Repeated apomorphine administration alters dopamine D1 and D2 receptor densities in pigeon basal telencephalon

When pigeons are repeatedly administered a dose of apomorphine they show an increasing behavioral response, much as rodents do. In birds this expresses itself in an augmented pecking response. This sensitization is assumed to be largely due to a conditioning process. Here we present evidence that sensitization is accompanied by an alteration of the D 1 to D 2 dopamine receptor densities. An experimental group of pigeons was repeatedly injected with apomorphine, and a control group with saline. The basal forebrain tissue, known to be rich in dopamine receptors, was subjected to binding assays using tritiated specific D 1 and D 2 dopamine receptor antagonists. There was a trend towards an increase in D 1 and a significant decrease in D 2 receptor densities in apomorphine-treated birds compared to the saline-treated controls. We conclude that extended apomorphine treatment modifies the D 1 dopamine receptor density in the opposite manner to the D 2 dopamine receptor density.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46541/1/221_2004_Article_2158.pd

Behavioral sensitization to apomorphine in pigeons (Columba livia) : blockade by the D₁ dopamine antagonist SCH-23390

Repeated administration of apomorphine leads to a context-dependent pecking response sensitization. Previously sensitized pigeons (Columba livia) challenged with saline in the same context show a conditioned response (CR). The authors studied the effects of intrastriatal injections of the dopamine (D₁) antagonist SCH-23390 on both the sensitized response and the CR. When coadministered with apomorphine, SCH-23390 inhibited the initial response to apomorphine, prevented the development of sensitization, and impaired the maintenance of an already developed sensitization. However, SCH-23390 had no effect on the retrieval of a previously established CR. It is concluded that the activation of D₁ receptors in the caudal avian striatum is necessary for the acquisition and maintenance of the sensitization, but not for the expression, of the CR

Apomorphine and psychostimulant addiction

Apomorphin wurde Mitte des 19. Jahrhunderts ausgehend von Morphium hergestellt. Gleich nach der Synthese fiel dessen emetische Wirkung auf. Eine analgetische und euphorisierende Wirkung wie Morphium hatte es nicht. Klinisch ist es dann in höheren Dosen bei Vergiftungen und später auch zeitweise bei der Alkoholaversionstherapie verwendet worden. Tierversuche haben aber dann gezeigt, dass es in niedrigeren Dosen auffällige orale Stereotypien auslöst. Bei Kröten und Fischen sind das Schnappanfälle, bei Tauben und Hühnern Putz- und Pickanfälle und bei Ratten und Mäusen Kau- und Nageanfälle. Auch bei Menschen werden u. U. Kaustereotypien beobachtet. In den 50er Jahren wurden bei Ratten und Mäusen Ähnlichkeiten mit der Wirkung von Psychostimulanzien, insbesondere Amphetamin und Kokain, erkannt. Labortechnisch äußert sich das nicht zuletzt dadurch, dass es nach Gaben dieser Drogen und Apomorphin bei den Nagern neben den Stereotypien zu nachhaltigen, leicht messbaren Laufaktivitätssteigerungen in Aktometern kommt. Dadurch, dass Amphetamin und Kokain als Dopaminagonisten erkannt wurden, unter anderem weil sie bei wiederholter Einnahme zu psychoseähnlichen Symptomen führten und Schizophrenie wiederum als eine Hyperdopaminie angesehen wurde, kam es zur Feststellung, dass Apomorphin ebenfalls ein Dopaminagonist sei. Der beste Beweis dafür ist, dass Haloperidol, der klassische Dopaminantagonist, sehr effizient die pharmakologische Wirksamkeit von Apomorphin zu unterbinden vermag. Inzwischen ist es nachgewiesen, dass sich Apomorphin direkt und spezifisch an die Dopaminrezeptoren der D 1 und D2 Familien bindet und dies mit einer Effektivität, die die des Transmitters Dopamin um etwa das Tausendfache übersteigt. Das ist auch ein Grund, warum Apomorphin, allerdings meistens nur vorübergehend, in der Parkinsontherapie verwendet wird. Neuerdings soll es in niedrigen posen als männliches Sexualstimulantium, welches vielleicht Viagra ausstechen kann, vermarktet werden. Kokain und Amphetamin sind im Gegensatz zu Apomorphin indirekte und nicht ganz so spezifische Agonisten des Dopamins, wobei die erste Substanz vornehmlich den Rücktransport des Transmitters aus dem synaptischen Spalt in die präsynaptischen Endigungen blockiert und die zweite Substanz vornehmlich eine vermehrte Ausschüttung von Dopamin aus den präsynaptischen Endigungen fördert. Inwieweit die direkten sehr spezifischen und die indirekten eher unspezifischen Wirkungsweisen der Drogen damit zu tun haben, dass Apomorphin gar nicht, aber Amphetamin und Kokain suchtauslösend wirken, wird noch zu kommentieren sein

