Sensitization to Morphine Induced by Viral-Mediated Gene Transfer

Abstract

Repeated administration of morphine sensitizes animals to the stimulant and rewarding properties of the drug. It also selectively increases expression of GluR1 (an AMPA glutamate receptor subunit) in the ventral tegmental area, a midbrain region implicated in morphine action. By viral-mediated gene transfer, a causal relation is shown between these behavioral and biochemical adaptations: Morphine's stimulant and rewarding properties are intensified after microinjections of a viral vector expressing GluR1 into the ventral tegmental area. These results confirm the importance of AMPA receptors in morphine action and demonstrate specific locomotor and motivational adaptations resulting from altered expression of a single localized gene product.

Rapid Synaptic Plasticity of Glutamatergic Synapses on Dopamine Neurons in the Ventral Tegmental Area in Response to Acute Amphetamine Injection

“…Moreover, it has been shown that overexpression of GluR1 by itself produces behavioral sensitization (Carlezon et al, 1997), suggesting that increases in synaptic GluR1 could explain our findings. One possible consequence of a large increase in GluR1 is the synaptic insertion of homomeric AMPA receptors lacking GluR2.…”

“…The simplest interpretation of these results is that the AMPA receptors at VTA synapses contain both GluR2 and GluR1 subunits even during the enhanced insertion postulated to occur after amphetamine exposure. Viral overexpression of GluR1 in the VTA, by strongly increasing the proportion of this subunit, is very likely to produce synapses with Ca 2 þ -permeable AMPARs, which may indeed contribute to the development of sensitization and other downstream behavioral changes (Carlezon et al, 1997).…”

“…Local effects of drugs of abuse on VTA neurons appear to be necessary and sufficient to trigger sensitization, because repeated local microinjections of amphetamine or morphine into the VTA elicit behavioral sensitization (Kalivas and Duffy, 1987;Kalivas and Weber, 1988;Druhan et al, 1993;Vezina, 1993;Cador et al, 1995) and microinjections of specific DA or glutamate receptor antagonists into the VTA prevent sensitization (Vezina and Stewart, 1989;Kalivas and Alesdatter, 1993;Bjijou et al, 1996;Kim and Vezina, 1998;Cador et al, 1999;Vezina and Queen, 2000). Several lines of evidence support the idea that synaptic plasticity at glutamate synapses in the VTA plays a key role in triggering sensitization and other neuroadaptations that may contribute to the development of addiction (Schenk and Snow, 1994;White, 1996;Carlezon et al, 1997;Ungless et al, 2001;Hyman and Malenka, 2001;Kauer, 2004). Most recently it has been demonstrated that the glutamate receptor complement (AMPAR/NMDAR ratio) at excitatory synapses onto VTA DA neurons is altered 24 h after exposure to several distinct drugs of abuse, but not by centrally acting drugs that are not addictive (Ungless et al, 2001;Saal et al, 2003).…”

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

“…This fact is otherwise in accordance with previous findings indicating that locomotor sensitization is better discerned following repeated low heroin doses (o100 mg/kg), because higher doses are known to induce hypolocomotion and catalepsy (Marinelli et al, 1998;Pontieri et al, 2001). Locomotor sensitization is the enduring enhancement in the motor stimulant effects elicited by repeated drug administration (Stewart and Badiani, 1993;Vanderschuren and Kalivas, 2000;Nestler, 2001), and neural adaptations that result in sensitization in animal models are likely the same that result in some forms of addictive behavior in humans (Robinson and Berridge, 1993;Carlezon et al, 1997;Nestler and Aghajanian, 1997;Nestler, 2001). Locomotor sensitization has been hypothesized to be a manifestation of enhanced motivational ('wanting') properties of drugs, or of the neural adaptations underlying drug craving (Robinson and Berridge, 1993).…”

“…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).…”