“…These findings strongly suggest involvement of NAcc D 3 receptors in stress-triggered reinstatement of cocaine-seeking. Provocatively, the NAcc contains some of the highest D 3 receptor densities in the brain (Bouthenet et al 1991;Landwehrmeyer et al 1993;Diaz et al 1995), whereas dorsal striatum has very low D 3 receptor density (Bouthenet et al 1991;Landwehrmeyer et al 1993). An important caveat, however, is that the NAcc is near the bed nucleus of the stria terminalis (BNST), a region well implicated in stress-triggered reinstatement (Shaham et al 2000a;Stewart 2000;Shalev et al 2002).…”
Section: Discussionmentioning
confidence: 99%
“…The involvement of mesolimbic dopamine (DA) in cocaine addiction and relapse (Wise 1996;Stewart 2000;Nestler 2001;Shalev et al 2002;Volkow et al 2002) has implicated DA receptors as targets for the development of anti-cocaine medication (Rothman and Glowa 1995;Platt et al 2002). Among the five DA receptor subtypes identified (Greengard 2001), the D 3 receptor has attracted special attention because it is highly localized in the nucleus accumbens (NAcc) and adjacent mesolimbic loci (Bouthenet et al 1991;Landwehrmeyer et al 1993;Diaz et al 1995). In addition, the D 3 receptor has the highest binding affinity for DA of all DA receptors (30-fold over D 1 or D 2 ) (see Sokoloff et al 1992;Levant 1997 for review).…”
“…These findings strongly suggest involvement of NAcc D 3 receptors in stress-triggered reinstatement of cocaine-seeking. Provocatively, the NAcc contains some of the highest D 3 receptor densities in the brain (Bouthenet et al 1991;Landwehrmeyer et al 1993;Diaz et al 1995), whereas dorsal striatum has very low D 3 receptor density (Bouthenet et al 1991;Landwehrmeyer et al 1993). An important caveat, however, is that the NAcc is near the bed nucleus of the stria terminalis (BNST), a region well implicated in stress-triggered reinstatement (Shaham et al 2000a;Stewart 2000;Shalev et al 2002).…”
Section: Discussionmentioning
confidence: 99%
“…The involvement of mesolimbic dopamine (DA) in cocaine addiction and relapse (Wise 1996;Stewart 2000;Nestler 2001;Shalev et al 2002;Volkow et al 2002) has implicated DA receptors as targets for the development of anti-cocaine medication (Rothman and Glowa 1995;Platt et al 2002). Among the five DA receptor subtypes identified (Greengard 2001), the D 3 receptor has attracted special attention because it is highly localized in the nucleus accumbens (NAcc) and adjacent mesolimbic loci (Bouthenet et al 1991;Landwehrmeyer et al 1993;Diaz et al 1995). In addition, the D 3 receptor has the highest binding affinity for DA of all DA receptors (30-fold over D 1 or D 2 ) (see Sokoloff et al 1992;Levant 1997 for review).…”
“…D3 dopamine receptor mRNA and protein expression are limited primarily to olfactory tubercle, nucleus accumbens, and islands of Calleja (located ventral to the ventral pallidum and nucleus accumbens), phylogenetically ancient limbic brain regions linked to motivated and emotional behaviors (Levesque et al, 1992;Bouthenet et al, 1991;Richtand et al, 1995;Landwehrmeyer et al, 1993;Gurevich and Joyce, 1999;Levant, 1998). Protein and mRNA expression are highly colocalized, suggesting that receptor expression occurs primarily on perikarya, proximal dendrites, and short axons as opposed to long axon terminals from other brain regions (Levesque et al, 1992).…”
Section: Dopamine and Behavioral Sensitizationmentioning
confidence: 99%
“…In human brain, most D3 mRNA-expressing cells also express D2 mRNA (Gurevich and Joyce, 1999), whereas in rodent brain, in contrast, D2 and D3 receptors appear to have predominantly complementary rather than overlapping patterns of expression (Bouthenet et al, 1991). In the nucleus accumbens shell, colocalized D1 and D3 receptors exert synergistic effects on substance P gene expression (Ridray et al, 1998;Schwartz et al, 1998).…”
Section: Dopamine and Behavioral Sensitizationmentioning
Behavioral sensitization, the progressive and enduring augmentation of certain behaviors following repetitive drug use, alters rodent locomotion in a long-standing manner. The same dopamine pathways playing an important role in drug dependence and psychosis also play a critical role in sensitization. Individual dopamine receptor subtypes have markedly different functional responses to stimulation, with D3 dopamine receptor stimulation inhibiting rodent locomotion. The D3 receptor has highest affinity of the dopamine receptor subtypes for dopamine, and is occupied to a greater degree following stimulant drug administration. D3 receptor activity may be regulated through the expression of an alternatively spliced, truncated receptor isoform (termed 'D3nf') altering receptor localization and function via dimerization with the full-length subunit. The expected physiological response to repetitive drug administration is tolerance. Tolerance of D3 receptor inhibition of locomotion would contribute to sensitization to stimulant drugs. We hypothesize that repetitive D3 receptor stimulation contributes to the development of behavioral sensitization through decreased responsivity of D3-receptor-mediated locomotor inhibition. Increased D3nf expression may direct altered receptor localization and subsequent release of D3-receptormediated inhibition, contributing to the expression of sensitization. These hypotheses follow directly from the affinities of the receptor subtypes for dopamine; dopamine concentrations following stimulant administration; the effects of individual dopamine receptor subtype stimulation on locomotion; and the expected homeostatic response of the system to perturbation by drug. Clarifying these mechanisms underlying sensitization may suggest new interventions for neuropsychiatric conditions in which dopamine plays an important role, including psychosis, drug dependence, and Parkinson's disease. This information may also elucidate a previously unrecognized mechanism regulating receptor trafficking and desensitization.
“…It has been proposed that the D 3 receptor is involved in schizophrenia pathology and antipsychotic action (Sokoloff et al 1990;Gurevich et al 1997;Joyce and Meador-Woodruff 1997), and plays a role in drugseeking behavior (Caine and Koob 1993;Staley and Mash 1996). It has been shown that in the rodent the D 3 receptor is much less abundant than the D 2 receptor, has a restricted distribution, and exhibits a significant degree of segregation from the D 2 receptor in the nucleus accumbens (Bouthenet et al 1991;Meador-Woodruff et al 1991;Huang et al 1992;Diaz et al 1995;Le Moine and Bloch 1996). This limited distribution suggested a specific function for the D3 receptor subtype distinct from that of the D2 receptor and related to the mesolimbic rather than nigrostriatal system.…”
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