Martin J. Acerbo

The induction of behavioural sensitization is associated with cocaine-induced structural plasticity in the core (but not shell) of the nucleus accumbens

Repeated exposure to cocaine increases the density of dendritic spines on medium spiny neurons in the nucleus accumbens (Acb) and pyramidal cells in the medial prefrontal cortex (mPFC). To determine if this is associated with the development of psychomotor sensitization, rats were given daily i.p. injections of 15 mg/kg of cocaine (or saline) for 8 days, either in their home cage (which failed to induce significant psychomotor sensitization) or in a distinct and relatively novel test cage (which induced robust psychomotor sensitization). Their brains were obtained 2 weeks after the last injection and processed for Golgi–Cox staining. In the Acb core (AcbC) cocaine treatment increased spine density only in the group that developed psychomotor sensitization (i.e. in the Novel but not Home group), and there was a significant positive correlation between the degree of psychomotor sensitization and spine density. In the Acb shell (AcbS) cocaine increased spine density to the same extent in both groups; i.e. independent of psychomotor sensitization. In the mPFC cocaine increased spine density in both groups, but to a significantly greater extent in the Novel group. Furthermore, when rats were treated at Home with a higher dose of cocaine (30 mg/kg), cocaine now induced psychomotor sensitization in this context, and also increased spine density in the AcbC. Thus, the context in which cocaine is experienced influences its ability to reorganize patterns of synaptic connectivity in the Acb and mPFC, and the induction of psychomotor sensitization is associated with structural plasticity in the AcbC and mPFC, but not the AcbS.

Behavioural consequences of nucleus accumbens dopaminergic stimulation and glutamatergic blocking in pigeons

Upon systemic administration of apomorphine, a potent dopamine agonist, pigeons show a bout of pecking behaviour. When the drug is repeatedly administered a sensitization takes place that is associated with pronounced discrimination learning. Here we show that intra-cerebral injections of apomorphine in the periphery of the nucleus accumbens of pigeons also elicit pecking. We additionally show that injections of 5-amino-phosphonohepatnoic acid, a NMDA-glutamate receptor blocker, into the Acc impairs the performance of a learned visual discrimination incorporating pecking as a choice response. We conclude that, as it is the case in mammals, the control mechanisms of learned sensory-motor behaviour in birds involves dopaminergic and glutamatergic synaptic transmission within the nucleus accumbens area.

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.

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 (D(1)) 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 D(1) receptors in the caudal avian striatum is necessary for the acquisition and maintenance of the sensitization, but not for the expression, of the CR.

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.

Cognitive effects of dopaminergic and glutamatergic blockade in nucleus accumbens in pigeons

In earlier studies it was found that glutamatergic transmission within the nucleus accumbens septi is involved in the performance of a learned visual shape discrimination in pigeons. This study examines what effects several kinds of glutamate and dopamine antagonists have on the same task. Pigeons were trained with the relevant discrimination, bilaterally implanted with cannulas into the nucleus accumbens and tested after various transmission blockers had been administered intracerebrally. SCH-23390, a D1 dopamine antagonist, at the dose used, had no effect, and Spiperone, a D2-dopamine and 5HT2a-serotonine antagonist, significantly decreased the error repeat trials. CNQX, a non-NMDA glutamate receptor antagonist, and Cycloleucine, an antagonist of the glycine allosteric site of NMDA receptors, had no effect. CGS-19755, a selective competitive NMDA antagonist, significantly impaired performance by significantly decreasing the percent correct trials and increasing the error repeat trials. CPPG, a II/III metabotropic glutamate antagonist, remarkably improved performance. MMPG, a III/II metabotropic glutamate antagonist, at the dose used, did not have any significant effect. The preparation employed may be a useful animal model of perceptual disturbances in schizophrenia.

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 D1 to D2 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 D1 and D2 dopamine receptor antagonists. There was a trend towards an increase in D1 and a significant decrease in D2 receptor densities in apomorphine-treated birds compared to the saline-treated controls. We conclude that extended apomorphine treatment modifies the D1 dopamine receptor density in the opposite manner to the D2 dopamine receptor density.

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.

Drogeninduziertes Lernen : Sensitivierung bei Apomorphin

Drug-induced learning: Sensitization to apomorphine. The effect on behaviour of psychostimulants such as cocaine and amphetamine, mainly indirect dopamine agonists, increases with repeated consumption of one and the same dosage. This sensitization probably plays an important rote during the development of addiction. Repeated administration of apomorphin (apo), a direct, non-addictive dopamine agonist also Ieads to sensitization. Here we report that this increased reactivity can be advantageously studied using the pecking fits that apo causes in birds. Experimental results are presented which show that the sensitization is based on a Iasting pavlovian learning process. The sensitization is strongly related to specific contexts, even concerning the pecking targets. Some peculiarities of the sensitization can be accounted by the fact that besides being an unconditioned stimulus apo also has conditioned Stimulus properties. Neuropharmacological results suggest that the sensitization to apo is based on a synaptic interaction leading to a glutamatergic transmission efficacy increase in the ventral striatum.