Effects of 4′-Chloro-3α-(diphenylmethoxy)-tropane on Mesostriatal, Mesocortical, and Mesolimbic Dopamine Transmission: Comparison with Effects of Cocaine

Abstract

Increase in dopamine (DA) neurotransmission resulting from blockade of the DA transporter (DAT) after administration of cocaine is believed to play a major role in mediating its behavioral and reinforcing effects. Since it was hypothesized that drugs that block the DAT have cocaine-like behavioral effects, it was of interest to study in the present article the stimulant effects of cocaine on locomotor activity and on pattern of activation of DA neurotransmission in different DAergic terminal areas in rats and compare these effects with those of 4Ј-chloro-3␣-(diphenylmethoxy)-tropane (4-Cl-BZT), a benztropine analog showing higher affinity for the DAT, but reduced behavioral effects compared with cocaine. Administration of cocaine resulted in a dose-dependent stimulation of locomotor activity and DA neurotransmission in the nucleus accumbens shell and core, dorsal caudate, and in the medial prefrontal cortex (PFCX) measured by microdialysis. At comparable doses, the effects of 4-Cl-BZT on DA levels in all brain areas except the PFCX were generally reduced compared with those of cocaine, as were the effects on locomotor activity. The differences in behavioral effects corresponded generally to differences between the drugs with regard to their stimulation of extracellular DA levels, although the mechanism(s) for the differences in extracellular DA may involve effects mediated by sites other than the DAT or differences in the efficiency of the two drugs in blocking DA uptake. Nonetheless, the present results suggest that the differences in behavioral effects between cocaine and 4-Cl-BZT are related to differences in their patterns of activation of DA transmission.

Effects of Muscarinic M1Receptor Blockade on Cocaine-Induced Elevations of Brain Dopamine Levels and Locomotor Behavior in Rats

“…The maximal effects of cocaine at the doses studied were obtained within 30 min after injection. These effects of cocaine are similar to those shown previously in this and other laboratories (Kuczenski et al, 1991;Tanda et al, 1997Tanda et al, , 2005, and a replication of the effects of 3.0 mg/kg cocaine in the NAc shell showed no significant differences in effects (F 1,12 ϭ 0.024; p ϭ 0.880).…”

“…Under a mixture of ketamine and xylazine (60.0 and 12.0 mg/kg i.p., respectively) anesthesia, rats were placed in a stereotaxic apparatus, the skull was exposed, and a small hole was drilled to expose the dura. Rats were then randomly implanted in the right or left brain side with a concentric dialysis probe (see below) aimed at the NAc shell or core, or at the medial PFCX, as described previously (Tanda et al, 1997(Tanda et al, , 2005; also see Fig. 1 for placements).…”

Combinations of Cocaine with Other Dopamine Uptake Inhibitors: Assessment of Additivity

“…Concentric dialysis probes were prepared with AN69 dialyzing membranes (Hospal Dasco, Bologna, Italy) as described for rats (Tanda et al, 2005 and modified in size for mice. The exposed dialyzing surface of the membrane, i.e., the surface not covered by glue, was limited to the lowest 1.0-mm portion of the probes, and the probes were less than 18 mm in total length.…”

Modulation of the endocannabinoid system: Therapeutic potential against cocaine dependence

“…Drugs of abuse and intra cranial self stimulation produce reinforcing effects through the same reward circuitry (122), and also increase dopamine neurotransmission in a dopaminergic reward-related area of such circuitry (1,2,3,78,129,130) that has been related to their reinforcing effects (5,79,80). Thus, it is not apparently clear why cocaine and cannabinoid CB1 receptor agonists, which share the ability to stimulate the brain reward circuitry, may have different and antagonistic effects in this procedure.…”

“…Stimulation of locomotor activity induced by cocaine and other psychostimulants has been extensively studied (see, for example citations 70, and 71). Administration of psychostimulants in rodents induces a dose-dependent increase in behavioral activation, which depends on the activation of selected brain striatal areas (72,73,74,75,76), and that is accompanied by stimulation of DA neurotransmission (3,77,78,79). Although this behavior is not a direct correlate of the reinforcing effects of cocaine, the fact that it can be obtained by injecting cocaine in the NAc (72,76,77), and that NAc DA transmission is involved in different aspects of drug abuse and addiction (5,80,81), makes monitoring of locomotor activation an easy preclinical target to test drugs that can interfere with the ability of cocaine to stimulate DA neurotransmission and potentially attenuate cocaine-induced reinforcement (82).…”