“…Moreover, it has been proposed that IEGs might couple some of the acute actions of these drugs to longterm alterations in neural function. Dopamine receptor-mediated IEG induction has been shown to exhibit some properties of tolerance with chronic administration (Hope et al, 1992), thus paralleling results of behavioral studies (De Montis et al, 1992).…”
Section: Discussionsupporting
confidence: 55%
“…Indeed, with daily MK-801 pretreatment, the striatum is, if anything, hyperresponsive to amphetamine. MK-801 previously has been shown to block behavioral responses to cocaine or amphetamine including sensitization (Itzhak and Stein, 1992;Wolf and Jeziorski, 1993;Hoffman, 1994;Ohno et al, 1994) or reverse tolerance (Karler et al, 1989) and tolerance (De Montis et al, 1992). The present data provide a molecular correlate of the ability of MK-801 to inhibit an effect of chronic amphetamine administration.…”
Amphetamine and cocaine induce the expression of both immediate early genes (IEGs) and neuropeptide genes in rat striatum. Despite the demonstrated dependence of these effects on D 1 dopamine receptors, which activate the cyclic AMP pathway, there are several reports that amphetamine and cocaine-induced IEG expression can be inhibited in striatum in vivo by NMDA receptor antagonists. We find that in vivo, the NMDA receptor antagonist MK-801 inhibits amphetamine induction of c-fos acutely and also prevents downregulation of IEG expression with chronic amphetamine administration. Such observations raise the question of whether dopamine/glutamate interactions occur at the level of corticostriatal and mesostriatal circuitry or within striatal neurons. Therefore, we studied dissociated striatal cultures in which midbrain and cortical presynaptic inputs are removed. In these cultures, we find that dopamine-or forskolin-mediated IEG induction requires Ca 2ϩ entry via NMDA receptors but not via L-type Ca 2ϩ channels. Moreover, blockade of NMDA receptors diminishes the ability of dopamine to induce phosphorylation of the cyclic AMP responsive element binding protein CREB. Although these results do not rule out a role for circuit-level dopamine/glutamate interactions, they demonstrate a requirement at the cellular level for interactions between the cyclic AMP and NMDA receptor pathways in dopamine-regulated gene expression in striatal neurons.
“…Moreover, it has been proposed that IEGs might couple some of the acute actions of these drugs to longterm alterations in neural function. Dopamine receptor-mediated IEG induction has been shown to exhibit some properties of tolerance with chronic administration (Hope et al, 1992), thus paralleling results of behavioral studies (De Montis et al, 1992).…”
Section: Discussionsupporting
confidence: 55%
“…Indeed, with daily MK-801 pretreatment, the striatum is, if anything, hyperresponsive to amphetamine. MK-801 previously has been shown to block behavioral responses to cocaine or amphetamine including sensitization (Itzhak and Stein, 1992;Wolf and Jeziorski, 1993;Hoffman, 1994;Ohno et al, 1994) or reverse tolerance (Karler et al, 1989) and tolerance (De Montis et al, 1992). The present data provide a molecular correlate of the ability of MK-801 to inhibit an effect of chronic amphetamine administration.…”
Amphetamine and cocaine induce the expression of both immediate early genes (IEGs) and neuropeptide genes in rat striatum. Despite the demonstrated dependence of these effects on D 1 dopamine receptors, which activate the cyclic AMP pathway, there are several reports that amphetamine and cocaine-induced IEG expression can be inhibited in striatum in vivo by NMDA receptor antagonists. We find that in vivo, the NMDA receptor antagonist MK-801 inhibits amphetamine induction of c-fos acutely and also prevents downregulation of IEG expression with chronic amphetamine administration. Such observations raise the question of whether dopamine/glutamate interactions occur at the level of corticostriatal and mesostriatal circuitry or within striatal neurons. Therefore, we studied dissociated striatal cultures in which midbrain and cortical presynaptic inputs are removed. In these cultures, we find that dopamine-or forskolin-mediated IEG induction requires Ca 2ϩ entry via NMDA receptors but not via L-type Ca 2ϩ channels. Moreover, blockade of NMDA receptors diminishes the ability of dopamine to induce phosphorylation of the cyclic AMP responsive element binding protein CREB. Although these results do not rule out a role for circuit-level dopamine/glutamate interactions, they demonstrate a requirement at the cellular level for interactions between the cyclic AMP and NMDA receptor pathways in dopamine-regulated gene expression in striatal neurons.
