Differential susceptibility to ethanol and amphetamine sensitization in dopamine D3 receptor-deficient mice

Abstract

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.

A functional role for the dopamine D3 receptor in the induction and expression of behavioural sensitization to ethanol in mice

“…The latter finding agrees with our current results with U99194A. We did not, however, observe increases in D3R binding associated with EtOH sensitization (Harrison and Nobrega 2009), possibly because we did not examine brains during the induction phase but only after sensitization was already expressed. Alternatively, EtOH-sensitized mice may become functionally more responsive to D3R ligands by mechanisms other than increases in D3R density.…”

“…Since EtOH sensitization was not associated with changes in D3R mRNA expression or binding (Harrison and Nobrega 2009), a functional up-regulation of D3Rs after chronic EtOH, would imply changes in intracellular mechanisms, downstream from the membrane-bound receptor. Interestingly, Richtand et al (2003) reported that following amphetamine sensitization (an effect not associated with changes in D3R binding), rats were less responsive to the D3R agonists PD128907 and 7-OH-DPAT, suggesting a functional down-regulation of D3Rs (Richtand et al 2003).…”

“…For drug challenge experiments, a 14-day drug-free period followed EtOH sensitization at which time an acute injection of a D3R ligand preceded a test injection of EtOH (1.8 g/kg, i.p.). The sensitizing and challenge doses of EtOH were chosen based on literature identifying these as doses that reliably elicit locomotor stimulant rather than sedative effects in mice, both in ours and other laboratories (Harrison and Nobrega 2009;Masur et al 1986;Phillips et al 1994Phillips et al , 1995Quadros et al 2002a). The 15-min test duration was used because the stimulant effects of EtOH are observed within the first 0-15 min of drug administration, after which, point sedative effects dominate the behavioural profile (Crabbe et al 1982;Lessov and Phillips 1998).…”

“…We have found that mice lacking the D3R are resistant to EtOH sensitization, suggesting a necessary role for the D3R in the sensitization process (Harrison and Nobrega 2009). The present study investigated whether the D3R plays a stronger role in the induction vs. expression of sensitization by examining the effects of pharmacological D3R blockade at different stages of repeated EtOH administration.…”

“…More recently, we reported that EtOH sensitization does not alter D3R binding or D3R mRNA expression (Harrison and Nobrega 2009), although this does not rule out the possibility of alterations in D3R function. Since the D3R is largely expressed in terminal projection sites of the mesolimbic DA pathway such as the NAcc shell (Diaz et al 1995;Levesque et al 1992;Stanwood et al 2000), the D3R has been hypothesized to play a stronger role in the expression rather than induction of behavioural sensitization (Filip et al 2002;Richtand 2006;Richtand et al 2003;van Kampen and Stoessl 2003).…”