Info

+ Sulpiride

Yes

+ CPP

Yes

+ Bicuculline

Block

Note: Agonists: NMDA (glutamate), THIP (GABAa); antagonists: sulpiride (D2), CPP (NMDA), bicuculline (GABAa).

Note: Agonists: NMDA (glutamate), THIP (GABAa); antagonists: sulpiride (D2), CPP (NMDA), bicuculline (GABAa).

systemically blocked induction and expression, but, intrastriatally, it blocked only induction and not expression, which implies that induction and expression represent distinct circuits and that the non-NMDA participation in the circuit that controls expression involves a brain locus other than the site tested in the striatum. Subsequent studies have indicated that a locus for the non-NMDA component of expression exists in the globus pallidus (Karler, unpublished).

3.2. Agonist-Antagonist Interactions

The data in Table 3 summarize the stereotypic effects of the intrastriatal administration of dopamine, glutamate, and GABAa agonists and the influence of their antagonists, also administered intrastriatally, on the observed agonist effects. The details of these studies have been published previously (18). The agonist data indicate that both NMDA and the GABAa agonist THIP, as well as dopamine and amphetamine, produce stereotypy when injected into the striatum. Of these drugs, only amphetamine causes stereotypy when administered systemically. Although the various agonists administered intrastriatally produced stereotypy, neither single nor repeated intrastriatal administration resulted in sensitization. The failure of intrastriatally administered amphetamine to produce sensitiza-tion has been reported by other investigators (37). Although several laboratories have claimed that amphetamine injected intrastriatally in sensitized rats can elicit a sensitized response (see, e.g., ref.38), we have been unable to repeat this observation in mice.

Because the three types of agonists caused stereotypy, the corresponding antagonists were used in combination with the agonists intrastriatally in order to determine the sequence of the agonist effects in the striatum. All three classes of antagonists block the dopamine- or amphetamine-induced stereo-typy, which suggests that the dopaminergic stimulus in the striatum represents the initial event in the resulting motor response. With NDMA as the agonist, sulpiride was ineffective, but the stereotypy was blocked by CPP and by bicuculline; on the other hand, THIP-induced stereotypy was blocked

Table 4

Influence of Intracortically Administered Dopamine, Glutamate, and GABA Receptor Antagonists on Amphetamine-Induced Stereotypy in Normal Mice and on the Induction and Expression of Sensitization

Sensitization

Antagonist treatment (i.c.)

Acute

Induction

Expression

Dopamine

Di (SCH-23390) D2 (sulpiride) Glutamate NMDA (CPP) Non-NMDA (CNQX) GABA

GABAa (bicuculline)

Block Enhance

Block No effect

Enhance

Block Block

Block No effect

No effect

Block No effect

Block No effect

No effect only by bicuculline. These results imply the following sequence of events in the striatum: Stereotypy is initiated by a dopaminergic stimulus, which, in turn, activates the NMDA system, which stimulates the GABAa system. That dopamine appears to activate the glutamate system is contrary to the reports that have suggested that the cortical glutamatergic input controls the release of striatal dopamine (39). Neuroanatomically, these two transmitter systems are known to synapse on common dendrites (10), so that an interaction between the two neurotransmitters is possible; however, the results of the striatal studies described here mean that amphetamine releases dopamine, which, in turn, releases glutamate to produce stereotypy, and not vice versa. The proposal that glutamate in the striatum controls the release of dopamine has been based on the results obtained with electrical stimulation of the cortex; these studies measured only transmitter release without any behavioral correlates. In contrast, the present study focuses on the behavioral effects of amphetamine or dopamine; therefore, in terms of stereotypy, dopamine in the striatum appears to release glutamate, which, in turn, releases GABA.

Because the major efferents from the striatum are GABAergic, the findings that, intrastriatally, a GABAA agonist can produce stereotypy and a GABAA antagonist can block evoked stereotypy suggest that an evoked striatal stimulus serves to release GABA within the striatum, which, in turn, inhibits the inhibitory outflow; therefore, the excitatory motor effect produced by the stimulants appears to be the result of the inhibition of the inhibitory outflow from the striatum (18).