“…It has been accepted that NMDARs are critical for the development of cocaine-induced sensitization. This notion is primarily based on evidence that co-administration of MK801 with cocaine completely blocks [15][16][17][18][19][20][21][22][23] or reduces [16,33,49,76,77] cocaine-induced sensitization. However, this conclusion is still highly controversial and the role of NMDARs in addiction remains unclear [78].…”
Section: Discussionmentioning
confidence: 99%
“…Co-administration of MK801 prevents the development of sensitization to cocaine [15][16][17][18][19][20][21][22][23], amphetamine [24][25][26][27][28] and methamphetamine [29,30]. Moreover, MK801 similarly prevents the development of cocaine, amphetamine, and methamphetamineinduced conditioned place preference, a prominent associative memory model of drug seeking behavior [31][32][33].…”
h i g h l i g h t sCPP co-administration with cocaine altered the acute response to cocaine. NMDAR antagonism with CPP had no effect on cocaine-induced behavioral sensitization. NMDAR antagonism with CPP abolished cocaine-induced conditioned place preference.
a r t i c l e i n f o
a b s t r a c tRecently, the notion that memory and addiction share similar neural substrates has become widely accepted. N-methyl-d-aspartate receptors (NMDAR) are the cornerstones of synaptic models of memory. The present study examined the effect of the competitive NMDAR antagonist CPP on the induction of behavioral sensitization and conditioned place preference to cocaine. Conditioned place preference is an associative memory model of drug seeking, while sensitization is a non-associative model of the transition from casual to compulsive use. There were three principal findings: (1) co-administration of CPP and cocaine altered the acute response to cocaine, suggesting a direct interaction between the two drugs; (2) NMDAR antagonism had no effect on behavioral sensitization; and (3) NMDAR antagonism abolished conditioned place preference. A review of prior evidence supporting a role for NMDARs in sensitization suggests that NMDAR antagonists directly interfere with cocaine's psychostimulant effects, and this interaction could be misinterpreted as a disruption of sensitization. Finally, we suggest that addiction recruits multiple kinds of plasticity, with sensitization recruiting NMDAR-independent mechanisms.
“…The behavioral characteristics of cocaine as a CNS stimulant was similar to those of amphetamines. The interactions between MK-801 and cocaine have been evaluated in the behaviors of rats, but not in those of mice (14)(15)(16).…”
ABSTRACT-Alterationsof cocaine effects, which were induced by prior repeated 5-time administration of MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) (i.p.) alone or in combination with cocaine (s.c.) at 3-to 4-day intervals, were investigated by means of ambulatory activity in mice. The repeated administration of either cocaine (10 and 20 mg/kg) alone or MK-801 (0.3 mg/kg) alone progressively enhanced each drug's effect. The enhanced effects of cocaine and MK-801 were estimated to be 1.8-2.2 times and about 1.4 times, respectively, as great as those at the 1st administration. Although the coadministration of MK-801 with cocaine produced a significant enhancement in the ambulation-increasing effect, the comparatively higher doses of MK-801 (0.3 and 1 mg/kg) acted not only to reduce cocaine sensitivity but also to inhibit the development of cocaine sensitization. Thus, the mice that had been given MK-801 (0.3 and 1 mg/kg) alone 5 times showed lower sensitivities to cocaine (20 mg/kg) than the mice given saline alone. The mice coadministered MK-801 (0.3 and 1 mg/kg) with cocaine (10 and 20 mg/kg) also exhibited lower sensitivities to cocaine (10 and 20 mg/kg) than those given cocaine alone. However, MK-801 could not ameliorate the established sensitization to cocaine. Similar interactions have been demonstrated between MK-801 at 1 mg/kg, but not 0.3 mg/kg, and methamphetamine. The present results indicate that MK-801 can inhibit the development of sensitization to cocaine at a lower dose than that required to inhibit methamphetamine sensitization.
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