Classical Conditioning Theory Part 3

Classical Conditioning vs. Pure Physiology in Drug Tolerance

• Early view: drug tolerance = solely physiological (liver enzymes, receptor down-regulation, enhanced excretion).
• Newer hypothesis (Shepard Siegel, $1975$): classical (Pavlovian) conditioning contributes to tolerance, overdose, and withdrawal.
• Key logic:
  • Unconditioned Stimulus (US): morphine/heroin administration.
  • Unconditioned Response (UR): analgesia (pain reduction, euphoria).
  • Conditioned Stimulus (CS): environmental context (room, odors, sights) or interoceptive cues (body sensations).
  • Conditioned Response (CR): compensatory physiological processes (opposite to UR) that diminish drug effect → tolerance.
• Links to previous lectures
  • Comparator hypothesis: context crucial in predicting US.
  • Autoshaping example: light (CS) → peck (CR) when paired with food (US/UR). Analogy: context (CS) → compensatory CR when paired with morphine (US/UR).
  • Eyeblink conditioning studies show neural circuitry relevance; damage = anterograde/retrograde amnesia → supports role of learning mechanisms here too.

Field Observations that Sparked the Research

• Siegel rode with paramedics responding to heroin overdoses.
• Repeat observations:
  • Victims often unconscious with syringe partly full → dose unfinished.
  • Dose identical to previous self-administered amounts; purity not suspect.
  • Overdoses frequently occurred in novel contexts (e.g., subway vs. usual home setting).
• Hypothesis: absence of usual CS (home context) removes compensatory CR → full strength of UR manifests → overdose.

Experimental Model: Paw-Lick Latency (PLL) Assay

• Need non-damaging, mildly aversive pain test.
• Method:
  • Rat placed on metallic plate.
  • Plate temperature gradually raised.
  • Measure latency (s) until rat lifts paw & licks it.
  • Longer PLL = reduced pain sensitivity (effective analgesia).

Experiment 1 (Siegel $1975$)

Design

• 4 groups; 4 daily sessions.
  • Saline Hot-Plate (SAL-HP).
  • Morphine Hot-Plate (MOR-HP).
  • Morphine Cold-Plate (MOR-CP).
  • Morphine Cage → Hot-Plate on Day 4 (MOR-CAGE).
• Dose schedule
  • SAL-HP: $ext{saline}$ each day in HP room; PLL measured daily.
  • MOR-HP: identical morphine dose each day in HP room; PLL measured daily.
  • MOR-CP: morphine dose in HP room but plate OFF (cold) Days 1–3; Day 4 plate ON, PLL measured.
  • MOR-CAGE: morphine dose in home vivarium Days 1–3; Day 4 same dose in HP room, plate ON, PLL measured.

Predictions If Only Physiology Matters

• All three morphine groups should show identical tolerance and Day-4 analgesia because dose & physiology identical.

Results

• Days 1–3 (only SAL-HP & MOR-HP measurable):
  • Day 1: SAL-HP PLL ≈ $10\,\text{s}$; MOR-HP ≈ $25\,\text{s}$ → strong analgesia.
  • Day 2: MOR-HP PLL drops toward $10\,\text{s}$.
  • Day 3: MOR-HP ≈ SAL-HP (full tolerance).
• Day 4 (all groups):
  • SAL-HP & MOR-HP ≈ $10\,\text{s}$.
  • MOR-CP ≈ $10\,\text{s}$ (tolerant despite first true heat exposure).
  • MOR-CAGE ≈ $25\,\text{s}$ → analgesia restored! Context shift removed CS, so no compensatory CR.

Interpretation

• Context (CS) critical for tolerance. Remove CS → tolerance attenuates.
• Real-world parallel: habitual user ups dose at home; injects same large dose in novel setting → no CR → overdose.

Experiment 2: Conditioned Withdrawal After Washout

Rationale

• Reports of users feeling withdrawal when exposed to drug-related posters.
• Test whether CS alone (context) elicits opposite reaction (hyper-algesia).

Procedure

1. Phase 1: MOR-HP injections + PLL until tolerance (4 sessions).
2. $2\text{-week}$ wash-out (no injections).
3. Phase 2: SAL-HP injections (CS alone) across 4 sessions; PLL measured.

Results (expressed as % change from baseline)

• Phase 1 replicates tolerance curve (initial +$150\%$ PLL → baseline by Day 4).
• Phase 2: First saline test → PLL drops to –$50\%$ (hypersensitivity). Repeated saline exposures gradually return to baseline (extinction).

Take-Home

• CS without US evokes withdrawal-like CR (hyper-algesia, irritability).
• Provides mechanistic basis for cue-induced craving/withdrawal.

Experiment 3: Extinction of Contextual CS

Groups

1. MOR → Rest (home cage) $2\,\text{weeks}$ → MOR.
2. MOR → Placebo (saline in HP room daily for $2\,\text{weeks}$) → MOR.

Logic

• Placebo sessions = CS-only exposures (extinction).

Findings

• Both groups tolerize in Phase 1.
• Phase 2 MOR injection:
  • MOR-Rest-MOR still tolerant (PLL ≈ baseline).
  • MOR-Placebo-MOR shows renewed analgesia (PLL ↑). Extinction of CS blunted compensatory CR.

Clinical Implication

• Cue-exposure therapy or remaining in same environment with substitute agonist (methadone) could weaken CS-CR link and prevent relapse/overdose.

Bonus Experiment 4 (Siegel $1999$): Drug-Onset Cues vs. Environmental Cues

• Observation: Users who “hit the vein” precisely show context-linked tolerance; “missers” (drug diffuses slowly) still develop tolerance but not tied to context.

Hypothesis

• When US delivery is slow/protracted, immediate interoceptive sensations of drug onset become the CS, not external context.

Method & Findings

• Rats given either:
  • Rapid bolus morphine → context CS drives tolerance (replicates earlier work).
  • Slow infusion morphine → little context learning.
  • BUT the initial $30\,\text{s}$ segment of slow infusion, when isolated, acts as effective CS producing compensatory CR.

Conclusion

• Learning still occurs; the form of CS shifts with timing (parallels Marlin ISI study in autoshaping).
• Supports idea that both exteroceptive (room) and interoceptive (body) cues can serve as conditioned stimuli.

Ethical, Therapeutic & Practical Implications

• Overdose risk rises in novel contexts; harm-reduction advice: maintain consistent environment or lower dose in new settings.
• Methadone maintenance & cue-exposure therapies work by severing CS–US link or by substituting a safer US.
• Public health messaging: environmental cues (posters, paraphernalia) can elicit craving/withdrawal; need thoughtful design.

Key Numerical Highlights (all values approximate)

• Initial morphine analgesia: PLL ↑ from $10\,\text{s}$ → $25\,\text{s}$ (≈ +$150\%$).
• Tolerance develops within $3$ daily sessions.
• Context shift (MOR-CAGE) restores analgesia to $25\,\text{s}$ despite identical dose.
• Conditioned withdrawal: saline CS alone lowers PLL by ≈ $-50\%$ relative to baseline.
• Extinction (daily saline for $14$ days) reduces contextual CR and reinstates morphine efficacy.

Conceptual Summary

• Drug tolerance and overdose are not solely pharmacological; they are partly learned via classical conditioning.
• CS (context or bodily cues) predicts US (drug), evoking compensatory CR that dampens UR → tolerance.
• Removing or extinguishing CS unleashes full UR (risk of overdose) or produces opposite CR (withdrawal).
• Timing and delivery profile of US shape which cues serve as CS.
• Therapeutic strategies can leverage extinction, cue management, and substitute agonists to mitigate addiction harms.