Presynaptic and postsynaptic actions of dextroamphetamine (DEX) were studied on dopamine (DA) sensitive neurons of the subesophageal ganglion of the garden snail Helix aspersa utilizing standard microelectrode techniques. Dextroamphetamine (5.5 × 10-7-10-4 M) produced effects on DA-sensitive neurons similar to that caused by DA (5.5 × 10-7-10-4 M). On cells excited by DA, surfused DEX (5.5 × 10-7 M) caused an excitation that could be blocked by chlorpromazine (0.5-1 × 10-6 M) or haloperidol (0.5-1 × 10-6 M). Elevating the extracellular Mg2+ from 4 to 20 mM reduced the depolarization caused by DEX from 11 to 2.5 mV without affecting the response to DA. The response remaining is attributed to a direct response to DEX on DA receptors. Surfused DEX caused an inhibition of cells inhibited by DA. Both DA and DEX effects were selectively blocked by dihydroergotamine (0.5-1 × 10-6 M). Elevating the [Mg2+] decreased the hyperpolarization caused by DEX from 11 to 3 mV without affecting the DA response. The effect of elevated magnesium in decreasing responses to surfused DEX suggests that the primary action of DEX is at the nerve terminal to cause DA release. Iontophoretic application of DEX caused minimal excitation or inhibition of DA neurons. This is attributed to the fact that DA receptors at the site of drug application are not associated with synaptic innervation. The response obtained with iontophoretically applied DEX suggest a weak direct action on DA receptors.

Nasal administration of analgesics for achieving rapid pain relief is currently a topic of great interest. The blood-brain barrier (BBB) restricts access to the central nervous system (CNS) for several central-acting drugs, such as morphine and dihydroergotamine, which results in a substantial effect delay. Evidence for the olfactory transfer of drugs from the nasal cavity to the CNS after nasal administration, bypassing the BBB, is available for both animals and humans. The aims of this thesis were to study the olfactory transfer of morphine to the CNS after nasal administration, and to compare the nasal transport of analgesic drugs across nasal respiratory and olfactory mucosa. In vivo studies in rodents demonstrated that morphine is transferred via olfactory pathways to the olfactory bulbs and the longitudinal fissure of the brain after nasal administration. Further, olfactory transfer of morphine significantly contributed to the early high morphine brain hemisphere concentrations seen after nasal administration to rats. Olfactory transfer was tracked by collecting and analysing brain tissue and blood samples after right-sided nasal administration and comparing the results to the situation after i.v. administration. The olfactory transfer was also visualised by brain autoradiography. In vitro studies indicated that the olfactory mucosa should not be a major barrier to the olfactory transfer of dihydroergotamine or morphine, since transport of these drugs was no more restricted across the olfactory mucosa than across the nasal respiratory mucosa. The in vitro studies were performed using the horizontal Ussing chamber method. This method was further developed to enable comparison of drug transport across nasal respiratory and olfactory mucosa which cannot be achieved in vivo. In conclusion, these analgesic drugs showed potential for olfactory transfer, and access to the CNS by this route should be further investigated in humans, especially for the drugs with central effects that are currently under development for nasal administration.