Conditioning of successive adaptive responses to the initial effects of drugs

Data in the literature indicate that conditioned responses (CRs) generated by repeated pairing of conditional stimulus (CS) with administration of a neurotropic drug may resemble its unconditional effects or they may be opposite in direction; furthermore, the CRs may change as such pairings are continued. In explanation, it is hypothesized that as in conditioning of physiological reflexes, a CS repeatedly paired with administration of a neurotropic drug eventually comes to activate central“processing” events that are evoked by the“stimulus” properties of the drug,i.e., the effects of the drug at receptor sites inside or outside the pia mater which lie in the afferent arms of“reflex” neural circuits; or, the CS comes to activate central processing events that are evoked by centripetal feedback responses to the effects of the drug at receptor sites in the processing or efferent arms of reflex neural circuits. Depending on the receptor site action of the drug, the conditioned autonomic and/or neuromuscular responses that are observed may be in the same direction as, or opposite in direction to the unconditioned effects of the drug. With continued pairings of CS and drug, the unconditioned processing events evoked by the stimulus properties of the drug, and hence the CRs also, change in consequence of compensatory (sometimes“overshooting”) biochemical alterations proximal to the receptor site of action of the drug, induced by negative or positive neuronal feedback mechanisms. These concepts are utilized in a theory of opiate addiction and relapse.