7-hydroxy-2-(n-n-propyl-n-(3-iodo-2--propenyl)-amino)tetralin and Substance-Withdrawal-Syndrome

Dopamine D3 receptors (D3Rs) have been implicated in behavioral sensitization to various drugs of abuse, but their role in ethanol (EtOH) sensitization has not been directly examined. We used D3R knockout (D3 KO) mice to examine whether the D3R plays a permissive role in EtOH and amphetamine (AMPH) sensitization. We also investigated whether EtOH sensitization is accompanied by alterations in D3R mRNA expression or binding.. After comparing EtOH sensitization in C57Bl/6 mice and DBA/2 mice, D3 KO, wild type (WT), and for comparison, D1 and D2 KOs received five biweekly injections of EtOH (2.2 g/kg, i.p.) or saline. Another group of D3 KOs and WT controls received six times AMPH (1.5 mg/kg, i.p.). D3R mRNA and binding were measured in EtOH-sensitized DBA/2 mice with in situ hybridization and [(125)I]-7-OH-PIPAT autoradiography, respectively.. C57Bl/6 mice expressed EtOH sensitization albeit to a lesser extent than DBA/2 mice. Compared to WT mice, D3 KOs were resistant to EtOH sensitization. The behavioral profile of D3 KOs was more similar to D1 KOs than D2 KOs, which also failed to develop EtOH sensitization. However, D3 KOs developed AMPH sensitization normally. EtOH sensitization was not accompanied by changes in either D3R mRNA or D3R binding in the islands of Calleja, nucleus accumbens, dorsal striatum, or cerebellum.. These results suggest a necessary role for the D3R in EtOH but not AMPH sensitization, possibly through postreceptor intracellular mechanisms. Results also suggest that different neurochemical mechanisms underlie sensitization to different drugs of abuse.

Topics: Alcoholic Intoxication; Amphetamine; Amphetamine-Related Disorders; Animals; Autoradiography; Behavior, Animal; Central Nervous System Depressants; Central Nervous System Stimulants; Ethanol; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Knockout; Motor Activity; Protein Binding; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3; RNA, Messenger; Species Specificity; Substance Withdrawal Syndrome; Tetrahydronaphthalenes

Previous research suggests that cocaine dysregulates dopamine D3 receptors. The present study examined the time course of changes in dopamine D3 receptor binding after terminating a cocaine self-administration regimen. [125I]-7-hydroxy-2-[N-propyl-N-(3'-iodo-2'-propenyl)-amino]-tetralin was used to label dopamine D3 receptors in rats that had undergone testing for cocaine-seeking behavior reinstated by a cocaine priming injection (15 mg/kg, i.p.; the behavior results have been previously published), and were killed 24 h after the test at time points that were either 2, 8, or 31-32 days after their last cocaine self-administration session. The results indicated a time-dependent increase in D3 receptor binding relative to controls that received saline yoked to the delivery of cocaine in an experimental animal. Specifically, there was no significant change in D3 receptor binding in cocaine-experienced rats killed at the 2- or 8-day time points relative to controls, but there was an increase in D3 receptor binding in the nucleus accumbens core and ventral caudate-putamen in rats killed at the 31- to 32-day time point. In a subsequent experiment, we replicated the increase in D3 receptor binding in rats that underwent a less extensive self-administration regimen, then were tested for cocaine-primed reinstatement of cocaine-seeking behavior, and then were killed 24 h later at a time point of 22 days after their last self-administration session. Furthermore, the increase in binding was attenuated by repeated 7-hydroxy-N,N-di-n-propyl-2-aminotetralin administration (1 mg/kg/day, s.c. for 14 days), a regimen that also reduces cocaine-seeking behavior in animals when tested in a nondrug state. Collectively, the findings suggest that regulatory responses of D3 receptors may be functionally related to changes in propensity for cocaine-seeking behavior.

Topics: Animals; Autoradiography; Brain; Cocaine; Cocaine-Related Disorders; Dopamine Agonists; Male; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Dopamine D3; Self Administration; Substance Withdrawal Syndrome; Tetrahydronaphthalenes

Previous postmortem studies have identified divergent alterations in D2 and D3 receptors in schizophrenia but those results cannot be interpreted without further understanding of whether antipsychotic regulation of the D3 receptor is different from that of the D2 receptor. Depot parenteral administration of haloperidol decanoate was utilized to achieve consistent high levels in rat brain for 9 months with 2-month withdrawal or 11 months with 48-h withdrawal and compared to vehicle control and acute haloperidol (48-h) treatment groups. Autoradiographic means for measuring levels of D2 ([(3)H]-spiperone) and D3 receptors ([(125)I]trans 7-OH-PIPAT) and of D3 mRNA by in situ hybridization histochemistry in rat caudate-putamen, nucleus accumbens, islands of Calleja, and olfactory tubercle determined that there were significant group differences for regulation of D2 receptor. Chronic haloperidol for 9 or 11 months elevated D2 but not D3 receptors or D3 mRNA in all regions measured. Acute haloperidol treatment had no significant effects for any measure. Treatment for 9 months with a 2-month withdrawal resulted in a persistent increase in D2 receptors that was greater than that observed in the 11 months with 48-h withdrawal. This effect was most noticeable in the olfactory tubercle. These data confirm previous findings that short- or long-term haloperidol treatment leads to elevations in D2 but not D3 receptors or D3 mRNA, and long-term withdrawal from chronic haloperidol does not lead to elevations in D3 receptors or D3 mRNA. This suggests that an elevation in D3 receptors identified at postmortem in schizophrenics withdrawn from antipsychotics is not the result of the previous drug history [Gurevich et al. (1997) Arch Gen Psychiatry 54:225-232].

Topics: Animals; Brain; Dopamine Antagonists; Drug Administration Schedule; Haloperidol; Iodine Radioisotopes; Male; Neurons; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Dopamine D3; RNA, Messenger; Spiperone; Substance Withdrawal Syndrome; Tetrahydronaphthalenes; Time Factors; Tritium; Up-Regulation