Sensitization to apomorphine, effects of dizocilpine NMDA receptor blockades

The dopamine agonist apomorphine (apo) elicits bouts of stereotyped pecking in pigeons, a response which increases with successive apo injections. This sensitization is strongly context-specific and has been suggested to arise through a Pavlovian conditioning to both external and internal cues. We hypothetized that this learning involves dopamino–glutamatergic interactions and investigated the issue by inducing NMDA glutamate receptor blockades with the antagonist dizocilpine (diz). A first experiment examined the effects that four different doses (ranging between 0.05 and 0.12 mg/kg) of diz co-administered with a standard dose of 0.5 mg/kg of apo had on the development of the incremented response and on the later expression of the conditioned pecking response. Both responses were impaired by doses of around 0.10 mg/kg diz. A second experiment assessed whether either a diz treatment or a diz plus apo co-treatment affected the development of a subsequent sensitization to apo. The first treatment had no effect on the latter sensitization. A part sensitization that arose with the second treatment did not transfer to the final sensitization. The last experiment examined whether the administration of diz had an immediate effect on the incremented responding to apo and on the conditioned response shown by already sensitized pigeons. No effect was apparent with the first treatment, but there was a marked response inhibition with the second treatment. It is concluded that NMDA glutamate receptors play an important role in apo-induced sensitization in pigeons which is compatible with the Pavlovian conditioning account of sensitization

Apomorphine sensitization : evoking conditions, context dependence, effect persistence and conditioned nature

When repeatedly administered a dose of apomorphine (Apo), pigeons, much like rodents, show behavioural sensitization. In birds this sensitization expresses itself as an increasing pecking response to the drug and is found to be partially dependent on the environmental context in which Apo takes effect. In the first experiment we examined what effect different inter-Apo administration intervals have on the development of Apo sensitization and found that, with some smaller variations, intervals between 3 hours and 5 days all yielded comparable courses of sensitization. In the second experiment we examined how long pigeons had to be exposed to the same distinct cage to reveal a maximal context-dependent sensitization. Pigeons were therefore repeatedly injected with Apo and consistently placed in an experimental cage for different lengths of time (5 to 60 min; the overall drug effect lasted for about 1 h) before being returned to their standard home cages. Subsequent tests in the experimental cage and a standard cage showed that 20-min post-injection exposures were sufficient to yield a maximal response in the experimental cage. After training with 20- and 60-min exposures, the pigeons pecked about three times more in the experimental cage than in the standard cage. This confirmed the marked context dependency of the sensitization effect. In the third experiment, groups of pigeons were injected repeatedly with Apo and directly afterwards placed either consistently into the same experimental cage or into different experimental cages. The same-cage group evidenced a significantly much stronger sensitization than the different-cage group. A cage-habituation group served as a control for the possibility that the weaker sensitization of the different-cage group might be due to a cage novelty effect. This cage-habituation group was run under the same conditions as the different-cage group but with additional exposures to the crucial cage while injected with saline. This extra treatment did not augment the pecking response to Apo in that cage. In the fourth experiment we examined how long the sensitization to Apo lasts and found that, even after 2 years of drug abstinence, it only waned to 50% of the original asymptotic response. The overall results support the hypothesis that a very major part of the sensitization to Apo in pigeons is due to a conditioning to the environmental context and to the drug state itself

Effect Of Pharmacological Manipulation Of Nucleus Subpretectalis On Figure-Ground Discrimination In Pigeons

Olga F. Lazareva (Mentor)Our earlier research has shown that nucleus rotundus (Rt), a thalamic nucleus processing visual information in pigeons, together with its inhibitory complex, nucleus subpretectalis/interstitio-pretectosubpretectalis (SP/IPS), had significantly higher activity than control after figure-ground discrimination (Acerbo et al., 2012). In a follow-up study, we also found that bilateral lesion of SP selectively 28 impairs figure-ground discrimination. Here, we conducted bilateral microinjections of GABAergic receptor antagonist (bicuculline), GABAergic receptor agonist (muscimol), and glutamatergic receptor antagonists (CNQX) to further clarify a role of SP in figure-ground discrimination. Preliminary results showed that both bicuculline and muscimol had a detrimental, dose-dependent effect on accuracy on background trials while leaving figure trials relatively intact. It is therefore possible that inhibitory projections from SP might be suppressing activity of neurons in nucleus rotundus responding to features belonging to background regions. In contrast, the injections of CNQX mostly affected figure trials, suggesting that the excitatory input from the optic tectum may be critical for accurate performance on figure trials but not on background trials.Drake University, Department of Psychology, College of Arts & Science

Sensitization to apomorphine in pigeons : a multifactorial conditioning process

Apomorphine (apo), an unspecific direct dopamine agonist, elicits an intense and lasting pecking bout in pigeons. Apo yielded orderly dose–response functions, and repeated administrations led to sensitization. Strain and individual differences in sensitivity to apo were at least partly due to genetic factors. However, a strong cage-context dependency of the sensitization, which is indicative of conditioning, occurred in both pigeon strains studied. Apo-induced pecking and sensitization also occurred in total darkness. Pigeons could be conditioned to discriminate between an apo state and a non-apo state. A small dose of apo was effective as a conditioned stimulus when paired with a high dose as an unconditioned stimulus. The conditioned response (CR) was strongly specific to the context in which the sensitization to apo took place. The resistance to extinction of the CR could be increased through an oversensitization treatment. The incremental responses arising during the sensitization treatment and the CRs shown afterward by individual pigeons correlated significantly. The sensitization to apo in pigeons is well accounted for by a conditioning schema in which an interoceptive drug state is a conditional conditioned stimulus for the full expression of the incremental response. Variants of the scheme might also account for the sensitization of rodents to psychostimulants. A neural model that embodies the characteristics of the conditioning scheme has been proposed