The nighttime reduction in cocaine efficacy and the ability of melatonin to counteract the effects of cocaine on embryonic gene expression or embryonic survival, also suggests that circadian factors could potentially serve as preventive or therapeutic agents.
Similar to what was found for zGH and zDAT, increasing the dosage reduced cocaine efficacy in changing the gene expression, independent of the initial direction of the effect observed.
For example, both increases and decreases in the reinforcing efficacy of cocaine have observed following paradigms that produce tolerance to cocaine effects at the DAT.
The ID50 of WAY 163909 predicted to decrease the reinforcing efficacy of cocaine or sucrose as well as reinstatement upon exposure to cocaine-associated cues was ∼5 12-fold lower than that predicted to suppress horizontal ambulation (ID50 = 5.89 mg/kg) and ∼5 12-foldlower than that predicted to suppress vertical activity (ID50 = 2.3 mg/kg).
To directly assess the behavioral efficacy of cocaine in the discrete-trials choice procedure, we measured the ability of the first cocaine self-injection of the day to induce locomotion on day 1, 5 and 15.
Thus, selective stimulation of the 5-HT2CR decreases the reinforcing efficacy of cocaine and sucrose in freely-fed rats, but differentially alters the incentive-salience value of cocaine- vs. sucrose-associated cues at doses that do not impair locomotor activity.
The results indicated that administration of a D1/5 (SCH-23390) or a D2/D3/D4 (eticlopride), but not a D3 (U99194A) or D4 (L-750,667), dopamine receptor antagonist into the core and shell of the nucleus accumbens decreased the reinforcing efficacy of cocaine.
WAY 163909 dose-dependently reduced the reinforcing efficacy of cocaine (ID50 = 1.19 mg/kg) and sucrose (ID50 = 0.7 mg/kg) as well as reinstatement (ID50 = 0.5 mg/kg) elicited by exposure to cocaine-associated contextual cues, but not sucrose-associated contextual cues.
Collectively, these results indicate that D1-like and D2 dopamine receptors in the nucleus accumbens shell selectively modulate the reinforcing efficacy of cocaine, whereas D1-like and D2 dopamine receptors in the accumbens core have a more general influence on reinforced behaviors.
A wide range of pharmacological agents has been tested for efficacy in cocaine dependence, but generally with disappointing or, at best, equivocal results.
As seen in Figure 5, E196 301 protected the mice from death after the first injection of 180 mg/kg cocaine, but lost the efficacy at the second injection of 180 mg/kg cocaine 24 h later.
