Behavioral Sensitization, Alternative Splicing, and D3 Dopamine Receptor-Mediated Inhibitory Function

Abstract

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.

Alternative splicing of G protein-coupled receptors: physiology and pathophysiology

“…As described above, mGlu1 receptor isoforms (a and b) are differentially expressed during neuronal development and differentiation, and the mGlu1a and 1b isoforms appear to have distinct cellular localizations and constitutive activities, as well as exhibiting potency and/or efficacy differences with respect to agonists [56,57,140]. Similarly, alternative splicing of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 D3nf isoform [38,143]. Quaternary interaction of D3nf with full-length D 3 (or D 1 ) dopamine receptors to form dimers can reduce trafficking of the dopamine-binding isoform to the plasma membrane [143].…”

“…Similarly, alternative splicing of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 D3nf isoform [38,143]. Quaternary interaction of D3nf with full-length D 3 (or D 1 ) dopamine receptors to form dimers can reduce trafficking of the dopamine-binding isoform to the plasma membrane [143]. Altered splicing efficiency with respect to the D3 dopamine receptor and the consequent alteration in the proportion of full-length and truncated forms generated in neuronal populations has been hypothesized to be linked to schizophrenia [18,38,143].…”

“…Quaternary interaction of D3nf with full-length D 3 (or D 1 ) dopamine receptors to form dimers can reduce trafficking of the dopamine-binding isoform to the plasma membrane [143]. Altered splicing efficiency with respect to the D3 dopamine receptor and the consequent alteration in the proportion of full-length and truncated forms generated in neuronal populations has been hypothesized to be linked to schizophrenia [18,38,143].…”

Advanced Research on Dopamine Signaling to Develop Drugs for the Treatment of Mental Disorders: Proteins Interacting With the Third Cytoplasmic Loop of Dopamine D2 and D3 Receptors

“…The gene encoding D3R is also organized to allow for production of different transcripts via alternative splicing, and at least seven distinct D3R splice variants have been identified: full-length D3R; a mouse shorter receptor isoform (D3SR) lacking 21 amino acids within the third cytoplasmic loop, but no correspondence to the human gene, D3 (TM3-del); D3 (TM4-del); D3 (O2-del); rD3in; and D3nf (9). Although both D3R and D3SR exhibit high-affinity dopamine binding, the other five variants do not bind dopamine and are believed to function to regulate receptor dimerization (9). D3nf, which is expressed in human brain, is the most investigated of these with particular attention on the third cytoplasmic loop.…”

“…The resultant GT genotype is associated with relatively lower expression of D2SR mRNA in prefrontal cortex and striatum, as well as with significantly reduced performance on a cognitive task relative to the GG genotype in humans (8). The gene encoding D3R is also organized to allow for production of different transcripts via alternative splicing, and at least seven distinct D3R splice variants have been identified: full-length D3R; a mouse shorter receptor isoform (D3SR) lacking 21 amino acids within the third cytoplasmic loop, but no correspondence to the human gene, D3 (TM3-del); D3 (TM4-del); D3 (O2-del); rD3in; and D3nf (9). Although both D3R and D3SR exhibit high-affinity dopamine binding, the other five variants do not bind dopamine and are believed to function to regulate receptor dimerization (9).…”