4. INTRACORTICAL DRUG EFFECTS 4.1. Antagonists

Table 4 summarizes our previously published data on the effects of the intracortical (ic) administration of dopamine, glutamate, and GABA receptor antagonists on amphetamine-induced stereotypy in normal and sensitized animals, as well as on the induction of sensitization (40). The Dx antagonist in the cortex blocked all three of the effects, which were also blocked following systemic or intrastriatal administration, although the dose differential found systemically to block induction compared to the other two effects (Fig. 3) was not apparent either in the cortex or, as described above, in the striatum. These results indicate that yet another site must account for the systemic effect of this drug on induction. In contrast to the Dx antagonist effects, the results with the D2 antagonist administered intracortically differed qualitatively from those obtained systemically or intrastriatally. D2 antagonists (sulpiride or eticlopride) administered by either of the latter two routes block all three of the effects, but, intracortically, they

Table 5

Influence of Dopamine and GABA Agonists Administered Intracortically on the Acute Response to Amphetamine and on Sensitization

Table 5

Influence of Dopamine and GABA Agonists Administered Intracortically on the Acute Response to Amphetamine and on Sensitization

Agonists (i.c.)

Acute

Induction

Sensitization

Expression

Amphetamine

Block

Block

No effect

Dopamine

Block

Block

No effect

D2 (PPHT)

Block

Block

No effect

GABAa (THIP)

Block

Block

Block

Note: Acute effect represents the response in nonsensitized animals to amphetamine, 12 mg/kg ip; expression represents the response in sensitized animals to amphetamine, 6 mg/kg ip.

Note: Acute effect represents the response in nonsensitized animals to amphetamine, 12 mg/kg ip; expression represents the response in sensitized animals to amphetamine, 6 mg/kg ip.

block only induction; in striking contrast, they actually enhance the acute effect and were ineffective in terms of expression. Here, we see a clear separation between the functional roles of the Dx and D2 systems, which was not the case with either the systemic or intrastriatal administration. The function of the Dx in the cortex mirrors that observed with both the systemic and intrastriatal administration of an antagonist; that is, a functional Dx system in the cortex is necessary for all three effects of amphetamine to manifest themselves. In contrast, activation of the D2 system in the cortex appears to inhibit or modulate the motor effect of amphetamine; this is clearly an opposite effect of that subserved by the Dx system. On the other hand, activation of both the Dx and D2 systems are necessary for the induction of sensitization; therefore, only some of the functions of the D2 system in the cortex are distinct from those of the Dx system.

The NMDA antagonist, which blocks all of the effects systemically and intrastriatally, also blocked all of the effects intracortically. In contrast, the non-NMDA antagonist was completely ineffective in the cortex, indicating that the effects on induction and expression seen after systemic administration must be mediated by a different locus (see Table 2). The GABAa antagonist, which systemically and intrastriatally blocks all the effects, intracortically, however, enhanced the acute response; yet, this enhanced acute effect was not associated with any concomitant enhancement of induction, which clearly shows a separation between these two phenomena. Furthermore, bicuculline was also ineffective in the test for expression, indicating that the acute effect is lost in sensitized animals. The data shown in Table 4 emphasize that the transmitter systems investigated can subserve different functions in different brain areas and that sensitization is associated with qualitative changes in some of their functions.

4.2. Agonists

The data in Table 5 qualitatively summarize the influence of dopamine and GABA agonists administered intracortically on the systemic effects of amphetamine. The details of these experiments have been published previously (40,41). In these studies, the various agonists were injected intracortically followed by 12 mg/kg of amphetamine ip. The dopamine agonists (amphetamine, dopamine, or the D2 agonist PPHT) were given intracortically; each blocked the acute response, as well as the induction of sensitization to amphetamine, and their inhibitory activity on stereotypy disappeared on expression in sensitized animals. The inhibitory activity of the agonists and the disappearance of this activity in sensitized animals is consistent with the data shown in Table 4, in which a D2 antagonist enhanced the acute effect of amphetamine and the enhanced effect disappeared in sensitized animals. Sensitization to cocaine was also associated with a loss of the corticodopaminergic inhibitory function (41). The cause-effect relationship between the loss of cortical inhibition and the manifestation of sensitization is further strengthened by the persistence of the phenomenon in sensitized animals (41). Furthermore, the sensitization induced by a D2 agonist, such as PPHT, is also associated with a loss of the cortical dopamine inhibition, and the lack of persistence of this sensitization correlates with the recovery of this inhibitory activity of dopamine in the cortex (33). The results of the D2 antagonist and agonist studies described above in normal and in sensitized animals provide a possible explanation of the mechanism of sensitization; that is, the sensitized response is the result of the loss of the normal dopaminergically mediated cortical inhibition of a dopaminergically initiated motor stimulus (40). That a fundamental change in function associated with sensitization occurs in the cortex is consistent with the observations that protein-synthesis inhibitors systemically administered block induction (25), and this effect occurs in the frontal cortex but not in either the striatum or the substantia nigra (Karler, unpublished). The results of the studies in the frontal cortex of dopaminergic activity and those of the protein-synthesis inhibitors combine to focus on this structure as a primary site of the fundamental changes in function that result in the phenomenon of sensitization to the stimulants.

