Chiodo LA, Bunney BS. Typical and atypical neuroleptics: differential effects of chronic administration on the activity of A9 and A10 midbrain dopaminergic neurons. J Neurosci 3: 1607-1619


Extracellular single unit recording techniques were used to study the effects of both acute and repeated oral neuroleptic administration on the in vivo activity of rat A9 and A10 dopaminergic (DA) neurons. All antipsychotic drugs examined acutely (haloperidol, l-sulpiride, chlorpromazine, and clozapine) increased the number of spontaneously firing DA neurons in both A9 and A10 compared to controls. Repeated (21 day) treatment with haloperidol, l-sulpiride, and chlorpromazine (antipsychotic drugs which can cause extrapyramidal side effects) markedly reduced the number of active DA cells below control levels in both regions. The "silent" DA neurons were in an apparent state of tonic depolarization inactivation since they could be induced to discharge by the microiontophoretic application of the inhibitory neurotransmitter gamma-aminobutyric acid, but not the excitatory amino acid glutamate. The depolarization inactivation observed may be specific for antipsychotic drugs since a non-neuroleptic phenothiazine (promethazine), the inactive isomer of sulpiride (d-sulpiride), and a tricyclic antidepressant (desmethylimipramine) neither increased DA activity when given acutely nor induced depolarization inactivation when administered repeatedly. In contrast to the other drugs tested, repeated treatment with clozapine (an effective antipsychotic drug which does not produce extrapyramidal side effects) resulted in the depolarization inactivation of A10 neurons but not A9 cells. These data suggest that neuroleptics which can induce extrapyramidal side effects produce depolarization inactivation of both A9 and A10 neurons whereas antipsychotic drugs which lack this property inactivate only A10 neurons. It is suggested that the time-dependent development of A9 DA neuron inactivation induced by repeated neuroleptic treatment may provide a mechanism for understanding the delayed onset of extrapyramidal side effects often observed with these drugs.

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    • "These data support and extend insight in different dynamics of agents with antagonistic vs. partial agonistic action on D 2 receptors on the activity of VTA DA neurons. Acutely, D 2 receptor antagonists robustly increase the firing activity of VTA DA neurons by blocking the D 2 receptor-mediated autoinhibitory signal of dopamine (Chiodo and Bunney, 1983; Ghanbari et al., 2009). Depending on their degree of intrinsic activity, partial D 2 receptor agonists acutely either decrease (e.g. "

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    • "The involvement of dopamine receptor-mediated processes in CLZ tolerance is also supported by early findings showing that repeated CLZ treatment leads to a suppressed firing (i.e. depolarization inactivation) of dopamine neurons in the ventral tegmental area but not in the substantia nigra and a suppressed release of dopamine in the nucleus accumbens but not in the striatum [43] [44]. Since CLZ also acts on many other receptors (e.g. "
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    • "Thus, Agid et al. (2003) showed that the onset of antipsychotic action can occur within the first few doses of APD treatment. Although this does not parallel what one observes in normal rats, it is important to note that in the normal rat APDs induce a large increase in DA neuron population activity that can act to offset the effects of receptor blockade (Bunney and Grace, 1978; Chiodo and Bunney, 1983; White and Wang, 1983a). As a result, one would predict that in the normal individual, the effects of APDs administered acutely would be blunted. "
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