Altered Behavioral Response to Dopamine D3 Receptor Agonists 7-OH-DPAT and PD 128907 Following Repetitive Amphetamine Administration

Abstract

Behavioral sensitization, the progressive and enduring enhancement of certain behaviors following repetitive drug use, is mediated in part by dopaminergic pathways. Increased locomotor response to drug treatment, a sensitizable behavior, is modulated by an opposing balance of dopamine receptor subtypes, with D1/D2 dopamine receptor stimulation increasing and D3 dopamine receptor activation inhibiting amphetamine-induced locomotion. We hypothesize that tolerance of D3 receptor locomotor inhibition contributes to behavioral sensitization. In order to test the hypothesis that expression of behavioral sensitization results in part from release of D3 receptor-mediated inhibition, thereby resulting in decreased response to D3 receptor agonists, we examined the effect of repetitive amphetamine administration on the behavioral response to the D3 receptor preferring agonists 7-OH-DPAT and PD 128907. D3-selective effects have recently been described for both drugs at a low dose. At 1 week following completion of a repetitive treatment regimen, amphetamine-pretreated rats displayed a decreased response to D3-selective doses of both 7-OH-DPAT and PD 128907, when compared to animals receiving saline pretreatment. Moreover, in addition to the quantitative alteration in response, there was a change in the inter-relation between response to amphetamine and D3 agonist. A highly significant inverse relation between locomotor inhibitory response to PD 128907 and the locomotor-stimulant response to amphetamine was observed prior to amphetamine treatment. In contrast, 10 days following repetitive amphetamine treatment, the relation between response to PD 128907 and amphetamine was not detected. The observed behavioral alteration could not be accounted for by changes in D3 receptor binding in ventral striatum. These findings suggest a persistent release of D3 receptor-mediated inhibitory influence contributes to the expression of behavioral sensitization to amphetamine.

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

“…D3 receptor binding is also decreased in adult rats following neonatal hippocampal lesion (Flores et al, 1996), suggesting hyperlocomotor behavioral responses in that model also result from decreased D3 receptor inhibitory function (Wan and Corbett, 1997). In contrast to the studies described above, we have not detected significant alterations in full-length D3 mRNA expression (Hondo et al, 1999) or D3 receptor binding in ventral striatum of AMPH-treated rats (Richtand et al, 2003). Studies of D3 expression in human cocainedependent subjects have also had conflicting results (Staley and Mash, 1996;Mash and Staley, 1999;Segal et al, 1997;Meador-Woodruff et al, 1995).…”

“…If persistent release of D3-receptor-mediated inhibitory influence contributes to the expression of sensitization, the behavioral response to D3 agonists should be attenuated in sensitized animals. Consistent with this prediction, D3-receptor-mediated locomotor inhibition is dramatically reduced in sensitized rats (Richtand et al, 2003). We determined the behavioral response to D3 receptor agonists 7-OH-DPAT and PD 128907 1 week following repetitive AMPH treatment.…”

“…This study also found, unexpectedly, that the locomotor response to AMPH, and locomotor inhibition by D3 agonist, are negatively correlated within individual animals, accounting for over 50% of the individual variance in locomotor response to AMPH, and that this relationship is abolished following repetitive AMPH treatment. In combination, these findings suggest that release of D3-receptor-mediated inhibition contributes to the expression of behavioral sensitization (Richtand et al, 2003).…”

Risperidone Pretreatment Prevents Elevated Locomotor Activity Following Neonatal Hippocampal Lesions

“…The loss of a D3 receptor-mediated 'brake' on these behaviors would be expressed as the emergence of augmented locomotor response to amphetamine in rodents and paranoid psychotic symptoms in humans. We (Richtand et al, 2000(Richtand et al, , 2003 and others (Chiang et al, 2003;Wan and Corbett, 1997;Flores et al, 1996a;Henry et al, 1995;Wallace et al, 1996) have described evidence supporting this hypothesis in rodent behavioral sensitization and other 'animal models' of psychosis.…”

“…Stress activates dopamine release in prefrontal cortex (Ventura et al, 2002;Cabib and Puglisi-Allegra, 1996), and both D3 receptor protein expression and receptor binding have been identified in prefrontal cortex (Diaz et al, 2000;Khan et al, 1998). Because the D3 receptor has the highest dopamine affinity, and is the only dopamine receptor occupied at concentrations in the range of basal dopamine concentrations, the 'D3 dopamine receptor hypothesis' of psychosis (Richtand et al, 2001(Richtand et al, , 2003(Richtand et al, , 2005 suggests that elevated dopamine concentrations from stress or other environmental factors prior to the development of psychosis result in a compensatory downregulation of prefrontal cortical D3 receptor function, thereby releasing D3 receptor-mediated inhibition of limbically modulated behaviors. The D3 receptor inhibits both novelty-stimulated locomotion Xu et al, 1997;Menalled et al, 1999;Ekman et al, 1998;Accili et al, 1996) and amphetaminestimulated locomotion (Waters et al, 1993) in rodents, and may also inhibit expression of analogous limbically modulated behaviors in humans including paranoia, delusions, and hallucinations (Ellinwood et al, 1973;Ellinwood, 1967).…”