Dissociable effects of the kappa-opioid receptor agonists bremazocine, U69593, and U50488H on locomotor activity and long-term behavioral sensitization induced by amphetamine and cocaine
Ljmj. Vanderschuren et al., Dissociable effects of the kappa-opioid receptor agonists bremazocine, U69593, and U50488H on locomotor activity and long-term behavioral sensitization induced by amphetamine and cocaine, PSYCHOPHAR, 150(1), 2000, pp. 35-44
Rationale: Mesolimbic dopaminergic neurotransmission plays a critical role
in the locomotor effects of psychostimulant drugs, but a general involvemen
t in the induction of long-term psychostimulant sensitization is questionab
le. By influencing dopaminergic neurotransmission, opioid drugs can alter t
he behavioral effects of psychostimulants. Objectives: The effects of the k
appa-opioid receptor agonists bremazocine, U69593, and U50488H on the locom
otor stimulant and the long-term sensitizing effects of amphetamine and coc
aine were investigated in rats. Unlike U69593 and U50488H, bremazocine is a
lso an antagonist at mu- and delta-opioid receptors, as well as an agonist
at a subtype of delta-opioid receptors inhibiting dopamine D1 receptor-stim
ulated adenylate cyclase. Methods: Bremazocine, U69593, and U50488H were ad
ministered prior to amphetamine and cocaine, and locomotor activity was mea
sured. In separate studies, the opioids were co-administered with amphetami
ne and cocaine for 5 days, and locomotor sensitization was assessed 3 weeks
post-treatment. Results: Bremazocine and U69593 attenuated the psychomotor
stimulant effects of amphetamine and cocaine. U50488H attenuated the locom
otor effect of cocaine and biphasically affected amphetamine-induced locomo
tion, i.e., suppression followed by stimulation. Bremazocine prevent ed the
development of amphetamine-induced but mot cocaine-induced long-term sensi
tization. Neither U69593 nor U50448H affected the induction of long-term am
phetamine or cocaine sensitization. Conclusions: In agreement with previous
studies, the present data suggest versus the long-term sensitizing effects
of psychostimulants, and the induction of long-term sensitization by amphe
tamine versus cocaine. Stimulation of kappa-opioid receptors does not seem
to block the induction of longterm psychostimulant sensitization. Thus, bre
mazocine is likely to block the induction of amphetamine sensitization thro
ugh a non-kappa-opioid receptor mechanism. We suggest that this effect of b
remazocine is the result of its unique agonist action at a subtype of delta
-opioid receptors, thereby acting as a functional dopamine D1 receptor anta
gonist. This would be consistent with the literature showing that the induc
tion of long-term amphetamine sensitization depends on the activation of do
pamine D1 receptors. In addition, the present data are in keeping with stud
ies showing that dopamine neurotransmission is not critical for the inducti
on of long-term cocaine sensitization.