PhD

dissertationTo study the functional interactions between neurotensin (NT) and dopamine (DA) systems in the rat brain, the effects of altering dopaminergic activity on the levels of NT-like immunoreactivity (NTLI) in the neostriatum, the nucleus accumbens and the substantia nigra were measured. Dopamine Di receptors were found to help regulate NT systems as methamphetamine (METH)-induced elevations in NTLI contents of these structures were completely blocked by the Di antagonist, SCH 23390. Administration of receptor-selective, direct-acting agonists revealed that Di and D2 receptors have opposite effects on NT systems in both the striatum and the nucleus accumbens. In contrast, stimulation of Di activity by itself did not affect the nigral NT systems, but after activation of D2 receptors a significant increase in the nigral level of NTLI was observed; surprisingly, stimulation of D2 receptors alone reduced the nigral NTLI content. These data suggest that although selective activation of D2 receptors opposes the effect of the Di subtype on nigral NT systems, in combination with Di stimulation, they are facilitatory to nigral Di activity. Elimination of greater than 85% of the central dopaminergic activity completely blocked the elevation in NTLI content caused by METH. For these experiments, depletion of dopamine was achieved by either (i) nigral administration of the dopaminergic neurotoxin, 6-hydroxydopamine, 7 to 10 days before administrations of METH or (ii) multiple doses of reserpine and a-methyl-p-tyrosine. Interestingly, these DA-depleting treatments by themselves induced significant increases in the NTLI content of the striatum and the nucleus accumbens. Although the nigral NTLI content was unaffected by the long-lasting treatments, a single dose of reserpine caused a significant decrease in nigral NTLI content by 18 h after the treatment. These results suggest that NT systems examined are tonically regulated by basal dopaminergic activity, although the nigral response appears to be short-lived. Administration of selective Di or D2 agonists with reserpine showed that tonic dopaminergic regulation of NT systems is mediated primarily by D2 receptors in the striatum and the nucleus accumbens but by Di receptors in the substantia nigra. This was further supported by the observations that interruption of dopaminergic transmission by D2 antagonists (e.g., sulpiride, SULP) increased NTLI levels only in the striatum and the nucleus accumbens whereas the Di antagonist decreased the nigral NTLI content. Finally, another transmitter system(s) appears to be involved in dopaminergic regulation of extrapyramidal NT systems, as destruction of striatal interneurons and/or striatal efferents with the excitotoxin, ibotenic acid, or a knife cut, blocked the METH- and SULP-induced alterations in NT activity of these structures. This linking transmitter system does not appear to be cholinergic since the muscarinic antagonist, atropine, did not attenuate the METH-induced increase in the striatum. However, other studies have shown that glutamatergic projections mediate the effects of METH on NT systems as concurrent blockade of N-methyl-D-aspartate receptors with MK 801 blocked the increases in NTLI contents caused by METH. The SULP-induced alterations, on the other hand, were not blocked by MK 801 suggesting that glutamatergic pathways may not be involved in basal D2 receptor-mediated regulation of NT systems