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The anterior subventricular zone (SVZa) is the site for postnatal neurogenesis of interneurons of the olfactory bulb (OB). Concurrently or after proliferation, neuronal precursors therein migrate within it to reach the OB, an event known as the rostral migratory stream (RMS). We used bromodeoxyuridine (BrdU) incorporation with short survival times to investigate the distribution of S-phase nuclei in the SVZa/RMS of the postnatal mouse. We observed that they were distributed along a radial, outside-in, decreasing gradient that persisted until postnatal day 10 (P10), then faded away to finally disappear by P16. After longer post-injection survival times labeled cell distribution became homogeneous. GFAP-positive glia are present at the periphery but not at the core of the SVZa. Our results represent the first evidence of a discrete spatial organization of a cell cycle phase within the SVZ, and also suggests a segregation of proliferating and migrating cells in the rostral migratory stream of the early postnatal mouse.

High doses of apomorphine induce sensitization to locomotor stimulant effects whereas low doses induce locomotor inhibition. We examined whether repeated low dose apomorphine induced sensitization and conditioning to the locomotor inhibitory effect. Three doses of the D1/D2 agonist, apomorphine, were used in a Pavlovian conditioning protocol: 0.05 mg/kg (autoreceptor level), 0.5 and 2.0 mg/kg (post-synaptic level). Rats received 5 daily apomorphine treatments paired or unpaired to an open-field environment (conditioning phase) followed by a saline test (conditioning test) and an apomorphine challenge test (sensitization test). Locomotion was measured for 30 min. During the acquisition phase, the 0.05 mg/kg paired treatment decreased locomotion while the high dose paired treatments increased locomotion. The 0.05 mg/kg paired treatment did not induce conditioning but induced inhibitory locomotor sensitization. The post-synaptic paired treatments produced conditioned and sensitized locomotor stimulation. For the low dose results, we propose an expanded contextual stimulus, which includes interoceptive drug cues. In the sensitization test, the same interoceptive drug cues and test environment cues are present as those during acquisition. In the conditioning test, normative dopaminergic activity is present which generates internal cues that may or may not generalize to the drug-induced cues and, permit or prevent retrieval of conditioning.

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The SCH-23390 findings are supportive of a critical role for D1 receptors in apomorphine effects whereas the sulpiride effects diminish the importance of conditioning and dopamine autoreceptor subsensitivity mechanisms in the mediation of apomorphine sensitization.

These findings suggest that sensitization substantially enhances the associative sensitivity of contextual stimuli and imply that brief exposure to cues linked to drugs of addiction followed by treatments that inhibit neurotransmitter systems may provide a new direction in drug abuse treatment.

Sensitization is a common feature of psychostimulants and sensitization effects are generally considered to be linked to the addictive properties of these drugs. We used a conventional paired/unpaired Pavlovian protocol to induce a context specific sensitization to the locomotor stimulant effect of a high dose of apomorphine (2.0mg/kg). Two days following a 5 session sensitization induction phase, a brief 5min non-drug test for conditioning was conducted. Only the paired groups exhibited locomotor stimulant conditioned response effects. Immediately following this brief test for conditioning, the paired and the unpaired groups received injections of 0.05mg/kg apomorphine, 2.0mg/kg apomorphine or vehicle designed to differentially impact memory re-consolidation of the conditioning. Two days later, all groups received a sensitization challenge test with 2.0mg/kg apomorphine. The 2.0mg/kg apomorphine post-trial treatment potentiated sensitization while the 0.05mg/kg eliminated sensitization. These effects were only observed in the paired groups. The activation of dopaminergic systems by the high dose of apomorphine strengthened the drug/environment association whereas the inhibition of dopamine activity by the low auto-receptor dose eliminated this association. The results point to the importance of conditioning to context specific sensitization and targeting memory re-consolidation of conditioning as a paradigm to modify sensitization.

No abstract