The role of the dopamine transporter in cocaine abuse

There have been many studies aimed at understanding the role that the dopamine transporter plays in cocaine abuse. Most studies suggest that inhibition of dopamine uptake by cocaine is the primary mechanism by which its behavioral effects are produced. Because of the strong relationship between binding to the dopamine transporter and the behavioral effects of cocaine, the dopamine transporter has on occasion been referred to as the cocaine binding site. Chronic studies using cocaine or selective inhibitors of dopamine, norepinephrine, or serotonin uptake suggest that while a selective dopamine uptake inhibitor can produce sensitization to cocaine, the long-lasting sensitized response to a cocaine challenge observed in cocaine-pretreated rats is due to cocaine's action on a system other than, or in addition to, dopamine. Thus, while dopamine appears to be important for the behavioral effects of cocaine, it appears that neurochemical systems other than dopamine likely play a role in the behavioral effects of chronic cocaine

1 - Basic Pharmacological Mechanisms of Cocaine

The chapter discusses the increasing dopaminergic activity of cocaine, by binding to the dopamine transporter and inhibiting dopamine uptake. The primary method by which dopamine is deactivated after its release into the synapse is also presented. Auto radiographic studies using cocaine or an analog of cocaine suggest that there are high densities of dopamine transporter labeling in dopaminergic terminal regions. The discussion on cocaine inhibition involving the re-uptake of norepinephrine and serotonin into presynaptic terminals is covered. The primary effect of cocaine is to inhibit dopamine uptake, thereby increasing extracellular dopamine, which remains available to act on pre- and postsynaptic dopamine receptors. Chronic treatment with cocaine has pronounced effects on opioid peptide levels. This chapter illustrates pretreatment with a protein kinase C inhibitor injected into the Ventral Tegmental Area (VTA) that inhibits, both the ability of cocaine to stimulate locomotor activity and the cocaine induced increase in extracellular dopamine in the nucleus accumbens. This suggests that protein kinases may be important in cocaine's effects. The studies highlight considerable evidence that the dopamine transporter and the inhibition of dopamine uptake by cocaine play a major role in the production of cocaine's effects

Tolerance and sensitization to the locomotor-activating effects of cocaine are mediated via independent mechanisms

Tolerance or sensitization to the locomotor-activating effects of cocaine occurs depending upon the treatment regimen that is used. When cocaine is injected on a daily basis, sensitization occurs, whereas continuously infused cocaine leads to tolerance. Male Sprague–Dawley rats were treated for 7 days with continuous cocaine (50 mg/kg/day) via subcutaneously implanted osmotic minipumps, after which the pumps were removed. Locomotor activity was measured for 1 h each day. Some rats were challenged with an injection of cocaine (7.5, 15 or 30 mg/kg) either 2 or 9 days after pump removal. Two days after the pumps were removed (Day 10), there were no significant differences between cocaine- or saline-treated rats in the amount of locomotor activity produced by the challenge injections. However, cocaine-treated rats challenged with cocaine 9 days after pumps were removed (Day 17) exhibited significant tolerance, as evidenced by a shift downward of the cocaine curve, as compared to saline controls. When the rats were injected again on the next day (Day 18), the activity levels of both groups increased, as compared to the effects observed on Day 17. Thus, although the cocaine-treated rats were still tolerant compared to the saline-treated rats, they were sensitized compared to their previous response to a challenge injection. These findings indicate that tolerance and sensitization to the locomotor-activating effects of cocaine can exist simultaneously, which suggests that they are mediated by separate mechanisms

The effect of amfonelic acid or nisoxetine in combination with morphine on brain-stimulation reward

Many drugs of abuse, including stimulants such as cocaine and amphetamine, and opioids like morphine and heroin, will lower the threshold at which rats will work to receive electrical stimulation to the medial forebrain bundle-lateral hypothalamic region (MFB-LH). This effect is even greater when the two classes of drugs are coadministered. The underlying mechanisms by which this occurs are not completely understood, however there is considerable evidence suggesting that the catecholamines play a major role in mediating the reinforcing effects of these drugs. The present study was conducted to investigate the effects of amfonelic acid, an indirect dopamine agonist, and nisoxetine, a highly selective norepinephrine uptake blocker, alone and in combination with morphine, on the reward threshold for rewarding electrical intracranial stimulation. As in previous studies, morphine, as well as amfonelic acid, lowered the reward threshold with the amfonelic acid causing greater threshold lowerings than that of morphine. When a low (ineffective) dose of amfonelic acid was administered concomitantly with morphine, the threshold lowerings observed were larger than those seen with either drug alone and were often more than additive. Nisoxetine alone had no effect on the reward threshold and produced inconsistent results when combined with morphine. These findings support the thesis that amfonelic acid has abuse potential, and that its reinforcing effects may, in fact, be even greater than that of the opioids. Further, these results support the hypothesis that dopamine plays a more critical role in mediating brain-stimulation reward than dose norepinephrine

Potentiation of morphine analgesia by d-amphetamine is mediated by norepinephrine and not dopamine

Morphine will raise the threshold for escape from aversive electrical stimulation delivered to the mesencephalic reticular formation and this effect is potentiated by d-amphetamine. In order to study the roles which dopamine and norepinephrine play in modulating opiate analgesia, the effects of amfonelic acid, an indirect dopamine agonist, and nisoxetine, a selective norepinephrine reuptake blocker, were determined alone and in combination with morphine using this supraspinal model of analgesia. Amfonelic acid alone produced hyperalgesia and completely antagonized the analgesic effect of morphine. Nisoxetine had no effect by itself, however, it potentiated the analgesic effect of morphine when the two drugs were administered concomitantly. These findings suggest that norepinephrine and not dopamine plays a predominant role in the potentiation of opiate analgesia by d-amphetamine

Pretreatment with Δ9-tetrahydrocannabinol (THC) increases cocaine-stimulated activity in adolescent but not adult male rats

Marijuana (Cannabis sativa) remains one of the most widely used illegal drugs, with adolescents being particularly vulnerable to its use and abuse. In spite of this, most studies are conducted in adult animals even though the effects might be quite different in adolescents. Additionally, the use of marijuana often precedes the use of other psychoactive drugs including cocaine, especially when marijuana exposure begins during early adolescence. The purpose of this study was to examine the effects of repeated Δ9-tetrahydrocannabinol (THC), the major active ingredient in marijuana, in adolescents compared to adults and to determine its subsequent effects on cocaine-stimulated activity. To this end, adolescent (postnatal day PND 34) and adult (PND 66) rats were administered 3mg/kg/day THC for 8days and locomotor activity was measured on days 1, 2, 7 and 8 after dosing. On day 12 (4days after the last dose of THC), rats were injected with escalating doses of cocaine and behavior was recorded. Results show that THC depressed locomotor activity in adult rats but not in adolescents. However, following a cocaine challenge, adolescents exposed to THC showed increased locomotor responses to cocaine compared to chronic vehicle-injected controls. This was not seen in adults. These results show that the effects of cocaine are enhanced after THC in adolescents, but not adults, and that this might account for the greater transition to cocaine after early, as opposed to later, marijuana use. ►THC decreases activity in adult but not adolescent male rats. ►The effects of cocaine are increased after THC in adolescent but not adult rats. ►Early marijuana use produces increases in cocaine effects