elimination of polydipsia. The results suggest that food texture elicits excessive drinking independently of temporal factors and that elicitation of the sensitized drinking response must depend on other factors.