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-receptor-mediated 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.

Figure 1

D3 receptor alternative splicing.

Figure 2

D3/D3nf mechanism of behavioral sensitization to AMPH. (1) AMPH increases extracellular dopamine. (2) D1 and D3 receptor stimulation activate opposing intracellular signaling systems. D3 receptor has highest dopamine affinity. D3 stimulation results in homeostatic mechanisms opposing receptor stimulation, including (3) increased D3nf expression. (4) D3nf and D3 dimerize, directing the D3/D3nf dimer (5) toward intracytoplasmic trafficking pools and removing D3 receptor from the synaptic membrane. (6) At the next AMPH exposure, D3 receptor is not available to bind dopamine. (7) The result is release of D3 receptor-mediated opposition to D1 receptor stimulation of adenylate cyclase activity. For additional details see in the text.

Figure 3

Behavioral response to PD 128907 is diminished in behaviorally sensitized rats. Locomotion following injection with saline and PD 128907 is shown following saline or AMPH pretreatment. Saline pretreatment group: *PD 128907 vs saline injection planned comparison p = 0.021, one-tailed. AMPH pretreatment group: PD 128907 vs saline injection planned comparison p = 0.754. Saline vs AMPH pretreatment group response to saline injection mean comparison p = 0.368, two-tailed. Methods: Male Sprague-Dawley were treated in home cages for 5 consecutive days with either saline or AMPH (1 mg/kg). On days 12–14, rats were injected in random order with either saline or PD 128907 (10 μg/kg) on a rotating basis, allowing each animal to be used as its own control to measure D3-agonist-mediated inhibitory effect. Data analysis by oneway ANOVA revealed no difference in order of injection (saline first or PD 128907 first). Crossover data from 0 to 180 min following injection with saline and PD 128907 were analyzed using ANOVA techniques for independent observations. Results are expressed as geometric mean number of crossovers, ±SE, for each group. Planned t-tests were performed for hypotheses of interest. Adapted from Richtand et al (2003).