The agonist data shown in Table 5 demonstrate that activation of the GABAa system in the frontal cortex as well as the D2 dopamine system can also antagonize amphetamine-induced effects. In these experiments, the intracortical administration of the GABAA agonist THIP blocks all of the measured systemic effects of amphetamine; however, bicuculline, the GABAA antagonist, in contrast only enhanced the acute response and was without effect on either the induction or expression of sensitiza-tion (Table 4). That bicuculline enhanced the acute response and that the agonist blocked the response suggest that the GABAA system, as well as the D2 system in the cortex, serves an inhibitory function in the stimulant-activated circuit that generates stereotypy (40,41).

Not included in the data in Table 5 are the effects of the intracortical administration of NMDA and the Dx agonist SKF-38393. In a wide dosage range (0.5-5.0 |g/kg), NMDA exerted no effect on any of the responses to amphetamine, despite the findings in Table 4 that CPP, the NMDA antagonist, intracortically blocks all of the effects of amphetamine. Low doses of NMDA were clearly depressant, whereas relatively high doses were excitatory in terms of locomotor activity. The wide range of effects of NMDA may reflect the almost universal distribution of NMDA receptors on neurons, which may account for the failure of NMDA to produce stereotypy, as was expected from the CPP block of the effects of amphetamine. The Dx agonist in doses as high as 1 |g/side did not enhance any of the effects of amphetamine, despite the observations in Table 4 that the antagonist intracortically. blocks all of the effects. The lack of activity of the agonist suggests that D1 activation by amphetamine is not a limiting factor in the responses.

4.3. Agonist-Antagonist Interactions

The data shown in Table 6 represent the results of an examination of the relationship between the inhibitory effects of intracortical dopamine and those of THIP, which were described in Table 5. The results show that either sulpiride or bicuculline can antagonize the dopamine blockade of amphetamine-induced stereotypy, but only bicuculline can block the inhibitory effects of THIP (40,41). These results imply that the inhibitory effect of dopamine is transmitted by the activation of GABAergic neurons, which appears to mediate the inhibitory role of these two systems in the frontal cortex. Also shown in Table 6 is the absence of dopamine inhibition in sensitized animals, but this is not the case for the inhibitory activity of THIP. These findings indicate that in the sensitized animals only the dopamine-induced inhibition disappears, whereas the inhibitory activity of THIP persists, which demonstrates that the loss of cortical inhibition in sensitized animals is the result of a change in the functional role of dopamine and not that of GABA. The role of the GABA system in mediating the cortical inhibition of dopamine is also supported by the data shown in Table 4. Here, we found that bicuculline intracortically enhanced amphetamine-induced stereotype and that this property disappears in sensitized animals. This particular loss of activity appears to be the result of the loss of dopaminer-gic activation of the GABA system, which can account for the failure of bicuculline to enhance the amphetamine effect in sensitized animals.

Table 6

Interaction of Dopamine and GABA Agonists and Antagonists Administered Intracortically on Amphetamine-Induced Stereotypy Normal and in Sensitized Mice

Amphetamine treatment Pretreatment (i.c.) Normal response Sensitized response

Dopamine

Amphetamine treatment Pretreatment (i.c.) Normal response Sensitized response

Dopamine

+ Saline

Block

No effect

+ Sulpiride

No effect

+ Bicuculline

No effect

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