Autoradiographic mapping of mu opioid receptor changes in rat brain after long-term haloperidol treatment: relationship to the development of vacuous chewing movements.
Brain opioid systems modulating basal ganglia function may be involved in the development of neuroleptic-induced orofacial dyskinesias. This study examined changes in mu opioid receptors labeled with [3H]D-Ala2, N-MePhe4, Gly-ol5-enkephalin ([3H]-DAMGO) in 79 different brain regions of rats showing vacuous chewing movements after 21 weeks of treatment with haloperidol decanoate (HAL). Dopamine D2 receptors labeled with [3H]raclopride were also examined in the adjacent sections of the same brains. For brain analyses HAL-treated rats were divided into a group showing high incidence of vacuous chewing movements (VCMs) and a group showing low incidence of VCMs. As expected, long-term HAL resulted in a pronounced elevation of D2 receptors in caudate-putamen, n. accumbens, globus pallidus and olfactory bulbs (range: 27.70% increases) compared to controls. These changes were equal in magnitude in both HAL-treated groups, irrespective of the frequency of VCMs. In HAL-treated rats [3H]DAMGO was significantly decreased in several parts of the basal ganglia, including n. accumbens (-21%, P < 0.01), patchy area of the anterior caudate-putamen (-12%, P < 0.05), ventral pallidum (-27%, P < 0.01) and globus pallidus (-21%, P < 0.02). Statistically significant decreases were also seen in the subthalamic nucleus (-12%, P < 0.05) and ventrolateral thalamus (-21%, P < 0.05), both of which are targets of basal ganglia output. However, as in the case of [3H]raclopride binding, [3H]DAMGO changes were generally seen both in the High VCM and the Low VCM groups. These results confirm that long-term haloperidol leads to a decrease in mu-opioid binding in basal ganglia and related structures, similar to what is seen after 6-OHDA denervation. The observed mu-receptor binding changes may be a contribution factor, but do not appear sufficient to account for the differential development of neuroleptic-induced vacuous chewing movements.
Sasaki
T
T
Neurogenetics Research Section, Clarke Institute of Psychiatry, Toronto, Ontario, Canada.
Kennedy
J L
JL
Nobrega
J N
JN
D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity*; D001345:Autoradiography; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D018492:Dopamine Antagonists / Q000633:toxicity*; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000378:metabolism; D006220:Haloperidol / Q000633:toxicity*; D008297:Male; D008409:Mastication / Q000187:drug effects*; D020891:Raclopride; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D012457:Salicylamides / Q000378:metabolism
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D004745:Enkephalins; D017448:Receptors, Dopamine D2; D017450:Receptors, Opioid, mu; D012457:Salicylamides; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020891:Raclopride; D006220:Haloperidol