Basic Dopamine Transporter Mechanisms Of Cocaine

National Institute On Drug Abuse

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Abstract

The primary focus of this research is to develop a better understanding of the pharmacological mechanisms underlying the behavioral effects of cocaine that lead to its abuse, and the consequences of that abuse. This better understanding will advance basic knowledge of the pharmacology of cocaine, and drug abuse. A better understanding of the pharmacology of cocaine and drug abuse will lead to advances in our discovery of new treatment modalities for cocaine abuse which will ultimately have a positive public health impact in curtailing drug abuse and the transmission of HIV infection. Unique compounds based on the structure of cocaine and benztropine (BZT) have been synthesized that provide information on the nature of the interaction of cocaine with its binding site on the dopamine transporter (DAT). Benztropine (BZT) analogs have a chemical structure similar to cocaine and bind to the DAT recognition site with higher affinity than cocaine. Recent studies have demonstrated that BZT analogs express a behavioral profile different from that of cocaine. These compounds do not fully substitute for cocaine in animals trained to discriminate cocaine, and stimulate motor activity and are self-administered by non-human primates less than cocaine. As these behavioral effects are believed mediated by increases in DA transmission following DAT blockade, the reduced behavioral effects of BZT analogs suggest that they have other pharmacological features that render them different from cocaine. To investigate these effects further, the 4-Cl analog of BZT was compared to cocaine in their effects on DA transmission. To this end, activation of DA transmission was monitored in freely behaving rats implanted with microdialysis probes in four functionally different brain DAergic terminal areas: the dorsal caudate, the medial prefrontal cortex (PFCX), the nucleus accumbens shell (shell), and core (core). Administration of 4-Cl-BZT induced a rapid and prolonged (> 5h) increase of DA transmission at the highest dose tested in all dopaminergic areas. The increase was greatest between 30 and 60 min after administration of 4-Cl-BZT, depending on brain area. The increase of DA release was significant at the intermediate dose only in the shell and in the PFCX. Cocaine administration dose dependently increased DA transmission in all dopaminergic terminal areas with maximal effects during the first 10 or 20 min after administration. The effect lasted between 60 min (dorsal caudate) and 150 min (shell and core) at the highest dose. The present results show that 4-Cl- BZT induces a different pattern of activation of DA transmission as compared to cocaine. The increase in DA levels elicited by 4-Cl-BZT was graded in response to increments in dose in the accumbens shell and to a lesser extent in the PFCX. There was a higher threshold dose for increasing DA levels in the dorsal caudate and core and the response to dose was virtually quantal. It is interesting to note that at the intermediate dose, 4-Cl-BZT shows a selective increase in DA transmission in the shell as compared to the core. This effect is shared by almost all drugs abused by humans, suggesting that at this dose 4-Cl- BZT might possess reinforcing effects. It should be also noted that the long duration of action of this drug (>5 h) might reduce the expression of its reinforcing effects in self administration studies. In the PFCX, 4-Cl-BZT induced a dramatic increase of DA release at the highest dose. It has been shown that the ability of cocaine to increase DA transmission in the PFCX is mainly related to blockade of the noradrenaline transporter (NET). Indeed, GBR 12909, a preferential DAT blocker, administered at doses selective for DAT blockade does not increase DA transmission in the PFCX to the same extent as cocaine. Taken together these effects suggest that the ability of 4-Cl- BZT to increase DA release in the PFCX depends on other mechanism of action other than DAT blockade. Since 4-Cl-BZT is relatively selective for the DAT compared to the NET or the 5HT transporter, its effect on PFCX DA transmission might be related to other actions. Studies are in progress in our lab to more fully evaluate the pharmacology of 4-Cl-BZT in order to better understand its diminished cocaine-like effects and to examine its potential as a treatment for cocaine abuse. The reinstatement procedure has been used increasingly as a laboratory model of craving and relapse to abuse of drugs such as dopamine uptake inhibitors. With the number of reports involving this procedure growing. We examined the validity of the reinstatement procedure in relation to the following three types of models: 1) formal equivalence models, which are assessed on the basis of how well they resemble some phenomenon outside the laboratory (i.e. face validity); 2) correlational models, which are assessed on the basis of how well they predict outcomes of various interventions (such as drug administration or environmental change) when effected outside the laboratory (i.e. predictive validity); and 3) functional equivalence models, which are assessed on the basis of whether the laboratory phenomenon is mechanistically identical or reasonably similar to the phenomenon outside the laboratory (i.e. content validity). In its most general form, the reinstatement model has reasonable face validity; that is, there is a general agreement in appearance or form of the behavior in the model and the clinical target, relapse. This face validity is generally absent for the procedure when it is used as a model of craving. The predictive validity of the model has not been established. Evidence from studies of treatments for drug relapse have not supported the validity of the model, however from studies of the effects of the presentation of various types of stimuli (e.g. drug "priming") there is mixed evidence supporting predictive validity. With regard to functional equivalence, there is reasonable evidence supporting functional commonalities between drug self-administration in laboratory animals and human drug abusers, which lends support to the validity of the reinstatement model. However, there are several specific areas of departure between the methods and results using the model and clinical practices and observations about relapse, suggesting a lack of functional equivalence. There is reasonable evidence to support the face validity of the model, but at this time, neither its predictive validity nor functional equivalence has been fully established, which underscores the need for caution in generalizing results from the model to the clinical condition. The temporal patterns of cocaine self-administration are claimed to be highly regular, and substantial theory construction revolves around this purported regularity. Despite its theoretical importance, the regularity of drug self-administration has rarely been quantified or systematically compared across reinforcers. Over a range of doses, we quantitatively assessed the regularity of psychomotor stimulant (cocaine) and opioid (remifentanil) self administration, and compared those to behavior maintained by food reinforcement. Across all doses of each drug, food-maintained behavior was more regularly spaced than drug self administration. The regularity of latencies between successive self administrations of either drug was greatest at the highest doses. However, the drug level at the time an infusion was initiated was actually least consistent at these doses. These results suggest that theories suggesting that self administration behavior is governed by an exquisite regulation by the subject of the optimal level of drug intake, or resulting levels of neurotransmitter, are in need of revision.