Behavioral and neurochemical effects of the dopamine transporter ligand 4-chlorobenztropine alone and in combination with cocaine in vivo

The current studies evaluated the novel diphenylmethoxytropane analog 4-chl orobenztropine (4-Cl-BZT), cocaine, and combinations of the two drugs for t heir abilities to stimulate locomotor activity, produce cocaine-like discri minative stimulus effects, and elevate extracellular dopamine (DA) in the n ucleus accumbens (NAc) as measured by in vivo microdialysis. Peripherally a dministered cocaine was approximately twice as efficacious as 4-Cl-BZT as a locomotor stimulant and was behaviorally active at a lower dose than was 4 -Cl-BZT. Cocaine also was more efficacious than 4-Cl-BZT in producing discr iminative-stimulus effects in rats trained to discriminate i.p. injections of 10 mg/kg cocaine from saline. The time course of behavioral activation d iffered markedly between the two drugs, with much shorter onset and duratio n of locomotor stimulant effects for cocaine relative to 4-Cl-BZT. Similarl y, i.p. cocaine (10 and 40 mg/kg) induced a pronounced, rapid, and short-li ved increase in DA in the NAc, whereas i.p, 4-Cl-BZT was effective only at the higher dose and produced a more gradual, modest, and sustained (greater than or equal to 2 h) elevation in accumbens DA. In contrast to i.p. admin istration, local infusion of 4-Cl-BZT (1-100 mu M) into the NAc through the microdialysis probe elevated extracellular DA to a much greater extent tha n did local cocaine (nearly 2000% of baseline maximally for 4-Cl-BZT versus 400% of baseline for cocaine) and displayed a much longer duration of acti on than cocaine. However, when microinjected bilaterally into the NAc at 30 or 300 nmol/side, cocaine remained a more efficacious locomotor stimulant than 4-Cl-BZT. Finally, pretreatment with i.p. 4-Cl-BZT dose dependently en hanced the locomotor stimulant, discriminative stimulus effects, and NAc DA response to a subsequent low-dose i.p. cocaine challenge. The diphenylmeth oxytropane analog also facilitated the emergence of stereotyped behavior an d convulsions induced by high-dose cocaine. The current results demonstrate that DA transporter ligands that do not share the neurochemical and behavi oral profiles of cocaine nevertheless may enhance the effects of cocaine in vivo.