A general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function

Activation of the cAMP/PKA pathway in the dopaminoceptive neurons of the striatum has been proposed to mediate the actions of various classes of drugs of abuse. Here, we show that, in the mouse nucleus accumbens and dorsal striatum, acute administration of morphine resulted in an increase in the state of phosphorylation of the dopamine-and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr34, without affecting phosphorylation at Thr75. The ability of morphine to stimulate Thr34 phosphorylation was prevented by blockade of dopamine D1 receptors. DARPP-32 knockout mice and T34A DARPP-32 mutant mice displayed a lower hyperlocomotor response to a single injection of morphine than wild-type controls. In contrast, in T75A DARPP-32 mutant mice, morphine-induced psychomotor activation was indistinguishable from that of wild-type littermates. In spite of their reduced response to the acute hyperlocomotor effect of morphine, DARPP-32 knockout mice and T34A DARPP-32 mutant mice were able to develop behavioral sensitization to morphine comparable to that of wild-type controls and to display morphine conditioned place preference. These results demonstrate that dopamine D1 receptor-mediated activation of the cAMP/DARPP-32 cascade in striatal medium spiny neurons is involved in the psychomotor action, but not in the rewarding properties, of morphine.

Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Activation of the cAMP/PKA/DARPP-32 Signaling Pathway is Required for Morphine Psychomotor Stimulation but not for Morphine Reward

Borgkvist

Usiello

Greengard

et al. 2007

“…In general, changes in the ventral tegmentum believed to be related to the initiation of sensitization are transient, such as decreased sensitivity of somatodendritic D2 subtype dopamine autoreceptors (Kamata and Rebec, 1984;White and Wang, 1984;Henry et al, 1989;Ackerman and White, 1990). In contrast, neurochemical changes in the nucleus accumbens accompanying sensitization are persistent (Wolf, 1998), such as increased D1 receptor electrophysiological responsiveness (Henry and White, 1991;Higashi et al, 1989) and upregulation of cAMP signal transduction (Nestler et al, 1990;Terwilliger et al, 1991). Some of the changes in the nucleus accumbens, such as augmentation of the increase in extracellular dopamine elicited by stimulants (Robinson et al, 1988;Kalivas and Duffy, 1990), require a withdrawal time interval to be manifest.…”

Section: Development Vs Expression Of Behavioral Sensitizationmentioning

confidence: 99%

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

Richtand

2006

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.

“…Thus, repeated opiate exposure increases VTA TH levels as well as glutamate receptor subunits such as NMDAR1 during the induction phase of sensitization Fitzgerald et al, 1996;Shippenberg and Elmer, 1998;Brodkin et al, 1999). In the nucleus accumbens, chronic opiate treatment is known to up-regulate activity of the cAMP pathway, increasing levels of PKAa (Terwilliger et al, 1991). The present study reveals that there are also adaptive biochemical changes in the RLi/ PAG region after a repeated exposure to heroin (3-days), as revealed by TH upregulation, without changes in PKAa expression.…”

Section: Thmentioning

confidence: 99%

“…The latter is the enhancement in the motor stimulant effects elicited by repeated drug administration (Stewart and Badiani, 1993;Vanderschuren and Kalivas, 2000;Nestler, 2001), and neural and biochemical adaptations that result in sensitization in animal models are likely the same which result in some forms of addictive behavior in humans (Robinson and Berridge, 1993;Carlezon et al, 1997;Nestler and Aghajanian, 1997;Messer et al, 2000;Nestler, 2001). It is widely accepted that repeated opiate exposure is linked to biochemical traits in several mesolimbic regions, such as increase of TH in the VTA or protein kinase Aa (PKAa) upregulation in the nucleus accumbens (Terwilliger et al, 1991;Beitner-Johnson and Nestler, 1991;Brodkin et al, 1999). TH upregulation seems to be linked to augmented dopamine neurotransmission in the VTA and terminal regions such as the nucleus accumbens (BeitnerJohnson and Nestler, 1991;Sklair-Tavron et al, 1996), and heightened dopaminergic neurotransmission is thought to trigger the induction of transient immediate early genes, and more enduring transcription factors implicated in morphine's motor sensitization and reward (Nye and Nestler, 1996;Segal and Kuczenski, 1992;.…”

Section: Introductionmentioning

confidence: 99%

Role for Dopamine Neurons of the Rostral Linear Nucleus and Periaqueductal Gray in the Rewarding and Sensitizing Properties of Heroin

Flores

Galan-Rodriguez

Ramiro-Fuentes

et al. 2005

There is a mesencephalic dopaminergic network outside the ventral tegmental area (VTA), including structures such as the rostral linear nucleus (RLi) and periaqueductal gray (PAG). These nuclei project to neural areas implicated in reinforcing effects of drugs, indicating that they could participate in opiate reward. The objectives were to study the morphological characteristics of the dopamine network of the RLi/PAG region, and to discern its role on rewarding and sensitizing effects of heroin in rats, following dopamine depletion or local injection of dopaminergic antagonists. The findings indicated that this network is composed of small cells in the RLi/ventral PAG, large multipolar dopamine PAG neurons, and periaqueductal PAG neurons. Following repeated heroin, large PAG neurons and small RLi/ ventral PAG cells (not periaqueductal neurons) were activated, since tyrosine-hydroxylase was adaptively induced, without changes in protein kinase Aa. After dopamine depletion, small RLi/ventral PAG neurons and large cells of the PAG (not periaqueductal ones) were selectively affected by the neurotoxin. Dopamine neurons of the nearby VTA and dorsal raphe were not affected, as revealed by cell counting. After lesion, 'anxiety-like' responses and basal locomotion were not altered. However, conditioned place preference to heroin was found to be abolished, as well as heroin-induced motor sensitization. Following infusions of dopaminergic antagonists into RLi/PAG, D 2 (not D 1 ) receptor blocking dose-dependently abolished heroin-induced reward. The present study provides evidence that dopamine neurons of the RLi/PAG region (excluding PAG periaqueductal cells) show adaptive biochemical changes after heroin, and mediate the rewarding and sensitizing effects of this drug. D 2 dopamine receptors within the RLi/PAG region participate in these effects.