Info

Fig. 3. Dose-response curves for systemically administered SCH-23390 antagonism of amphetamine-induced stereotypy in nonsensitized (acute) and sensitized (expression) mice and of amphetamine-induced sensitization.

greater affinity may account for the SCH-23390 dose differential required to block induction. Even though the relationship between sensitization and the subjective effects of the stimulants is not clear, it is worth noting that the D5 receptor has recently been specifically implicated in drug-discrimination studies of cocaine (36).

Figure 4 represents the dose-response curves for the NMDA antagonist CPP against the three effects of amphetamine. Here, we found that the ED50 to antagonize the acute effect was 3.0 (2.1-4.4) mg/kg, and the ED50 to block expression was 2.5 (1.3-4.8) mg/kg; these values are not significantly different. The ED50 to block induction, however, was 0.82 (0.4-1.6) mg/kg, which is significantly different from the other two ED50s. These data imply a distinction between the NMDA pathway involved in the induction of sensitization and the pathway that mediates both the acute response and the expression of sensitization. That a different dopamine pathway for induction exists is consistent with the findings (above) for the quantitative character of blockade of induction by the D1 antagonist SCH-23390. These observations on the differential effects of the antagonists, coupled with those described above on the ability of morphine to promote stimulant-induced induction even in the absence of stereo-typy and on the enhancement of stereotypy by the muscarinic antagonists without affecting induction, further bolster the conclusion that the dopaminergic pathways that subserve stereotypy differ from those that support the induction of sensitization.

As indicated in Table 1, DNQX, the non-NMDA ionotropic glutamate antagonist, can block both the induction and the expression of sensitization, but it cannot affect the acute response to amphetamine. Although the data are not shown, the dose of DNQX required to block the two sensitization effects appears to be about equal, indicating that the two effects may involve a common pathway. The dose-response curve for the DNQX antagonism of expression is illustrated in Fig. 5, and these results suggest that the response to amphetamine in sensitized animals consists of two pharmacologically separable responses. The results shown indicate that DNQX cannot completely block the effect in sensitized animals, which contrasts with the dopamine antagonists, with CPP, the NMDA antagonist, and with bicuculline, the GABAa antagonist. All of these antagonists can completely block the stereotypic effect in both nonsensitized and sensitized animals, but the antagonist effect of DNQX appears to be

Fig. 4. Dose-response curves for systemically administered CPP antagonism of amphetamine-induced stereo-typy in nonsensitized (acute) and sensitized (expression) animals and of amphetamine-induced sensitization.
Fig. 5. Dose-response curve for systemically administered DNQX antagonism of amphetamine-induced stereotypy in sensitized mice. (Reprinted with permission, from Elsevier Science, Amsterdam.)

limited to that fraction of the amphetamine response contributed by sensitization. In these experiments, the sensitized response was elicited with a challenge dose of 6 mg/kg of amphetamine, which in non-sensitized animals yields a response of only 20% stereotypy, but 80% in sensitized animals; as can be seen in Fig. 5, DNQX reduces the sensitized response to the 20% control value. The results of the DNQX study illustrate that the sensitized response appears to consist of two separable components: one that represents the nonsensitized circuit; the other represents the sensitized circuit. Although the evoked behavior is indistinguishable in these two conditions, DNQX serves to functionally separate the

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BICUCULLINE (mg/kg)

Fig. 6. Dose-response curves for systemically administered bicuculline antagonism of amphetamine-induced stereotypy in nonsensitized (acute) and sensitized (expression) mice and of amphetamine-induced sensitization.

two responses, because the drug is ineffective against the nonsensitized response and only partially effective in sensitized animals. This differential effect of DNQX is not unique because identical results have been obtained with the use of calcium-channel blockers (30), nicotinic antagonists (26), and protein-synthesis inhibitors (25). Furthermore, in data not shown, combinations of these partial antagonists with DNQX also exhibited the same limited efficacy. These results add additional support to the interpretation that the response to amphetamine in sensitized animals consists of two distinct components— one derived from the normal pathway, the other from a pathway associated with sensitization.

The dose-response curves for bicuculline, the GABAa antagonist, are shown in Fig. 6: The ED50 for the antagonism of the acute amphetamine response is 0.83 (0.67-1.02) mg/kg; for induction, 0.84 (0.68-1.03); and for expression, 0.75 (0.61-0.92) mg/kg; none of these values are significantly different, so all three effects involve the activation of a common GABAA pathway. Although we previously reported limited quantitative data on the GABAA involvement in the motor effects of the stimulants, the present detailed data add further to our understanding of the fundamental role of the GABAA system in the circuits that produce the three effects of the stimulants.

3. INTRASTRIATAL DRUG EFFECTS 3.1. Antagonists

The data in Table 2 summarize the qualitative effects of the intrastriatal administration of dopamine, glutamate, and GABAA antagonists on amphetamine-induced stereotypy in nonsensitized animals, as well as on the induction and expression of sensitization; the quantitative details of these studies have been published previously (17,18). The purpose of these experiments was to determine the role of the striatum in mediating the systemic effects of the drugs found in Table 1 and in Figs. 1-6. Both D1 and D2 antagonists systemically block all three effects (Table 1), which is also true when these antagonists are administered intrastriatally. The systemic dose differential required for SCH-23390 to block the acute response and expression compared to that required to block induction (Fig. 3) was not evident in the striatum, which implies that some other locus accounts for the differential effect on

tn X

BICUCULLINE (mg/kg)

Table 2

Influence of Intrastriatally Administered Dopamine, Glutamate, and GABA Receptor Antagonists on Amphetamine-Induced Stereotypy and on Sensitization

Antagonist treatment

Acute

Sensitization

Induction

Expression

Dopamine

Di (SCH-23390) D2 (sulpiride) Ionotropic glutamate NMDA (CPP) Non-NMDA (CNQX) GABAa (bicuculline)

Block Block

Block No effect Block

Block Block

Block Block Block

Block Block

Block No effect Block

Fig. 7. Dose-response curves for intrastriatally administered CPP antagonism of amphetamine-induced stereotypy in nonsensitized (acute) and sensitized (expression) mice and of amphetamine-induced sensitization.

induction observed systemically. The results obtained with the NMDA antagonist CPP and with bicuculline, the GABAa antagonist, mirrored those obtained systemically. The relatively low systemic dose of CPP required to block induction was also found to be true in the striatum, as shown in Fig. 7. In these experiments, CPP was injected into the striatum bilaterally; its ED50 to block the acute response was 0.0076 (0.006-0.0096) ^g/side, and to block expression, 0.0055 (0.0044-0.0069) ^g/side; these two values are not significantly different. The ED50 to block induction, 0.0005 (0.0004-0.0006) ^g/side, however, is about one order of magnitude lower and is significantly different from the other two values. This dose-response differential for CPP to block induction in the striatum reflects the systemic effects seen in Fig. 4 and indicates that the NMDA path involved in the induction is distinct from the path involved in the other two responses; yet, the striatum is a locus for mediating all of the effects. The results with the non-NMDA antagonist CNQX also validate the existence of distinct circuits to support the induction and expression of sensitization; this drug administered

Table 3

Interaction of Dopamine, Glutamate, and GABA Agonists and Antagonists Administered Intrastriatally on Agonist-Induced Stereotypy

Table 3

Interaction of Dopamine, Glutamate, and GABA Agonists and Antagonists Administered Intrastriatally on Agonist-Induced Stereotypy

Agonists

Stereotypy

Amphetamine

Yes

Dopamine

Yes

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