Presynaptic D 2 dopamine (DA) autoreceptors, which are well known to modulate DA release, have recently been shown to regulate DA transporter (DAT) activity. To examine the effects of D 2 DA receptor deficiency on DA release and DAT activity in dorsal striatum, we used mice genetically engineered to have two (D 2 ϩ/ϩ ), one (D 2 ϩ/Ϫ ), or no (D 2 Ϫ/Ϫ ) functional copies of the gene coding for the D 2 DA receptor. In vivo microdialysis studies demonstrated that basal and K ϩ -evoked extracellular DA concentrations were similar in all three genotypes. However, using in vivo electrochemistry, the D 2 Ϫ/Ϫ mice were found to have decreased DAT function, i.e., clearance of locally applied DA was decreased by 50% relative to that in D 2 ϩ/ϩ mice. In D 2 ϩ/ϩ mice, but not D 2 Ϫ/Ϫ mice, local application of the D 2 -like receptor antagonist raclopride increased DA signal amplitude, indicating decreased DA clearance. Binding assays with the cocaine analogue [ 3 H]WIN 35,428 showed no genotypic differences in either density or affinity of DAT binding sites in striatum or substantia nigra, indicating that the differences seen in DAT activity were not a result of decreased DAT expression. These results further strengthen the idea that the D 2 DA receptor subtype modulates activity of the striatal DAT. Key Words: D 2 dopamine autoreceptorGene knockout mice-Dopamine uptake-In vivo microdialysis-In vivo electrochemistry-Striatum. J. Neurochem. 72, 148 -156 (1999).Dopaminergic neurotransmission in the CNS plays a key role in the control of motor, cognitive, and reward processes. Dopaminergic neurotransmission is a complex and tightly controlled process that involves synthesis, storage, release, receptor binding, subsequent activation of signal transduction systems, and termination of the action of the neurotransmitter. Extracellular levels of dopamine (DA) within the striatum are thought to largely depend on a balance between vesicular release of DA and reuptake of the released DA through the DA transporter (DAT). Multiple mechanisms have been identified for the short-and long-term regulation of DA release, whereas relatively little is known about mechanisms by which DAT may be acutely regulated.One well-characterized mechanism by which DA release can be modulated is via DA autoreceptors. DA receptors are divided into two general classes, the D 1 -like family, composed of the D 1 and D 5 receptor subtypes, and the D 2 -like family, composed of the D 2 , D 3 , and D 4 subtypes (see Sokoloff and Schwartz, 1995). Release-modulating DA autoreceptors belong to the D 2 -like family (see Langer, 1997). Studies using in vitro slice techniques, synaptosomes, and in vivo microdialysis have provided strong evidence that activation of these terminal autoreceptors with D 2 -like receptor agonists inhibits DA release within the rodent striatum (Dwoskin and Zahniser, 1986;Altar et al., 1987;Westerink and de Vries, 1989). D 2 DA receptors have been localized on dopaminergic axon terminals (Sesack et al., 1994), and at least a subpopul...

Common features shared by addictive drugs have been difficult to identify. One ubiquitous effect of these drugs is psychomotor stimulation. Further, repeated exposure commonly results in sensitization to drug stimulant effects. This study evaluates sensitization to drugs from several drug classes in C57BL/6J and DBA/2J inbred strain mice. DBA/2J mice showed sensitized responses to ethanol and methamphetamine, whereas C57BL/6J mice developed sensitization to morphine and methamphetamine. Strain susceptibilities to ethanol- and morphine-induced sensitization closely paralleled their sensitivities to the acute stimulant effects of these drugs; this was not the case for methamphetamine. The relative sensitivities of DBA/2J and C57BL/6J mice were not consistent across drugs, suggesting that the stimulant and sensitized responses to these drugs may be mediated by at least partially divergent neural mechanisms.

Genetic differences in sensitivity to cocaine's rewarding effect depend critically on temporal parameters of the place-conditioning procedure. One possible interpretation of these findings is that short trial durations produce conditioned activity responses that interfere more with expression of conditioned place preference in DBA/2J mice than in C57BL/6J mice. More generally, these findings underscore the need for caution when drawing conclusions about genetic differences in place conditioning, especially when using this paradigm to evaluate the effects of gene knockouts or insertions on drug reward.

Mice (DBA/2J) received a Pavlovian procedure in which a distinctive floor stimulus was paired 4 times with ethanol (2 g/kg). A different floor stimulus was paired with saline. Naloxone (0.0,1.5, or 10.0 mg/kg, intraperitoneal) given before each ethanol trial did not interfere with acquisition of conditioned preference, although naloxone alone produced conditioned aversion. When naloxone (0.0, 0.15, 1.5, 3.0, or 10.0 mg/kg) was given for the first time during testing, mice showed conditioned preference during the first 10 min. However, preference subsequently decreased dose-dependently over time. Control studies eliminated alternative interpretations based on pharmacokinetics or presence of an aversive state. The overall pattern of results suggests that naloxone facilitated extinction of conditioned place preference and supports the hypothesis that ethanol-induced conditioned reinforcement is mediated by the endogenous opioid system.Opioid system involvement in the hedonic (i.e., rewarding or aversive) effects of ethanol has been suggested by several different kinds of findings. Foremost among these findings are studies showing a suppressive effect of opiate antagonists on ethanol drinking or on operant responding for ethanol (e.g.,

This experiment examined the impact of a dopamine receptor blocker on ethanol's rewarding effect in a place conditioning paradigm. DBA/2J mice received four pairings of a tactile stimulus with ethanol (2 g/kg, IP), haloperidol (0.1 mg/kg, IP)+ethanol, or haloperidol alone. A different stimulus was paired with saline. Ethanol produced increases in locomotor activity that were reduced by haloperidol. However, conditioned preference for the ethanol-paired stimulus was not affected by haloperidol. Haloperidol alone decreased locomotor activity during conditioning and produced a place aversion. These results indicate a dissociation of ethanol's activating and rewarding effects. Moreover, they suggest that ethanol's ability to induce conditioned place preference is mediated by nondopaminergic mechanisms.