The effect of L-DOPA and the dopamine (DA) receptor stimulating drug apomorphine was studied in rats after unilateral degeneration of the nigrostriatal DA system by intracerebral injection of 6-hydroxydopamine. Both apomorphine and L-DOPA induced a strong rotational behaviour which was registered in a specially designed “rotameter”. The direction of the rotation indicated that the denervated striatum was more sensitive to DA receptor stimulating drugs than the innervated striatum. This supersensitivity probably corresponded to the decentralisation type of supersensitivity in the peripheral nervous system although it developed faster. The action of L-DOPA was inhibited by pretreatment with the DOPA-decarboxylase inhibitor Ro4–4602 which indicated that L-DOPA must be converted to DA in order to stimulate the supersensitive postsynaptic cells. Pretreatment with a single dose of reserpine also induced supersentitivity to apomorphine which reached its maximum on the 3rd day and then decreased on the 4th day. Postsynaptic supersensitivity after degeneration of the nigro-striatal DA system is probably an important reason for the effectiveness of the L-DOPA therapy against Parkinson's disease.

Postsynaptic supersensitivity after 6-hydroxy-dopamine induced degeneration of the nigro-striatal dopamine system.

Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum.

Amphetamine induced vigorous rotational behaviour in rats where the nigrostriatal dopamine (DA) system was unilaterally degenerated by an intracerebral injection of 6-hydroxydopamine (6-OH-DA). The rotational behaviour was analysed in a specially designed “rotometer” and found highly reproducable. The intensity of the rotation was proportional to the extent of degeneration in the DA system. The amphetamine site of action was in all probability presynaptic as amphetamine caused a rotation in the opposite direction as compared to the DA receptor stimulating drug apomorphine. Tyrosine hydroxylase inhibition abolished the amphetamine effect, while reserpine potentiated the effect. Evidence was also obtained that the amphetamine induced release of DA was dependent upon nerve impulses. The rotational behaviour reflected the degree of DA receptor stimulation, but changes in the noradrenaline (NA) transmission seemed to modulate the behaviour. Decreased NA transmission after dopamine-β-hydroxylase inhibition increased the rotational behaviour. The unilateral degeneration of the DA system was studied by the changes in posture and movements that occurred during the degeneration. After inhibition of the monoamine oxidase the rats showed a strong rotation beginning on the 23d and ending on the 33d hour after the operation. The rotational behaviour was probably due to degeneration release of DA and equivalent to the degeneration contraction of the nictitating membrane in the peripheral nervous system Amphetamine greatly potentiated the spontaneous degeneration release during this period.

Striatal dopamine release after amphetamine or nerve degeneration revealed by rotational behaviour.

Non-contingent “priming” drug injections and conditioned stimuli associated with drug injections led to reinstatement of responding after a period of extinction. Rats implanted with intravenous catheters were trained to self-administer cocaine (1 mg/kg/injection), and then given daily test sessions consisting of a period of self-administration followed by extinction conditions. Test drug injections or conditioned stimuli were presented during extinction and the latency to the first response and the total number of responses following the treatment were measured. Cocaine injections of 0.5, 1.0, and 2.0 mg/kg restored responding during extinction, regardless of the duration of the extinction period (between 10 min and 180 min) since drug self-administration. Amphetamine, apomorphine, and morphine but not ethanol, heroin, or methohexital reinstated previously cocaine-reinforced responding. Amphetamine, cocaine, and morphine did not increase responding in animals trained to bar press only for food reinforcement, suggesting that the reinstatement effect is specific to drug-reinforced responses. The final experiment showed that a tone that had been paired with drug infusions acquired a statistically significant tendency to facilitate responding when tested during extinction but this effect disappeared after the first test presentation of the tone.

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Reinstatement of cocaine-reinforced responding in the rat

The effects of dopa, apomorphine and dexamphetamine on compulsive gnawing behavior were studied in rats pretreated with α-methyl-dopa, α-methyl-tyrosine and iproniazid.

Mode of action of apomorphine and dexamphetamine on gnawing compulsion in rats.

WHETHER amphetamine exerts its behavioural excitatory action in the brain directly or indirectly by interference or synergism with the catecholamines (noradrenaline and dopamine) is open to debate1,2. The advent of α-methyl para-tyrosine3 (α-MPT), which inhibits the in vivo synthesis of 3,4-dihydroxyphenylalanine (DOPA)—the physiological precursor of the catecholamines—offers a new way of investigating this problem.

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I. Munkvad

Papers

Role of Catecholamines in the Amphetamine Excitatory Response